ANGIOGENESIS

Signal Transduction and Targeted Therapy www.nature.
com/sigtrans
REVIEW ARTICLE OPEN
Angiogenic signaling pathways and anti-angiogenic therapy

for cancer
Zhen-Ling Liu1, Huan-Huan Chen1, Li-Li Zheng1, Li-Ping Sun1 ✉ and Lei Shi 1✉
Angiogenesis, the formation of new blood vessels, is a complex and dynamic process regulated by various pro- and anti-angiogenic
molecules, which plays a crucial role in tumor growth, invasion, and metastasis. With the advances in molecular and cellular biology,
various biomolecules such as growth factors, chemokines, and adhesion factors involved in tumor angiogenesis has gradually been
elucidated. Targeted therapeutic research based on these molecules has driven anti-angiogenic treatment to become a promising
strategy in anti-tumor therapy. The most widely used anti-angiogenic agents include monoclonal antibodies and tyrosine kinase
inhibitors (TKIs) targeting vascular endothelial growth factor (VEGF) pathway. However, the clinical benefit of this modality has still
been limited due to several defects such as adverse events, acquired drug resistance, tumor recurrence, and lack of validated
biomarkers, which impel further research on mechanisms of tumor angiogenesis, the development of multiple drugs and the
combination therapy to figure out how to improve the therapeutic efficacy. Here, we broadly summarize various signaling
pathways in tumor angiogenesis and discuss the development and current challenges of anti-angiogenic therapy. We also propose
several new promising approaches to improve anti-angiogenic efficacy and provide a perspective for the development and
1234567890();,:
research of anti-angiogenic therapy.
Signal Transduction and Targeted Therapy (2023)8:198 ; https://doi.org/10.1038/s41392-023-01460-1
INTRODUCTION angiogenesis is locked or limited to a quiescent status owing to

Angiogenesis is a process in which new blood vessels develop the low levels of pro-angiogenic factors and vascular inhibitory
from existing capillaries and eventually create a complete, regular, signals in the extracellular matrix, so intratumoral vascularization
and mature vascular network. This process includes degradation rarely occurs (Fig. 1).15 When the solid tumor grows to a volume of
of the basement membrane and activation, proliferation, and more than 1–2 mm3, the resources in the surrounding tissue are
migration of the endothelial cells (ECs), which is regulated by hard to maintain the tumor growth.16 A microenvironment with
various pro-angiogenic and anti-angiogenic factors.1 Under hypoxia, ischemia, acidosis, and high interstitial pressure is
normal physiological conditions of healthy adults, endothelial gradually developed in tumor tissue, which releases abundant
cells are almost quiescent, and the frequency of mitosis is only growth factors and cytokines, stimulating angiogenesis and
0.5%.2 Angiogenesis mainly occurs in embryonic development, lymphangiogenesis to meet the needs of tumor growth and
tissue repair, the menstrual cycle, muscle growth, and organ lining metabolism.16,17 Due to the rapid proliferation of tumor cells, a
regeneration through a regular (strictly controlled by the body), microenvironment with more severe hypoxia, acidosis, and high
scope-limited (occurs locally), and short-lived (days, weeks, or interstitial pressure originated in organizations far from the blood
months) mode.3,4 Nevertheless, angiogenesis will be disordered vessels in tumor tissue, promoting the enlargement and cancera-
and excessive through the over-expression of pro-angiogenic tion of tumor tissue (Fig. 1). Afterwards it gradually evolves into a
factors and the inactivation of anti-angiogenic factors in several carcinoma, which acquires aggressiveness to induce the stromal
non-neoplastic angiogenic diseases like immune diseases (such as response, including intratumoral angiogenesis, leukocyte infiltra-
rheumatoid arthritis,5 psoriases,6 and Crohn’s disease),7 diabetic tion, fibroblast proliferation, and extracellular matrix deposition,
retinopathy (DR),8 age-related macular degeneration (AMD) and especially in cancerous tumors.18–20 Various pro-angiogenic
atherosclerosis.4,9 Angiogenesis also contributes to the progres- factors are persistently released or up-regulated by tumor cells
sion of various malignant tumors such as melanoma, breast cancer to activate endothelial cells, pericytes (PCs), tumor-associated
(BC),10 colorectal cancer (CRC),11 non-small cell lung cancer fibroblasts (CAFs), endothelial progenitor cells (EPCs), and immune
(NSCLC),12 and renal cell carcinoma (RCC).13 cells (ICs),21–23 subsequently causing telangiectasia, basement
The tumor is a biological tissue with rapid proliferation, vigorous membrane destruction, extracellular matrix remodeling, pericytes
metabolism, and tenacious vitality, which needs oxygen and shedding, endothelial cell differentiation to maintain a highly
nutrients far more than normal tissue cells. The initial stage of active stage of angiogenesis, eventually inducing tumor prolifera-
tumor growth is an avascular state, in which the tumor has not tion, diffusion, and metastasis.24 This phenomenon indirectly
acquired aggressiveness and absorbs oxygen and nutrients explains that tumors are called non-healing wounds.25 Further-
through the diffusion of surrounding tissue.14 Therefore, tumor more, metabolic stress in tumors can also be aroused by immune
1
Department of Medicinal Chemistry, Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 210009 Nanjing, China
Correspondence: Li-Ping Sun ([email protected]) or Lei Shi ([email protected])
Received: 16 November 2022 Revised: 20 March 2023 Accepted: 20 April 2023
© The Author(s) 2023

Angiogenic signaling pathways and anti-angiogenic therapy for cancer
Liu et al.
2
Fig. 1 The progression of the canceration through angiogenesis. The rapid expansion of tumor results in a reduction in the oxygen supply.
The consequent hypoxic tumor microenvironment stimulates excessive angiogenesis via increasing various angiogenic pro-factors including
VEGF, PDGF, FGF, and angiopoietin. Later, new blood vessels facilitate the transportation of oxygen and nutrients to further support the
survival, growth and proliferation of tumor cells. When tumor cells develop a more aggressive phenotype, they continue to proliferate, spread
and induce angiogenesis, with the invasion and metastasis of tumor cells into distant tissues through blood circulation
stimulation, inflammatory response, oncogene mutation, and drug efficacy may be caused by compensatory angiogenesis induced
treatment to aggravate tumor angiogenesis and further promote by alternative pro-factors, vessel co-option and other abnormal
tumor invasion and metastasis.26 modes. Hence, great efforts have been devoted to further
Up to now, although a significant number of research has been improving the therapeutic efficacy and mitigating drug resistance.
devoted to anti-cancer therapy to overcome this incurable and For example, a number of multi-targeted angiogenic inhibitors
lethal disease, none of them has achieved persistent clinical have been developed for cancer treatment. Additionally, the
efficacy.27,28 For example, chemotherapy is a form of systemic combination of angiogenic inhibitors with other conventional
treatment, which has been utilized for the treatment of cancer for cancer treatment including chemotherapy, radiotherapy, immune
over 70 years and remains a cornerstone in the treatment of many therapy, adoptive cell therapy, and cancer vaccines has been
types of cancers including BC, CRC, and NSCLC by directly killing evidently demonstrated through many pivotal clinical trials
or inhibiting the growth and reproduction of tumor cells under among patients with different types of cancer.47 With the in-
the administration of various cytotoxic agents such as cis- depth exploration of the tumor angiogenesis and drug resistance,
platinum, 5-fluorouracil, cyclophosphamide, methotrexate and great progress has been made in anti-tumor therapy in recent
doxorubicin.29,30 These cytotoxic chemotherapeutics have indis- years.
criminating cell lethality, poor tissue selectivity, and severe In the present review, we highlight the potent effects of
systemic adverse effects, resulting in poor tolerance and prognosis angiogenesis in tumor growth, proliferation, carcinogenesis,
of patients. Even so, tumor cells are not entirely killed, drug invasion and metastasis, summarize multiple signaling pathways
resistance rises unavoidably.31,32 Prior works have demonstrated in tumor angiogenesis and outline the development of anti-
that congenital and acquired drug resistance can be derived from angiogenic therapies, as well as classic anti-angiogenic drugs and
tumor genetic and phenotypic mutations.33–36 Furthermore, some potential clinical candidates. Moreover, we discuss the
cancerous tumors can escape into remote normal organizations challenges of anti-angiogenic treatment and some emerging
through blood and lymphatic circulation to invalidate the drugs therapeutic strategies to exploit the great advantages of anti-
and worsen the condition of patients.37–40 As an emerging angiogenic therapy.
treatment, anti-angiogenic therapy fights cancer by normalizing
tumor blood vessels, alleviating hypoxia of microenvironment,
increasing tissue concentration of drugs, and limiting distant PATHOPHYSIOLOGY
invasion and metastasis of tumors.41,42 Despite the ever-growing Blood circulation is a basis of cell metabolism, which flows in a
list of FDA-approved drugs, the clinical benefits of anti-angiogenic closed circuit from the heart to arteries, capillaries, veins, and
monotherapies are not long-lasting. Some limitations in che- finally back to the heart. In normal tissue, tight pericyte coverage
motherapy like acquired drug resistance and tumor recurrence and vascular endothelial cell junction ensure regular blood
have also been found in anti-angiogenic therapy.43–46 The limited circulation, forming a mature vascular structure.48 However, in
Signal Transduction and Targeted Therapy (2023)8:198

Liu et al.
3
Fig. 2 Most common modes in tumor angiogenesis. a Sprouting angiogenesis: main way in both physiological and pathological
angiogenesis, which is induce by proliferation and migration of endothelial tip cells. b Intussusception: the existing blood vessel is divided
into two vessels under mediation of cell reorganization. c Vasculogenesis: bone-marrow-derived endothelial progenitor cells differentiate into
endothelial cells, participating in the formation of new vascular lumen. d Vessel co-option: tumor cells approach and hijack the existing blood
vessels. e Vessel mimicry: tumor cells form a vessel-like channel around normal blood vessels to direct the transport of oxygen and nutrients
into tumor tissue. f Trans-differentiation of cancer cells: cancer stem-like cells differentiate into endothelial cells, which participate in the
formation of new blood vessels. (Modified from Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis.
Nature 473, 298–307 (2011).)
tumor tissue, more mechanical stress from the hypertrophic tumor lesions.68,69 Because of the tenacious viability, various pro-
tissue results in an uneven thickness and deformed architecture of angiogenic factors are secreted by tumor cells to stimulate
tumor vessels, which exhibit intensive sprouting orchestrated in endothelial cells proliferation and migration, promote vessel
an irregular convoluted manner that tends to hinder blood formation, increase blood circulation to meet the requirements
flow.49–51 Mechanical stress also disrupts lymphatic channels and of the tumor, and mitigate metabolic stress.
prevents lymphatic drainage of excess interstitial fluid. Besides, Tumor angiogenesis occurs mainly through any of the following
fragile and highly permeable tumor vessels, which have an modes described in Fig. 2. Among them, sprouting angiogenesis is
irregular arrangement of endothelial cells and thinly covered the most typical process in physiological and pathological
pericytes, lead to blood leakage and incoherent perfusion.52–54 angiogenesis. The patterns of vessel co-option and vessel mimicry
This spatially anomalous structure is manifested in low blood flow, are significantly related to tumor invasion, metastasis, and
which decreases the supply of oxygen and nutrient, causing therapeutic resistance in conventional anti-angiogenic therapy.
subsequent acidosis and hypoxia within tumor microenvironment Sprouting angiogenesis is so-called angiogenesis, in which new
and high interstitial hypertension.55 Highly permeable tumor vascular branches form in existing blood vessels and finally
blood vessels facilitate plasma and proteins into the surrounding infiltrate into tumor tissue through the migration of tip cells and
interstitium, increasing blood viscosity and interstitial pressure in the proliferation of stem cells (Fig. 2a).70,71 Intussusceptive
tumor microenvironment, further impeding blood flow.56–58 All angiogenesis involves the formation of a double lumen, which
these factors result in chaotic function and abnormal architecture splits into two vessels, infiltrating into tumor tissue (Fig. 2b).72,73
of tumor blood vessels, further aggravating acid and hypoxic Vasculogenesis refers to recruiting bone marrow-derived or vessel
tumor microenvironment, which contributes to tumor angiogen- wall resident endothelial progenitor cells, which differentiate into
esis, invasion, and metastasis.59,60 endothelial cells to form new blood vessels (Fig. 2c).71,74 In
Studies have shown that 50–60% of solid tumors are hypoxic, addition to the above three models, tumors can achieve
which disrupts the expression of multiple tumor genes profiles angiogenesis through vessel co-option, vessel mimicry, lymphan-
and causes tumor necrosis, stimulating the spread and metas- giogenesis, and rare stromal-sharing modes.3,24,75 Vessel co-
tasis of tumor.61 Since tumor growth and reproduction require option, in which tumor cells migrate around pre-existing blood
substantial energy, the tumor cells in a hypoxic environment are vessels or infiltrate into surrounding tissue space, eventually
forced to release energy through glycolysis and secrete wrapping the blood vessels and leading them into tumor tissue to
considerable acidic substances, aggravating the acidity of the supply nutrients for tumor cells (Fig. 2d).76 Vessel mimicry is a
microenvironment (pH is usually between 6.5–7.2, or even process that tumor cells extend to form a simulated vascular
lower).62,63 Furthermore, the interstitial pressure in normal lumen and then insert into the pre-existing blood vessels,
tissues is only 0–3 mmHg.64 In tumor tissue, high interstitial transporting the erythrocyte and oxygen into tumor tissue (Fig.
pressure (5–40 mmHg, even 75–130 mmHg in some cases) 2e).77 Researchers believe that vessel mimicry is closely connected
hinders the transport of blood and drugs,65 which is caused by with hypoxia, which stimulates the secretion of matrix metallo-
blood leakage of tumor vessels and the increase of interstitial proteinases (MMPs) and periodic acid Schiff-positive substances to
fluid, thus the tumor cannot obtain sufficient oxygen and irritate the formation of vascular mimicry.77 Another mode is that
nutrients.66,67 These factors affect the drug treatment and trans-differentiation of cancer stem-like cells (which obtain the
benefit tumor proliferation, adhesion, invasion, and metastasis, endothelial phenotype) into endothelial-like cells via epithelial-
eventually leading to tumor resistance and malignant endothelial transformation (Fig. 2f).

Liu et al.
4
KEY MOLECULES AND SIGNALING PATHWAYS IN TUMOR endothelial function and promotes cell mitosis and vascular
ANGIOGENESIS permeability.84 Meanwhile, it involves in cell homeostasis,
Various biomolecules that promote or inhibit angiogenesis hematopoietic stem cells survival, tumor cells survival, and
constitute a complex and dynamic angiogenic system, including invasion through autocrine or paracrine.85,86 Moreover, VEGF-A is
growth factors (such as vascular endothelial growth factor, the most important regulator of angiogenesis that plays an
fibroblast growth factor, transforming growth factor, hepatocyte irreplaceable role in tumor growth, proliferation, invasion,
growth factor), adhesion factors (integrin, cadherin), proteases metastasis, angiogenesis, and drug resistance.87,88 In specific body
(such as matrix metalloproteinase), extracellular matrix proteins parts, such as the heart, VEGF-B promotes neuronal survival and
(fibronectin, collagen), transcription factors (hypoxia-inducible cardiovascular growth through angiogenesis.89 VEGF-C and VEGF-
factor, nuclear factor), signaling molecule mechanistic target of D encourage tumor growth and metastasis through lymphangio-
rapamycin (mTOR), protein kinase B (AKT), p38 mitogen-activated genesis and lymphatic metastasis, which is mediated by VEGFR-3.
protein kinases (p38 MAPK), nitric oxide (NO), angiopoietin, Blocking this pathway leads to apoptosis of lymphatic endothelial
thrombospondin-1, angiostatin, endostatin, and interleukin (IL).78 cells and disruption of the lymphatic network.90,91 PlGF (isoforms
The vascular endothelial growth factor (VEGF) is the most typical 1–4) is a member of the cysteine-knot superfamily of growth
regulator in tumor angiogenesis, which can mediate vascular factors,92,93 which is widely expressed in various tumor or non-
permeability and tube formation.79 Platelet-derived growth factor tumor cells, like endothelial cells,94,95 vascular smooth muscle
(PDGF) promotes vascular maturation by recruiting parietal cells.80 cells,94 neurons,96 inflammatory cells,94 bone marrow cells,95 brain
Notch signal guides vascular sprouting and stretching and matrix cancer cells,97 and melanoma cells.98 Mediated by VEGFR-1, pro-
metalloproteinases activate angiogenesis by distinctly degrading angiogenic PlGF contributes to activation and proliferation of
the basement membrane.81 All of them initiate the downstream stromal cells including fibroblasts, macrophages, smooth muscle
signaling pathway transduction through transmembrane recep- cells and endothelial cells.45 With both pro- and anti-angiogenic
tors to activate gene expression and induce endothelial cells effects, the role of PlGF has remained increasingly debatable.99
proliferation, survival, and angiogenesis (Fig. 3). The tyrosine kinase receptor VEGFRs consist of a transmem-
brane domain, an extracellular ligand-binding domain with an Ig-
Growth factors and growth factor receptors like domain, and a tyrosine kinase with an intracellular domain.86
VEGF/VEGFRs. In the 1989s, Ferrara and his colleagues found a VEGFR-1 (known as FLT-1) is the first identified dual-function VEGF
45 kDa permeable substance through multiple layers of amino acid receptor, a 180–185 kDa glycoprotein, acting as a co-receptor for
sequences, named vascular endothelial growth factor, a family of VEGF-A, VEGF-B, and PlGF.100 VEGFR-1 is mainly active in various
soluble secreted homodimeric glycoproteins.82 VEGF regulates endothelial cells and non-endothelial cells (monocytes,101 macro-
vascular permeability, angiogenesis, and lymphogenesis.83 phages,102 hematopoietic stem cells,103 smooth muscle cells,104
VEGF family consists of seven members, including VEGF-A, and leukocytes103), which regulates monocytes migration,
VEGF-B, VEGF-C, VEGF-D, placental growth factor (PlGF), and non- endothelial progenitor cells recruitment, hematopoietic stem cells
human genome encoded VEGF-E and svVEGF.82 VEGF-A (known as survival, and liver epithelial cells growth.103 As a negative
VEGF) is a crucial secretory factor that maintains human regulator, VEGFR-1 competitively inhibits the activation of
Fig. 3 Schematic diagram showing crosstalk of multiple signaling pathways during tumor angiogenesis. Pointed arrows indicate activation
whereas flat arrows indicate inhibition

Liu et al.
5
redundant VEGF-A/VEGFR-2, regulates levels of VEGF-A in serum, recruitment that can initiate revascularization and stromal cell
and controls excessive vascular formation. However, as a activation required for wound healing.135,136 Moreover, it partici-
promoter, over-expressed VEGFR-1 facilitates the development pates in the growth and reproduction of endothelial cells,
and metastasis of breast cancer,105 leukemia,106 prostate can- angiogenesis, and vascular maturation.137,138 Studies have shown
cer,107 ovarian cancer (OC) and malignant melanoma.106 that PDGFs and PDGFR-α/β are commonly over-activated in
VEGFR-2 (known as KDR or FLK-1) is a 210–230 kDa transmem- numerous malignant tumors and tissues, including NSCLC,139
brane glycoprotein, generally expressed by vascular endothelial BC,139 OC,140,141 hepatocellular carcinoma (HCC),142,143 and
cells, lymphatic endothelial cells, endothelial progenitor cells, GIST.144 The proliferation, metastasis, invasion and angiogenesis
megakaryocytes, and hematopoietic stem cells.100 Under the of carcinomas can be obstructed by inhibition or neutralization of
mediation of VEGF-A, VEGFR-2 undergoes autophosphorylation PDGFRs,132 some PDGFR inhibitors and dual-targeted VEGFR/
and signal transduction, which potently activates typical down- PDGFR inhibitors are being developed.
stream signaling pathways such as PI3K/AKT/mTOR, p38 MAPK,
Ras/Raf/MEK/ERK that are related to the growth and survival of ECs EGF/EGFRs. Epidermal growth factor (EGF) is a single-chain small
and angiogenesis (Fig. 3).83,108 The most crucial signaling pathway molecule polypeptide composed of 53 amino acid residues.145 The
in physiological and pathological angiogenesis is VEGF-A/VEGFR-2, EGF receptors consist of four proteins, EGFR (ErbB1), HER2 (ErbB2),
which stimulates mitosis, chemotaxis, and morphogenesis of ECs, HER3 (ErbB3), and HER4 (ErbB4),146,147 which have an extramem-
and induces the proliferation, migration, invasion, and angiogen- brane binding domain, a single-chain transmembrane domain
esis in solid tumors.103 Studies have shown that over-expressed that contains a single hydrophobic anchor sequence, and an
VEGFR-2 has been detected in melanoma,109 OC,110 thyroid cancer intramembrane tyrosine kinase binding domain that generates
(TC),111 and other solid tumors.112,113 VEGF-A/VEGFR-2 is a popular and mediates intracellular signals.148,149
therapeutic target occupies the major research of angiogenic EGF is a mediator widely participates in cell growth, prolifera-
inhibitors (Table 1). tion, differentiation, migration, adhesion, apoptosis, and tumor
VEGFR-3 (FLT-4) is a precursor protein with a molecular weight angiogenesis through EGFR.150 As a promoter, EGF involves in
of 195 kDa, mainly expressed in lymphatic endothelial cells and endothelial cell proliferation and differentiation through activating
mediates the activation of VEGF-C and VEGF-D, impelling downstream signaling pathways (MAPK, PI3K/AKT/PKB, STAT, and
lymphoid proliferation and metastasis of tumor.86 VEGFR-3 is PLCγ/PKC), which is mediated by EGFR (Fig. 3).147 Besides, it
frequently over-expressed in metastatic CRC,114 BC,115 lung encourages mitosis and up-regulates the synthesis, expression,
cancer,116 gastric cancer (GC),117 cervical cancer (CC),118 and other and secretion of various angiogenic factors, such as VEGF through
malignant tumors.118,119 Both angiogenesis and lymphangiogen- the Ang-2 ligand, prompting tumor angiogenesis indirectly.41
esis are essential to metastatic tumors.39,49 VEGF-C,-D/VEGFR-3 is Some research proposed that HIF-1α induced the expression of
the primary signal pathway mediates lymphangiogenesis.120 EGF and EGFR, while EGFR up-regulated the expression of HIF-1α
Blocking VEGF-C,-D/VEGFR-3 pathway has potential in preventing and enhanced the oxygen tolerance of cells under a hypoxic
tumor metastasis. microenvironment, consequently aggravating angiogenesis and
progression of the tumor.151,152 The expression level of EGFR is
PDGF/PDGFRs. A factor secreted by platelets and some stromal usually up-regulated in various malignant tumors, including BC,
cells, which participates in coagulation or angiogenesis, is known OC, NSCLC, GBM, bladder cancer and pancreatic cancer, which
as platelet-derived growth factor (PDGF). As the main mitogen of directly promotes tumor growth by mediating gene expression
mesenchymal cells such as fibroblasts, smooth muscle cells, and and mediates tumor invasion and metastasis through angiogen-
glial cells, PDGF involves in cell growth and differentiation, wound esis.149,153 Several studies have shown that EGFR T790M gene
healing, angiogenesis, recruitment, and differentiation of pericytes mutation is the leading cause of drug resistance to EGFR kinase
and smooth muscle cells through paracrine or autocrine.121–123 inhibitors (gefitinib and erlotinib) in the early treatment of lung
PDGFs have four soluble inactive polypeptide chains, including cancer.154 But drug resistance from EGFR self-mutation is far less
PDGF-A, PDGF-B, PDGF-C, and PDGF-D, which perform biological than that caused by signals crosstalk between EGFR and others
functions after being translated into active homodimers or (such as c-Met).155
heterodimers such as PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC,
PDGF-DD.123,124 Among them, PDGF-AA drives cell proliferation, FGF/FGFRs. As a critical factor in promoting wound healing, the
differentiation, metastasis, invasion and angiogenesis, which acts fibroblast growth factor (FGF) family is one of the potent mitogens
as a cancer promotor mediated by PDGFR-α. For example, and drivers of endothelial cells and is the earliest discovered
phosphorylation of STAT3 (Y705) and the inactivation of tumor growth factor related to angiogenesis,156 which consists of 23
suppressor Rb1 can be motivated by PDGF-AA/PDGFR-α, accel- proteins with different structures.157,158 Secreted by vascular
erating the deterioration and angiogenesis of glioma stem cells.125 endothelial cells, stem cells, and damaged cardiomyocytes, FGF
Additionally, tumorigenic effects of PDGF-AB, PDGF-CC, and PDGF- regulates embryonic development, wound healing, tissue home-
DD are manifested through different forms. PDGF-AB promotes ostasis, cancer progression, and angiogenesis through synergistic
mitosis and chemotaxis.126 PDGF-CC induces tumor growth and FGFRs, heparan sulfate polysaccharide, and αvβ integrins.159–161
angiogenesis mediated by CAFs. PDGF-DD/PDGFR-β can irritate FGF-1 is an acidic fibroblast growth factor that stimulates the
the proliferation and metastasis of carcinomas.127,128 PDGF-BB is proliferation and differentiation of parietal vessel cells.157 The
one of the most studied factors in the PDGF family with potent most influential pro-angiogenic factor in the FGF family is FGF-2
cancer-driving efficacy through various downstream signaling (known as bFGF), which regulates the functional differentiation of
pathways (such as MAPK/ERK,129 PI3K/AKT,130 and JNK pathway), cardiac non-myocytes through paracrine and stimulates
which regulates the proliferation and migration of PDGF- angiogenesis-related processes such as migration and invasion
dependent cells.131,132 Over-expressed PDGF signals not only of ECs and production of plasminogen activators.158,162 bFGF is
enhance tissue fibrosis but also excite angiogenesis and drug often over-expressed in BC, lung cancer, bladder cancer, and
resistance in tumor progression and anti-VEGF therapy.121,133 leukemia, and is related to cancer metastasis and poor prognosis
PDGFRs (including PDGFR-α and PDGFR-β) are membrane- in patients.160,162,163 Besides, the up-regulation of bFGF is closely
bound proteins consisting of a transmembrane domain, a related to poor outcomes of CRC patients after treatment with
juxtamembrane domain, a kinase insertion domain, an intracel- combined regimens (bevacizumab plus fluorouracil and irinote-
lular domain, and five extracellular Ig-like domains.134 PDGF/ can),164 and GBM patients who are treated with cediranib (AZD-
PDGFR-β signaling pathway is a dominant commander of pericyte 2171, a potent VEGFR inhibitor).165

Liu et al.
6
Table 1. Anti-angiogenic drugs approved by FDA for clinical treatment
Drugs Targets Indications Companies Adverse effects
Monoclonal antibodies
Bevacizumab (Avastin®) VEGF-A CRC in 2004, Genentech/Roche Arterial or venous, back pain, dry skin,
NSCLC in 2006, exfoliative dermatitis gastrointestinal
RCC in 2009, perforation, headache, hemorrhage,
GBM in 2009, hypertension, lacrimation disorder,
CC in 2014 poor wound healing, proteinuria,
rhinitis, and taste alteration, thrombosis
Ranibizumab (Lucentis®, RG- VEGF-A wAMD in 2006, Genentech/Roche Conjunctival hemorrhage,
6321) DME in 2015, endophthalmitis, eye infection, eye
DR in 2017, pain, floaters, increased intraocular
Myopic choroidal pressure, rhegmatogenous retinal
neovascularization in 2017 detachment, and retinal hemorrhage
Ramucirumab (Cyramza®) VEGFR-2 NSCLC in 2014, Advanced GC in Genentech and Eli Abdominal pain, thrombocytopenia,
2014, GEJ adenocarcinoma in Lilly anorexia, arthralgia, constipation,
2014, metastatic CRC in 2015 cough, diarrhea, dyspnea, epistaxis,
fatigue, headache, hypertension,
leucopenia, nausea, neutropenia,
peripheral edema, proteinuria, upper
respiratory tract infection, and vomiting
Olaratumab (Lartruvo®) PDGFR-α STS in 2016 ImClone/Eli Lilly Appetite, abdominal pain, alopecia,
diarrhea, decreased fatigue, headache,
neuropathy, musculoskeletal pain,
mucositis, nausea, and vomiting
Bevacizumab-awwb (Mvasi®) VEGF CRC, NSCLC, RCC, GBM, and CC Amgen Altered taste, arterial and venous
in 2017 thromboembolic events, bleeding, dry
skin, epistaxis, exfoliative dermatitis,
headache, hypertension, hypertension,
infusion-related reactions, lacrimation
disorders, ovarian failure, perforation or
fistula, post-reversible encephalopathy
syndrome, proteinuria, proteinuria, and
rhinitis
Oligonucleotide aptamers
Pegaptanib (Macugen®) VEGF-A165 wAMD in 2004 Eyetech/Pfizer Endophthalmitis and retinal
detachment
Recombinant fusion proteins
Aflibercept (Eylea®) VEGF-A, VEGF-B, PlGF wAMD in 2011 Regeneron Cataracts, conjunctival hemorrhage,
CRC in 2012 decreased vision, eye pain, floaters,
DME in 2015 increased intraocular pressure, and
DR in 2019 vitreous detachment
ziv-Aflibercept (Zaltrap®) VEGF-A, VEGF-B, PlGF CRC in 2012 Sanofi and Abdominal pain, bleeding, decreased
Regeneron appetite, decreased ejection fraction,
diarrhea, dyspnea, epigastric pain,
fatigue, fatigue, gastrointestinal
perforation, headache, heart failure,
hypertension, impaired wound healing,
infection, leukopenia, nephrotic
syndrome, neutropenia, osteonecrosis
of the lower jaw, proteinuria, severe
diarrhea, stomatitis, thrombocytopenia,
and weight loss
mTOR inhibitors
Temsirolimus (Torisel®) mTOR RCC in 2007 Wyeth Acute renal failure, asthenia, edema,
elevated aspartate aminotransferases,
hyperlipidemia, hypersensitivity,
interstitial pneumonia, intestinal
perforation, lymphopenia, mucositis,
nausea, rash, thrombocytopenia
Everolimus (RAD001, mTOR RCC in 2009 Novartis Canker sores, increased heart rate,
Afinitor®) SEGA in 2010 paronychia, rash, swollen and painful
pNET in 2011 gums, tiredness, and tongue ulcers
HER2- BC

Liu et al.
7
Table 1. continued
Immunomodulatory agents
Thalidomide (Thalomid®) VEGF-A, TNF, NF-κB MM in 2006 Celgene Abdominal pain, constipation,
dizziness, drowsiness, dry oral mucosa,
facial puffiness, nausea, rash,
teratogenic, and tiredness
Lenalidomide (Revlimid®) VEGF-A, TNF, NF-κB MM in 2006 Celgene Anemia, diarrhea, fatigue, headache,
MCL in 2013 loss of appetite, low back pain, neo-
malignant neoplasms, neutropenia,
rash, renal insufficiency,
thrombocytopenia, and thrombotic
complications
Tyrosine kinase inhibitors

Sorafenib (Nexavar®, BAY- VEGFR-1/-2/-3, c-Kit, RCC in 2005 Bayer Abdominal pain, alopecia, decreased
439006) Flt-3, PDGFR-β, Raf, HCC in 2007 and Onyx/Amgen appetite, diarrhea, fatigue, hand-foot
Ret DTC in 2013 skin reaction, hypertension, nausea,
TC in 2014 rash, and weight loss
Sunitinib (Sutent®, SU11248) VEGFR-1/-2/-3, Flt-3, RCC in 2006 Sugen/Pfizer Abdominal pain, anorexia, asthenia,
c-Kit, Ret, PDGFR-α/- GIST in 2006 diarrhea, dysgeusia, dyspepsia, fatigue,
β, CSF-1R pNET in 2011 hypertension, mucositis, nausea, skin
discoloration, stomatitis, and
thrombocytopenia

Liu et al.
8
Table 1. continued
®
Pazopanib (Votrient , GW- VEGFR-1/-2/3, c-Kit, RCC in 2009 GlaxoSmithKline Anorexia, diarrhea, fatigue, fatigue, hair
786034) PDGFR-α/-β, STS in 2012 color changes, nausea, vomiting, and
weight loss
Vandetanib (Caprelsa®, VEGFR-2, VEGFR-3, MTC in 2011 AstraZeneca Diarrhea, headache, rash, hypertension,
ZD6474) EGFR, Ret nausea, and QTc prolongation
Regorafenib (Stivarga®) VEGFR-1/-2/-3, c-Kit, CRC in 2012 Bayer Anorexia, diarrhea, fatigue, hand-foot
PDGFR-β, Ret, Raf-1, GIST in 2013 skin reaction, hypertension, and oral
bRaf, FGFR-1, Tie-2 HCC in 2017 mucositis
Axitinib (Inlyta®, AG013736) VEGFR-1/-2/3, c-Kit, RCC in 2012 Pfizer Asthenia, constipation, decreased
PDGFR-α, PDGFR-β appetite, diarrhea, dysphonia, fatigue,
hand-foot syndrome, hypertension,
nausea, vomiting, and weight
decreased

Liu et al.
9
Table 1. continued
®
Ponatinib (Iclusig ) VEGFRs, PDGFRs, CML in 2012 Ariad/Takeda Abdominal pain, arthralgia, dermatitis,
EPHs, FGFRs, ABL, Ph+ AML in 2012 dry skin, fatigue, increased lipase,
Src, Ret, LYN, LCK, c- nausea, rash, and thrombocytopenia
Kit, HCK, FYN, FRK, c-
FMS, FGR, BLK
Cabozantinib (Cometriq®, VEGFR-2, c-Met, c-Kit, MTC in 2013 Exelixis Abdominal pain, constipation,
BMS-907351) Ret, Flt-3, Tie-2, AXL, RCC in 2016 decreased appetite, decreased weight,
RON HCC in 2019 diarrhea, dysgeusia, fatigue, hair color
changes, hypertension, nausea, oral
pain, palmar-plantar erythrodysesthesia
syndrome, and stomatitis
Apatinib (Aitan®) VEGFR-2, Src, c-Kit GC in 2014 Hengrui Medicine Fatigue, gastrointestinal bleeding,
granulocytopenia, hand-foot syndrome,
hoarseness, hypertension, leukopenia,
proteinuria, and thrombocytopenia
Nintedanib (Ofev®, BIBF1120) VEGFRs, FGFRs, NSCLC in 2015 Boehringer Bleeding, decreased appetite, diarrhea,
PDGFRs, Flt-3, LCK, and Ingelheim electrolyte imbalance, mucositis,
LYN, Src nausea, neutropenia, peripheral
neuropathy, rash, and vomiting

Liu et al.
10
Table 1. continued
®
Lenvatinib (Lenvima , E7080) VEGFRs, PDGFRs, Ret, DTC and TC in 2015 Eisai Abdominal pain, arthralgia, decreased
c-Kit, FGFRs RCC in 2016 appetite, decreased weight, diarrhea,
HCC in 2018 dysphonia, fatigue, headache,
Endometrial Carcinoma in 2019 hypertension, myalgia, nausea,
proteinuria, stomatitis, and vomiting
ALL acute lymphoblastic leukemia, BC breast cancer, BTC biliary tract cancer, CC cervical cancer, CML chronic myeloid leukemia, CRC colorectal cancer, CSF
colony-stimulating factor, DME diabetic macular edema, DR diabetic retinopathy, DTC differentiated thyroid cancer, EC esophageal cancer, GEJ
gastroesophageal junction, GBM glioblastoma, GC gastric cancer, GIST gastrointestinal stromal tumor, HCC hepatocellular carcinoma, HER2 human epidermal
growth factor receptor 2, HNSCC head and neck squamous cell carcinoma, MCL mantle cell lymphoma, MM multiple myeloma, MTC medullary thyroid cancer,
mTOR mammalian target of rapamycin, NSCLC non-small cell lung cancer, Ph+ AML Philadelphia chromosome-positive acute myeloid leukemia, pNET pancreas
neuroendocrine tumor, RCC renal cell carcinoma, SEGA subependymal giant cell astrocytoma, STS soft tissue sarcoma, TC thyroid cancer, TNBC triple-negative
breast cancer, wAMD wet age-related macular degeneration
FGFR is a transmembrane receptor family with five members of demonstrated that the exon 14 mutation of c-Met promotes the
FGFR1–5 (only FGFR5 lacks an intracellular kinase domain),163 metastasis of advanced cancer, like lung adenocarcinoma, RCC,
whose genes are proto-oncogenes with tumorigenic potential and brain glioma.189 Besides, drug resistance in treatment with
after gene amplification, chromosomal translocation or point EGFR kinase inhibitors is partly attributed to signaling crosstalk
mutation.166–168 FGFR mediates the survival, multiplication, and between similar EGFR and c-Met.155,190 All of these functions
migration, angiogenesis, and drug resistance in target cells above are achieved through activation of downstream signaling
through autophosphorylation and activating downstream Src pathways including JAK/STAT,191 Ras/MAPK,192 PI3K/AKT,192 Wnt/
family kinases,169 PLCγ/DAG/PKC,157,163 Ras/Raf-MAPK, and PI3K/ β-catenin, or others (Fig. 3).193,194 As the role of the HGF/c-Met
AKT pathways activated by bFGF, playing a pro-angiogenic role in system in pathological and physiological angiogenesis and drug
the human body (Fig. 3).159,170,171 In tumor angiogenesis, FGF/ resistance continues to be revealed, HGF/c-Met axis becomes an
FGFR signaling plays a key role in stimulating the secretion of attractive target for anti-tumor therapy.
MMPs and regulates the proliferation, differentiation, migration,
morphological changes, and vascular maturation of endothelial IGF/IGFRs. Insulin-like growth factor (IGF) is a peptide growth
cells.171 Aberrant activations of bFGF/FGFR are essential alter- factor that regulates human growth, development, and energy
native angiogenic pathways that induce drug resistance in anti- metabolism, which participates in physiological circulation
VEGFR therapy.133,172 through autocrine, paracrine, and endocrine.195 IGF modulates
the survival, proliferation, and differentiation of multiplicate cells
HGF/c-Met. The hepatocyte growth factor (known as the scatter- and the physiological process of the blood system under different
ing factor) is a multi-effect precursor protein and a mitogen of physiological conditions.196 IGF1 and IGF2 are the two main
mature rat hepatocytes,173 mainly derived from mesenchymal subtypes mediated by insulin receptors IGF1R, IGF2R and
cells and activated by extracellular protease cleavage.174 As a IGFBPs.197,198 Highly expressed IGF1 and IGF2 induces VEGF
soluble heterodimer, HGF can be cleaved into α chain and β chain. synthesis and up-regulates the expression of HIF-1α and VEGF to
α chain is responsible for binding receptors while β chain can promote angiogenesis. Besides, autocrine IGF2 induces drug
trigger receptors and transduce signals.175 Transmembrane helical resistance in anti-tumor therapy.195 Moreover, studies have shown
receptor c-Met is a 170 kDa cell-stroma-epithelium transition that over-expression of IGF fosters the progression of diabetic
factor usually expressed on endothelial cells, epithelial cells, and retinopathy (DR),199,200 retinopathy of prematurity,201–203 athero-
melanocytes in the pathological liver, kidney, lung and other sclerosis, and cancer.204–207
organs.155,173,176 c-Met was firstly discovered as a proto-oncogene IGFBPs are high-affinity receptors of IGF, with six subtypes of
in 1984 and later identified as a specific receptor for HGF in IGFBP1–6, secreted by endothelial cells living in macro-vessels and
1991.177,178 Owing to instinctively actuate cell growth, differentia- capillaries.198 Pro-angiogenic IGFBP2 induces chemotaxis and
tion, morphogenesis and suppress apoptosis, HGF/c-Met is a migration of ECs by increasing VEGF transcription and IGF
crucial signaling pathway in wound healing, tissue regeneration levels.208,209 IGFBP3 up-regulates the expression of VEGF, MMP2,
and embryogenesis.155,173,175 Inhibition of this pathway will and MMP9 and promotes tube formation.210 IGFBP4, IGFBP5, and
seriously affect the self-repair of patients with myocardial IGFBP6 appear to inhibit angiogenesis indirectly.196 More studies
ischemia,179 diabetic retinopathy,180 liver damage,181 and arthri- are expected to dissect the roles and mechanisms of IGF family in
tis.182 Nevertheless, abnormal HGF/c-Met signals such as amplifi- tumor angiogenesis.
cation or secondary mutation of c-Met genes, transcription
dysregulation, and abnormally autocrine or paracrine of HGF TGF-β. In 1978, a signaling protein with multiple biological
caused by over-expression of c-Met, encourages the spread, effects, named transforming growth factor-β (TGF-β), was
invasion and angiogenesis of cancerous tissues,183–185 drug discovered by scientists in mouse fibroblasts. TGF-β is a secreted
resistance, and poor prognoses of patients.175,186–188 It has been cytokine that is concerned with body homeostasis, tissue repair,

Liu et al.
11
Fig. 4 The transduction of HIF-1α in normal and hypoxic conditions. Under normal conditions, HIF-1α is degraded by protease and loses
transcription function. In hypoxic environment, lack of enzyme degradation leads to efficient transcription of HIF-1α, resulting in over-
expression of pro-angiogenic factors including VEGF, PDGF, and MMPs
inflammation, and immune responses,211 which is also involved in unsatisfactory clinical outcomes. Accordingly, TGF-β simulta-
cell growth, differentiation, proliferation, autophagy, apoptosis, neously promotes tumorigenesis and induces angiogenesis to
and tumor angiogenesis.212 There are three types of single-pass nourish tumors. Perhaps TGF-β is the next breakthrough to fight
transmembrane receptors specifically interact with TGF-β, named against tumor angiogenesis and drug resistance.
type I (TβRI), type II (TβRII) and type III (TβRIII). Under the co-
transduction of these receptors, the downstream Smad- Transcription factors
dependent pathways, and non-Smad pathways (involves classical Hypoxia-inducible factor-1. Hypoxia is the most typical feature of
MAPK, JNK/p38 MAPK, PI3K/AKT, TAK1, and ERKs) are alternately the tumor microenvironment and is always associated with drug
activated to exert the physiological and pathological effects of resistance, tumor angiogenesis, aggressiveness, and recurrence.239
TGF-β.213–215 Apart from various physiological processes, TGF-β The hypoxia-inducible factor-1 (HIF-1) is a heterodimeric transcrip-
involves in multiple atherosclerosis and fibrotic diseases like tion factor that regulates cell adaptation to hypoxia, energy
cirrhosis and pulmonary fibrosis and affects cancer progres- metabolism, erythropoiesis, and tissue perfusion balance and
sion.216,217 During the initial stage of tumorigenesis, TGF-β acts as involves in cell survival, proliferation, migration, adhesion,
a suppressor that induces apoptosis and confines pre-cancerous apoptosis, erythropoiesis, and glucose metabolism.240,241 HIF-1 is
cells.216,218 But in mature tumor tissue, the aggressiveness of the composed of the constitutive nuclear protein HIF-1β and
tumor is awakened by TGF-β, which encourages various pro- environment-dependent isomer HIF-1α,151 which is an oxygen
cancer activities, including epithelial-mesenchymal transition regulator that increases oxygen delivery, reduces oxygen con-
(EMT), metastasis, invasion, fibrosis, angiogenesis, and immune sumption and maintains oxygen balance.240–242 HIF-2α and HIF-3α
suppression of carcinomas.219–221 are the analogs of HIF-1α which are not well understood.241,243
The tumorigenic effects of TGF can be manifested in various Under normoxic conditions, the proline residues in HIF-1α are
modes. Firstly, TGF-β induces the migration of endothelial cells to hydroxylated by the proline hydroxylase domain (PHD), which can
impel vessel sprouting.222,223 Secondly, TGF-β encourages infiltra- stabilize HIF-1α. Subsequently, HIF-1α is degraded by proteasomes
tion and invasion of the tumor through EMT.224 Thirdly, TGF-β up- after ubiquitination mediated by E3 ubiquitin ligase and ρVHL.
regulates the expression of MMP-2 and MMP-9 to mobilize tumor Besides, hydroxylation of asparagine residues, which regulates
invasiveness and angiogenesis.224–226 Last but not least, TGF-β HIF-1α transcriptional activity and specificity, disrupts the interac-
induces the expression of connective tissue growth factor tion between HIF-1α and co-activation factor p300 to inhibit the
(CTGF),227 VEGF, bFGF, and interleukin-1, which are essential for transcriptional activity of HIF-1α, consequently inhibiting the
tumor angiogenesis.228,229 Many studies have demonstrated that expression of VEGF and angiogenesis (Fig. 4).151,239 However, since
TGF-β is closely related to the tumorigenesis and poor prognosis the hydroxylation under hypoxic conditions can be limited by
of patients in multifarious human organizations. For example, high oxygen concentration, HIF-1α constitutes a dimerized complex
tissue concentrations of TGF-β have been detected in human with HIF-1β through nuclear translocation. This complex binds the
pancreatic cancer,230–233 NSCLC,234 HCC,235–237 and BC,238 which hypoxia response element (HRE) (located on the HIF target) after
motivates tumor progression and angiogenesis, leading to interacting with the coactivator p300, subsequently activating the

Liu et al.
12
transcription of the downstream target genes that encode VEGF, shedding to disturb vascular stability through competitively
MMPs, angiopoietin, and PDGF (Fig. 4). The complicated process binding Tie-2 and integrin receptors.276,277 The over-expression
enhances the affinity and invasiveness of tumor cells, induces of Ang-2 promotes vascular proliferation and the growth of
apoptosis of epithelial cells, inhibits apoptosis of tumor cells, and carcinomas. However, under a low concentration of VEGF-A, Ang-2
promotes tumor angiogenesis.244–246 induces apoptosis and vascular degeneration to inhibit tumor
The unfavorable effects of the hypoxic microenvironment in growth.268 In a peptide-antibody fusion trial, tumor growth,
tumor tissue are mainly realized by HIF-1α, which induces pro- angiogenesis, and endothelial cells proliferation were inhibited
oncogenic gene expression to disrupt the “homeostasis” of TME. by neutralizing Ang-2.267 With advanced research on Ang-1/-2,
In tumor progression, the expression of related genes of all VEGF some antibodies targeted angiopoietin (like trebananib, faricimab,
isoforms, PlGF, FGF, PDGF, and Ang-1 can be up-regulated by HIF- nesvacumab and vanucizumab) are undergoing clinical trials to
1α to promote tumor angiogenesis or induce drug resistance. HIF- testify their anti-tumor efficacy through inhibiting tumor angio-
1α also up-regulates TGF-β, PDGF, and CXCL2 secreted by tumor genesis.24 More functions of the Ang/Tie pathway in tumor
cells and macrophages, which prompt the reconstruction of angiogenesis will be proven in the near further.
extracellular matrix and impel the invasion and metastasis of
tumors induced by tumor-associated fibroblasts (TAFs).243,247 Notch-Delta/Jagged. Notch receptors are a kind of particular non-
Various model experiments and clinical trials have demonstrated RTK proteins that engage in numerous cellular processes, like
that over-expression of HIF-1α is significantly related to the morphogenesis, proliferation, migration, differentiation, apoptosis,
progression of BC,248,249 CC,250 NSCLC,251,252 and HCC,253,254 adhesion, EMT, and angiogenesis (Fig. 3).278 Notch is initially
especially some advanced metastatic cancers.151,255 Furthermore, verified in Drosophila melanogaster in the mid-1980s and is a
cell cycle arrest and compensatory angiogenesis initiated by highly evolutionarily conserved local signaling pathway.278 In
hypoxia are among the pivotal causes of drug resistance in mammals, the Notch receptors can be divided into four subunits
chemotherapy and anti-angiogenic treatment, respectively.256,257 named Notch-1, Notch-2, Notch-3 and Notch-4, and five ligands
HIF-1α is a crucial target for anti-tumor therapy, while some have been discovered, including Delta-like ligand-1 (Dll-1), Dll-3,
progress has been made in developing novel small-molecule Dll-4, Jagged ligand-1 (Jag-1), and Jag-2.279 This pathway is of
inhibitors that target HIF-1α (Table 3). great significance in adult tissue homeostasis, inflammation,
embryonic development, vascular maintenance, and vascular
NF-κB. Being discovered in 1986, the nuclear factor κB (NF-κB) is remodeling.280
an important transcription factor in the human body, and is Among the Notch family, Dll-4 and Jag-1 are the most
involved in cell survival, oxidative damage, inflammation, immune representative ligands in tumor angiogenesis.281,282 Highly
responses, and angiogenesis.258,259 As an indirect mediator, NF-κB expressed in the vasculature, Dll-4 is secreted by tip cells
regulates the development of various carcinomas (such as CRC, (differentiated from ECs) to induce excessive sprouting and
BC, and melanoma) by modulating the expression levels of increase microvessel density. Additionally, hypoxia is one of the
angiogenic factors, especially VEGF.260 Blocking NF-κB signals causes of cancer metastasis, and the interaction between Dll-4 and
in vitro and in vivo significantly decreased tumor angiogenesis HIF-1α significantly upregulates the expression of Dll-4 and
induced by VEGF, IL-8, and MMP-9.261 Targeting NF-κB may be a aggravates hypoxia, promoting the aggressiveness of cancer
prospective strategy for anti-angiogenesis. cells.283–285 Studies in vitro have shown that blocking Dll-4 could
simultaneously decrease tumor growth and stimulate vascular
Maturation, morphogenic, and guidance molecules sprouting and branching to increase tumor angiogenesis,
Angiopoietins/Tie. A coiled-coil amino-terminal domain and a although these new blood vessels formed with inferior morphol-
carboxy-terminal fibrinogen-like domain constitute the angiopoie- ogy and function.286 Jag-1 is mainly expressed by stem cells that
tin,262 which maintains quiescent endothelial cells homeostasis antagonizes Notch signal induced by Dll-4 within sprout and
and blood vessels morphology and involves in new blood vessels promotes the growth of new vessels. The progression of various
formation, embryonic development, and tumor angiogenesis. malignant tumors such as leukemia, BC,287 HCC,288 CC,289 and
Angiopoietins consist of four ligands, Ang-1, Ang-2, Ang-3, and cholangiocarcinoma290 is highly linked to the over-expression of
Ang-4.263 Ang-1 and Ang-2 are the main factors involved in Jag-1.291 Up-regulation of Jag-1 in breast cancer increases the
vascular homeostasis. The transmembrane protein Tie is a specific level of IL-6 and TGF-β to induce bone metastasis of cancer cells,
receptor family of Ang with high affinity. Tie-2 (known as TEK) is a which Jag-1 inhibitors can neutralize.292 Furthermore, aberrant
commonly studied receptor that mediates the functions of Notch-Dll/Jag transductions contribute to survival and growth of
angiopoietin.264 Tie-1 is an orphan receptor which can modulate cancer stem cells, metastasis, and drug resistance.279 Activated
the activity of Tie-2 receptor.263,264 Notch signal has been reported to promote the progression of
Ang-1 is a bifunctional protein and is mainly secreted by RCC, while inhibition of Notch signal limits the tumor growth
pericytes,265 smooth muscle cells, tumor cells,266 and others in vivo and in vitro.293 Excessive Notch-1 has also been detected in
around endothelial cells to mediate vessel remodeling and other various human cancers like cervical, lung, and hematologic
vascular stabilization.266 Ang-1 activates the signaling pathway carcinomas.294 In tumor models, EMT and invasion induced by
through receptor Tie-2 on macrophages to down-regulate the hypoxia could be offset after suppressing the Notch signaling
expression of PHD-2, reducing the leakage and interstitial pressure pathway.295 Notch-Dll/Jag is an indispensable pathway in the
of tumor vessels and preventing tumor metastasis.267 It also initial stage of physiological and pathological angiogenesis with
stimulates tumor growth by promoting endothelial cell survival visible advantages in anti-tumor therapy, but its complex
and vascular maturation, inhibits tumor cell extravasation, mechanisms and its relationships with other factors are not well
increases pericyte coverage and matrix deposition, and maintains illustrated.
the integrity of healthy blood vessels outside the tumor.266,268
Over-expressed Ang-1 strengthens the malignancy of NSCLC,269 Ephrins/EphR. Ephrins/EphR is a unique kinase family in regulat-
BC,270,271 OC,272 and gliomas,273,274 and impels angiogenesis in ing the interaction between adjacent cells through typical
brain tumors as well, which is dominated by bone marrow-derived bidirectional signal transduction (Fig. 3).296 Ligands ephrins (Eph
endothelial progenitor cells.275 receptor-interacting proteins) are divided into five glycosylpho-
Ang-2 may exert pro- or anti-angiogenic activities in different sphatidylinisotol (GPI) anchored A subunits and three B subunits
environments based on dynamic concentrations of VEGF-A. that contain a transmembrane domain and a short cytoplasmic
Stimulated by VEGF-A, Ang-2 promotes angiogenesis and pericyte region.297 Eph (erythropoietin-producing hepatocellular

Liu et al.
13
carcinoma) receptors are the largest transmembrane RTK family, serve as targets for anti-angiogenic therapy in cancer.313–316 In
which consists of nine members of type A and four members of addition to αvβ3 and αvβ5 integrins, α1β1, α2β1, α4β1, α5β1, α9β1,
type B.296,298 In human body, Ephrins/EphR signaling pathway α6β1, and α6β4 mediate tumor angiogenesis in different manners.
plays a vital role in cell morphogenesis, arteriovenous formation, For example, α4β1 maintains the stability of endothelial cells and
nervous system development, tissue formation, tissue home- pericytes under the mediation of pro-angiogenic factors VEGF,
ostasis, and various angiogenic processes.299–301 Among them, the bFGF, and TNF-α to support tumor angiogenesis.317 Integrin α5β1
most critical pathway is EphrinB2/EphB4, which potently promotes and its ligand fibronectin can be up-regulated in angiogenesis
sprouting, vascular maturation, and revascularization in tumor mediated by bFGF and IL-8.318 Integrin α9β1 promotes tumor
angiogenesis, and also acts as an essential member of the VEGF- angiogenesis in a VEGF-dependent way and regulates lymphan-
Dll4/Notch-EphrinB2/EphB4 cascade in angiogenesis.302 A study in giogenesis by interacting with VEGF-C and VEGF-D.319 Although
2020 demonstrated that EphrinB2 could involve angiogenesis and the biological functions and mechanisms of integrins are such
lymphangiogenesis through regulating internalization and activa- complex, the future of anti-integrin in anti-angiogenic therapy is
tion of VEGFR-2 and endocytosis of VEGFR-3.302 In vitro over- promising owing to crucial and fundamental roles in tumor
expression of EphrinB2 increased the secretion of VEGF and tube angiogenesis and lymphangiogenesis.
formation in hypoxia conditions, resulting in excessive angiogen-
esis in HUVECs.303 EphB4 plays a role in regulating vessel Proteinases
sprouting and branching,304 and inhibition of EphB4 can MMPs. Matrix metalloproteinases (MMPs) are a family of zinc-
effectively control micro-vessel density and cancer cell prolifera- and calcium-dependent endopeptidases secreted by connective
tion.305 Nevertheless, excessive inhibition of this receptor may tissue and stromal cells, like fibroblast, ECs, macrophages,
aggravate hypoxia within TME, further stimulating the expression osteoblasts, lymphocytes and neutrophils (Fig. 5).320 In various
of VEGF and tumor aggressiveness.306 All these evidences indicate angiogenesis, MMPs are dominant mediators in destroying ECM
that regulation of this pathway is of great significance to anti- and remodeling the basement membrane, which enzymatically
angiogenic therapy. And it much remains to be understood about degrades the peptide bonds of collagen, elastin, laminin, and
the mechanisms and signaling processes of EphrinB2/EphB4 due fibronectin.321 MMPs are attractive targets in anti-angiogenic and
to its complex nature, abilities for bidirectional signaling and anti-tumor therapy. All members within the MMPs family are
numerous unknown functions.302 Other components in Ephrins/ precursor enzymes that require proteolysis to be effective,
EphR family should also be concerned, in which various abnormal including collagenases, gelatinases, stromelysins, matrilysins, and
Ephrins/EphR signals have been detected in many cancerous MMP membrane-type (MT)-MMPs.322 The major subunits involved
tissues. For example, EphrinB2 is over-expressed in ovarian cancer, in tumor angiogenesis are MMP-2, MMP-9 and MMP-14.323 MMP-2
kidney cancer and melanoma, whereas EphrinA3 is up-regulated is a 72 kDa gelatinase A or type IV collagenase that degrades types
in squamous cell lung carcinoma (SCLC) and colon cancer.296 As I and IV collagen. MMP-9 is a 92 kDa gelatinase B or type IV
for receptor subunits, EphB3, EphB4 and EphB6 are excessively collagenase and MMP-14 is a type 1 membrane matrix metallo-
activated in colon cancer, but EphA2, EphA3, EphA4, EphA6, and proteinase (MT1-MMP) that can degrade multiplicate extracellular
EphA7 are expressed at a high level in lung cancer.296 matrix components.81,321 MMP-9 is the central protease for
extracellular matrix degradation, which increases the bioavail-
Adhesion molecules ability of VEGF and recruits pericytes to maintain homeostasis in
Integrins. Integrins are major adhesion factors in the extracellular tumor microenvironment.324,325 The essential component type IV
matrix, which engage in various cellular processes in the human collagen and other matrix proteins are degraded by MMP-9, which
body by regulating signaling transduction between cells and of induces basement membrane remodeling, triggers morphogen-
these cells with the surrounding matrix (Fig. 3).307,308 Up to now, esis and sprouting of ECs to stimulate tumor angiogenesis.326 The
about 24 unique integrin heterodimers have been uncovered, importance of MMP-2 is that the deletion of MMP-2 controls the
which consist of 18 α subunits and 8 β subunits through non- angiogenesis and growth of tumor in vivo.327 MMP-14 promotes
covalent binding.309,310 Each integrin subunit includes a single vascular lumen formation and induces ECs to infiltrate tumor
transmembrane domain, an extracellular region, and a cytoplas- tissue.328,329 Besides, MMP-1 and MMP-7 play unique roles in
mic region with a short chain.307 Unlike tyrosine kinase receptors, tumor angiogenesis. MMP-1 is an interstitial or fibroblast-type
integrins without intrinsic kinase or enzymic activities rely on focal collagenase that degrades interstitial types I-III collagen, whereas
adhesion complexes to activate cellular signaling pathways. Under MMP-7 is a matrilysin. MMP-1 releases bFGF by degrading the
the mediation of soluble ligands, extracellular matrix (ECM), or cell basement membrane to induce tumor angiogenesis, while MMP-7
surface bound ligands including growth factors, proteases, mediates ECs proliferation and up-regulates the expression of
cytokines, structural constituents of the ECM (like collagen and MMP-1 and MMP-2 to encourage tumor angiogenesis.330,331 In
fibronectin), plasma proteins, microbial pathogens, or receptors addition to regulating angiogenesis, MMPs contribute to the
specific to immune cells, integrin plays a pivotal role in cell malignant progression of tumors based on EMT, which plays an
homeostasis, immunity, inflammation, infection, thrombosis, irreplaceable role in tumor vasculogenesis, invasion and metas-
lymphangiogenesis, angiogenesis, and tumorigenesis within the tasis.332 EMT is a process in which the transition of epithelial cells
complex human internal environment.311,312 to mesenchymal migratory phenotypes,333 involves the degrada-
In tumor angiogenesis, over-expressed αv integrins can be tion of ECM and basement membrane and the destruction of
exploited by carcinomas to fight for vascular and stromal adhesion in cell-cell or cell-matrix.322
resources to encourage tumor progression and canceration. Actually, the expression level of MMPs is maintained in a
αvβ6 integrin is the first adhesion factor among αv integrins dynamic balance under the antagonism of endogenous tissue
shown to have angiogenic effects and is widely expressed on inhibitors of matrix metalloproteinases (TIMP), a family of multi-
activated vascular ECs within remodeling and pathological tissues. functional proteins. In addition to stabilizing MMPs, TIMPs are
αvβ3 is an indispensable factor in angiogenesis initiated by bFGF involved in erythrocyte proliferation and cell growth, including
and TNF-α signaling pathways, while αvβ5 is required for soluble TIMP-1, TIMP-2, TIMP-4, and insoluble TIMP-3.334 These
angiogenesis mediated by TGF-α and VEGF.307 Besides, αvβ5 inhibitory components have unique physiological roles in
modulates the role of VEGF in promoting vascular permeability regulating endothelial cell growth and proliferation through
and tumor metastasis.263 In some early preclinical studies, MMP-independent pathways and inhibiting tumor angiogen-
antibodies target αvβ3 and αvβ5 integrins prevented tumor esis.334–336 Moreover, as a cathepsin to promote angiogenesis,
angiogenesis and metastatic spread, supporting both of them MMP has some anti-angiogenic potential. As a potent inhibitor of

Liu et al.
14
Fig. 5 MMP-expressing stromal cells and functions of MMPs in tumor microenvironment. MMP precursors which are secreted by endothelial
cells, fibroblasts, and lymphocytes et al. converted into active MMPs through enzymolysis. Subsequently, active MMPs participate in different
biological processes including angiogenesis and tissue invasion by degrading specific extracellular matrix components
endogenous angiogenesis, angiostatin is a partial fragment of (NOS),351 pleiotrophin (PTN),352 steroid hormones,353 thrombos-
plasminogen that potently inhibits ECs proliferation.337 Coinci- pondin (TSP),354,355 and many other molecules also involve tumor
dentally, before the 2000s, scientists found that MMP-7 could angiogenesis to encourage tumor progression. The specific roles
hydrolyze the Pro (466)-Val (467) peptides bond, and MMP-9 could and mechanisms of these biomolecules in angiogenesis and
hydrolyze the Pro (465)-Pro (466) bond between cyclic domains 4 tumorigenesis will gradually be explored by researchers.
and 5 of human plasminogen, finally producing angiostatin
fragments with potential anti-angiogenic effects.81 Later, in
2002, studies reported that MMP-2/-3/-12 could cleave plasmino- ANTI-ANGIOGENIC THERAPY: A VALUABLE STRATEGY FOR
gen to create angiostatin fragments, and MMP-3/-9/-13/-20 were CANCER TREATMENT
related to the production of endostatin.338 The physiological and The concept of angiogenesis has been proposed for more than 50
pathological functions of the MMPs family are significantly specific years, and the initial understanding is only “angiogenesis in
to different internal environments and a comprehensive study of tumor”: the growth, survival and proliferation of tumor rely on
their processes will be long-term research. angiogenesis after the tumor beyond a certain volume. At present,
In an intricate angiogenic system, almost all biomolecules act in this theory has been extended to various non-neoplastic diseases
interrelated manners to activate the proliferation, survival, such as cardiovascular disease, rheumatoid arthritis (RA), and
migration, and morphogenesis of target cells to excite tumor diabetic retinopathy.
angiogenesis. Apart from the factors above and downstream The formation of new blood vessels has been observed since
pathways shown in Fig. 3, Apelin/APLNR family,339 Slit/Robo the earliest time, especially wound healing. But this process has
family,340 adrenomedullin,341,342 COX-2,343,344 CXC chemo- only ever been regarded as a simple pathological or physiological
kines,345,346 interleukins,347 interferons,348–350 nitric oxide synthase process unrelated to malignancies. In the 1860s, some researchers

Liu et al.
15
have observed the development of blood vessels presents as a Jain twi-proposed “tumor vascular normalization to improve the
scattered pattern of branches,356,357 and pathologist Virchow also delivery of drugs and oxygen” based on previous research to
described a rich vascular network in tumors in his Die Krankhaften impel anti-angiogenic therapy (Fig. 6).370,371 Vascular normal-
Greschwulste.358 Then in the 1960s, Greenblatt et al. used the ization means that the disordered condition of tumor angiogen-
“tumor angiogenesis” firstly and proposed that tumors could esis can be back to the normal state through measurable anti-
produce soluble angiogenic substances.359 Professor Folkman angiogenic agents. As a result, the functional and morphological
carried out related research in the following years based on characterizations of the vessels are restored to a more normal
previous achievements of others, and in 1971 proposed that condition, and the TME is more stable, finally improving drug
“tumor growth depends on angiogenesis, and anti-angiogenic transportation and delaying drug resistance and aggressive-
substances can treat tumors”. Although this hypothesis attracted ness.372 According to clinical and preclinical research, the effects
little scientific interest, Folkman persisted research and success- of vascular normalization are closely related to the “time
fully cultured ECs in capillaries, which facilitated multiple classical window”.50 It indicates the period during which the blood vessels
angiogenic models, such as chick chorioallantoic membrane exhibit a normal phenotype after proper drug administration.
(CAM) and corneal transplantation models.360,361 During the “time window”, anti-tumor drugs might be more easily
Among the 1980s, people gradually realized indeed angiogen- transported to tumor tissue through blood circulation, which may
esis in tumors, but did not believe that it could be a therapeutic be quite beneficial to tissue concentration and efficacy of
target, and most people still insisted that “it is an inflammatory drugs.373 Despite several conventional angiogenic inhibitors that
response from tumor necrosis”, “it is the defense response of host have been demonstrated effective in remodeling the tumor blood
to tumors”, and “new blood vessels in tumor will gradually mature vessels, vascular normalization is still hard to maintain for a long
like normal blood vessels”. Until 1983, Senger et al. discovered time.374,375 Almost two decades, considerable efforts to optimize
that vascular permeability could be enhanced by a substance angiogenic inhibitors, administration regimens and medical
derived from tumors named vascular permeability factor (VPF), detection methods, in order to prolong the “time window” of
which was shown to have a strong angiogenic effect in vascular normalization, and maximize the benefits of anti-
subsequent scientific research, and was re-named as vascular angiogenic drugs and the efficacy of tumors to chemotherapy,
endothelial growth factor (VEGF).362 In 1984, the first tumor- radiotherapy and immunotherapy. Li et al. comprehensively
derived pro-angiogenic factor from chondrosarcoma was success- evaluated imaging methods that commonly used to detect
fully isolated by Shing et al. and named as basic fibroblast growth vascular changes in tumor tissue.376 Viallard et al.,26 R. Zheng
factor (bFGF).363 Then in the following years, tumor-dependent et al.,377 and Luo et al. suggested some promising strategies to
angiogenesis was testified by a large number of experiments, anti- optimize vascular normalization.378 Anti-angiogenic therapy is a
angiogenic therapy was more possible, and Folkman’s theory was promising therapeutic method mixed with benefits and chal-
recognized by some researchers. Followed by some major events lenges. The timeline of milestones regarding the research on
in the field of angiogenesis: discovery to withdrawal of drugs such tumor angiogenesis are shown in Fig. 7.
as TNP-470, the discovery of the anti-angiogenic effect of
thalidomide,364 and the development of angiostatin and endo-
statin, the theory of tumor angiogenesis was generally accepted, THE DEVELOPMENT OF ANGIOGENIC INHIBITORS FOR ANTI-
and more researchers devoted to anti-angiogenic therapy. TUMOR THERAPY
In earlier studies, scientists believed that serious toxic effects Anti-angiogenic therapy is achieved by inhibiting tumor growth
and drug resistance would not develop in anti-angiogenic therapy and metastasis through anti-angiogenic drugs to limit the blood
because angiogenic inhibitors targeted genetically stable vascular supply to tumor tissue. Although molecular and mechanistic
ECs rather than tumor cells.358,365 Traditional anti-angiogenic studies have indicated that numerous regulators engaged in
therapy on the basis of “starving tumors”, which obstructed the tumor angiogenesis, research on angiogenic inhibitors still focuses
energy supply for tumor tissue by blocking angiogenesis to guide on VEGF/VEGFR signaling pathway due to its dominance in the
the death of tumor cells.366 In 2004, the first anti-angiogenic drug angiogenic system. Among them, recombinant monoclonal
bevacizumab (Table 1) approved by FDA significantly prolonged antibodies and small molecule tyrosine kinase inhibitors are the
the PFS rates of RCC patients in combination with chemotherapy, mainstream drugs used in anti-angiogenic treatment. Inhibitors
and in the following years, other anti-angiogenic drugs were approved for anti-angiogenic therapy are summarized in Table 1,
launched. Although some positive results were achieved, the and potential agents evaluated in clinical trials are described in
clinical benefits did not meet expectations, the PFS rates of Table 2.
patients improved modestly, the improvement of OS rates were
minimal, and even in some failed cases, it was observed that the Angiogenic inhibitors approved by FDA for clinical treatment
toxicity suffered by the patients far more than the treatment Anti-angiogenic monoclonal antibodies. Monoclonal antibodies
effects. For example, in November 2010, the FDA withdrew the are derived from artificially prepared hybridoma cells, which have
approval of bevacizumab (Avastin®) for the treatment of HER2 the advantages of high purity, high sensitivity, strong specificity,
negative metastatic BC based on four disappointing clinical trials: and less cross-reactivity. When compared with kinase inhibitors,
serious adverse events (like hypertension and organ failure) and these immanent unique advantages in clinical treatment are
minimal treatment benefits among BC patients treated with comparatively beneficial to patients. The most representative
bevacizumab. antibody is bevacizumab (Avastin®) (Table 1). In 1993, anti-VEGF
Although numerous perspectives and reflections rose in anti- monoclonal antibody trials demonstrated that inhibitors targeting
angiogenic therapy,367,368 proponents continued anti-angiogenic VEGF could decrease tumor growth, provoking scientists to
research and found that excessive limitation of angiogenesis not investigate the clinical efficacy of bevacizumab. Known as the
only affects the transportation of drugs but also exacerbates first formal angiogenic inhibitor, bevacizumab is a macro-
pathological manifestations of TME, inducing stronger hypoxic molecular recombinant human monoclonal antibody that
responses and aggressiveness of tumor, and eventually causing obstructs the transduction of VEGF pathway by neutralizing all
drug resistance or even cancer metastasis.369 Because of the high- VEGF isoforms to inhibit tumor angiogenesis.379 In a phase III
permeability and distortion of tumor vessels, complexity and clinical trials with IFL treatment (combination of irinotecan,
unpredictable changes of tumor tissue, these shortcomings are fluorouracil (5-FU), and leucovorin), the PFS rate of previously
understandable for an emerging treatment method, which have untreated metastatic CRC patients increased from a median of 6.2
also motivated more in-depth research. In the 2000s, Rakesh K. months to 10.6 months, the OS rate increased from 34.8% to

Liu et al.
16
Fig. 6 Diagramatic illustrations of the relationship between tumor blood vessels, pro-angiogenic and anti-angiogenic factors. a Blood vessels
with regularity and completeness depend on dynamic balance of pro-factors and anti- factors in normal tissues. b Abnormal vessels with
chaos, leakage and feeble blood circulation are caused by imbalance of mediators in tumor tissue. c Blood vessels are repaired through
neutralizing abundant pro-factors or increasing anti-factors under the guidance of angiogenic inhibitors. d Blood vessels in tumor tissue are
destroyed by excessive inhibitors, which aggravates hypoxia within tumor tissue and hinders drug transportation
Fig. 7 Timeline of the milestones regarding the research on tumor angiogenesis
44.8%, and the median duration of response increased 3.3 months combining multiple chemotherapy drugs to treat recurrent or
owing to the addition of bevacizumab.380 Hence, bevacizumab metastatic malignant tumors. For example, the combination of
was approved by FDA for patients with CRC in 2004. In addition to bevacizumab, carboplatin, and paclitaxel (or gemcitabine) was
the first indication, bevacizumab has been approved for a variety approved by FDA for later treatment after bevacizumab mono-
of other cancers as monotherapy, as a surgical adjuvant, or in therapy in platinum-sensitive recurrent epithelial ovarian cancer in
combination with chemotherapy, and more potential in anti- 2016.44,75 Then in 2020, bevacizumab was approved for untreated
angiogenic therapy is being tested through clinical trials.381 locally advanced or metastatic RCC in combination with mono-
Moreover, because of excellent anti-angiogenic activity, bevaci- clonal antibody atezolizumab, an immune checkpoint inhibitor of
zumab has achieved satisfactory results in several clinical trials by PD-L1.75 Bevacizumab is an anti-angiogenic drug with excellent

Liu et al.
17
Table 2. Current status of potential angiogenic inhibitors in clinical development
Agents Targets Phase Status Conditions or diseases Trial ID
Antibodies
Bemarituzumab (FPA144) FGFR-2 I Not yet Solid tumors (unspecified) NCT05325866
recruiting
III Recruiting GC or CEJ adenocarcinoma NCT05052801
JY-025 VEGFR-2 II/III Not yet NSCLC with EGFR 19 exon deletion or 21 exon mutation NCT04874844
recruiting
BAT-5906 VEGFR III Not yet wAMD NCT05439629
recruiting
II Completed wAMD NCT05141994
I/II Recruiting DME NCT04772105
Olinvacimab VEGFR-2 II Recruiting Metastatic TNBC NCT04986852
I/II Not yet Metastatic CRC who failed two prior standard NCT04751955
recruiting chemotherapies
Ak109 VEGFR-2 I/II Recruiting Advanced solid tumor NCT05142423
I/II Recruiting Advanced gastric adenocarcinoma or GEJ adenocarcinoma NCT04982276
I Unknown Advanced solid tumors NCT04547205
CTX-009 (ABL001) VEGF-A, Dll-4 I/II Recruiting Advanced or metastatic solid tumors; unresectable NCT04492033
advanced, metastatic or recurrent BTC
NOV-1105 (YYB-101) HGFR I/II Recruiting Metastatic or recurrent CRC NCT04368507
MCLA-129 c-Met, EGFR I/II Recruiting Advanced NSCLC or other solid tumors NCT04930432
I/II Recruiting Metastatic or advanced NSCLC, HNSCC or other solid tumors NCT04868877
SYD-3521 (BYON3521) c-Met I Recruiting Locally advanced or metastatic solid tumors NCT05323045
VRDN-001 IGF-1 I/II Recruiting TED NCT05176639
Oligonucleotide agents
IGV-001 – II Not yet GBM or GBM multiforme NCT04485949
recruiting
Anti-angiogenic fusion proteins
9MW-0813 VEGFR III Recruiting DME NCT05324774
I Completed DME NCT05324592
Tyrosine kinase inhibitors
Surufatinib VEGFR-1/-2/-3, II Recruiting Advanced CRC who failed front-line anti-angiogenic TKI NCT05372198
CSF1R, FGFR-1 therapy
II Recruiting Advanced HCC NCT05171439
II Recruiting HR+ unresectable metastatic BC refractory to endocrine NCT05186545
therapy
II Recruiting High-grade advanced-neuroendocrine neoplasm NCT05165407
II Not yet Inoperable or metastatic advanced intrahepatic NCT05236699
recruiting cholangiocarcinoma (ICC)
II Not yet OC with platinum-resistance and received prior PARP NCT05494580
recruiting inhibitors
II Not yet Advanced gastric adenocarcinoma or GEJ adenocarcinoma NCT05235906
recruiting
PDGFR-α, c-Kit - Approved Locally advanced unresectable or metastatic GIST NCT03862885

IV GIST NCT04825574

Liu et al.
18
Table 2. continued
Avapritinib (BLU-285) Active, not

recruiting
II Recruiting Locally advanced or metastatic malignant solid tumors with NCT04771520
c-Kit or PDGFR-α mutation-positive
II Recruiting Chinese patients with GIST NCT05381753
II Active, not Indolent systemic mastocytosis NCT03731260
recruiting
I/II Recruiting Solid tumors with mutations in c-Kit or PDGFR-α, or gliomas NCT04773782
with the H3K27M mutation
I/II Active, not Chinese subjects with unresectable or metastatic GIST NCT04254939
recruiting
I Recruiting Metastatic or unresectable GIST, recurrent gliomas, or other NCT04908176
c-Kit mutant tumors
Olverembatinib (GZD824) Bcr-Abl, c-Kit III Recruiting CML in chronic phase who are resistant and/or intolerant to NCT05311943
at least two second-generation tyrosine kinase inhibitors
II Recruiting Myeloproliferative neoplasms, ALL or AML with FGFR1 NCT05521204
rearrangement
II Recruiting Advanced CML NCT05376852
II Not yet Ph+ ALL NCT05466175
recruiting
I Not yet Relapsed or refractory Ph+ ALL NCT05495035
recruiting
Pemigatinib FGFR-1/-2/-3 III Recruiting Unresectable or metastatic cholangiocarcinoma with FGFR2 NCT03656536
rearrangement
II Completed Advanced/Metastatic or surgically unresectable NCT02924376
cholangiocarcinoma with FGFR2 translocations who failed
previous therapy
II Recruiting Previously treated GBM or other primary central nervous NCT05267106
system tumors with FGFR1–3 alterations
II Recruiting GBM, or other primary CNS tumors, or adult-type diffuse NCT05267106
gliomas with FGFR mutation
II Recruiting Advanced NSCLC with FGFR alterations who have failed NCT05287386
standard therapy
II Recruiting Advanced GC or CRC with FGFR alterations who have failed NCT05202236
standard therapy
II Recruiting HER2 negative advanced BC with FGFR 1–3 alterations who NCT05560334
have failed standard therapy
II Recruiting Advanced gastrointestinal cancer (excluding BTC) with FGFR NCT05559775
1–3 alterations who have failed standard therapy
II Recruiting Relapsed or refractory advanced NSCLC with FGFR mutation NCT05253807
II Active, not Advanced or unresectable CRC with FGFR mutation NCT04096417
recruiting
II Active, not Advanced, metastatic or unresectable cholangiocarcinoma NCT04256980
recruiting
FGFR-1/-2/-3/-4 III Recruiting Advanced, metastatic, or recurrent unresectable NCT04093362
cholangiocarcinoma harboring FGFR2 gene rearrangements
III Recruiting Advanced or metastatic STS NCT03784014
II Recruiting Advanced or metastatic HCC with FGF19 positive NCT04828486

Liu et al.
19
Table 2. continued
Futibatinib II Recruiting Advanced/metastatic GC or GEJ cancer, myeloid or NCT04189445

lymphoid neoplasm, or other solid tumors with FGFR1
mutation
I/II Recruiting Advanced NSCLC, or other advanced or metastatic solid NCT04965818
tumors with KRas mutation
I/II Recruiting HER2 mutated NSCLC or other advanced solid tumors NCT05532696
Rogaratinib FGFR-1/-2/-3/-4 II/III Completed Locally advanced or metastatic urothelial carcinoma with NCT03410693
FGFR-positive
II Completed Cancer (unspecified) NCT04125693
II Recruiting Advanced GIST, STS NCT04595747
II Active, not Pretreated advanced SQCLC NCT03762122
recruiting
I Completed FGFR positive refractory, locally advanced or metastatic solid NCT03788603
tumors
I Recruiting Metastatic FGFR1/2/3 positive, hormone receptor positive NCT04483505
BC
Erdafitinib FGFR-1/-2/-3/-4 IV Recruiting Bladder cancer with FGFR mutation NCT05052372

II Recruiting Recurrent non-invasive bladder cancer with FGFR3 mutation NCT04917809
II Recruiting NSCLC with FGFR genetic alterations NCT03827850
II Recruiting Advanced solid tumors with FGFR alterations NCT04083976
II Active, not Advanced urothelial cancer with selected FGFR aberrations NCT05564416
recruiting
I/II Recruiting Relapsed refractory multiple myeloma NCT03732703
I Recruiting Bladder cancer with FGFR genetic alterations NCT05316155
I Recruiting Metastatic urothelial carcinoma with alterations in FGFR 2/3 NCT04963153
genes
Telatinib PDGFR-β, II Unknown Advanced HER2 negative advanced gastric or GEJ NCT03817411
c-Kit, VEGFR adenocarcinoma
II Recruiting Advanced GC, GEJ adenocarcinoma, or HCC NCT04798781

Liu et al.
20
Table 2. continued
Tepotinib c-Met II Recruiting Solid tumors with Met amplification or Met exon 14 skipping NCT04647838
mutation
II Recruiting Advanced or metastatic NSCLC with Met amplifications NCT03940703
I/II Recruiting Advanced NSCLC with Met mutation NCT04739358
I/II Recruiting advanced GC, GEJ cancer with Met amplified or Met exon 14 NCT05439993
alternated
I Completed Patients with hepatic impairment NCT03546608
I Not yet Brain tumors with Met alternations NCT05120960
recruiting
ALL acute lymphoblastic leukemia, AML acute myeloid leukemia, BC breast cancer, BTC biliary tract cancer, CML chronic myeloid leukemia, CRC colorectal cancer,
DME diabetic macular edema, GEJ gastroesophageal junction, GBM glioblastoma, GC gastric cancer, GIST gastrointestinal stromal tumor, HCC hepatocellular
carcinoma, HER2 human epidermal growth factor receptor 2, HNSCC head and neck squamous cell carcinoma, NSCLC non-small cell lung cancer, PARP poly
ADP-ribose polymerase, Ph+ AML Philadelphia chromosome-positive acute myeloid leukemia, RCC renal cell carcinoma, SQCLC squamous-cell non-small cell
lung cancer, STS soft tissue sarcoma, TNBC triple-negative breast cancer, TED thyroid eye disease, wAMD wet age-related macular degeneration
research and application value, which has great potential for Bevacizumab-awwb (Mvasi®) is the first anti-tumor biosimilar of
emerging combination therapies to synergy chemotherapeutic bevacizumab approved by FDA.388,389 Ranibizumab (Lucentis®) is a
48 kDa humanized anti-VEGF monoclonal antibody fragment,
drugs and immune checkpoint inhibitors.
which can bind all VEGF-A isoforms, including VEGF110, VEGF121,
Ramucirumab (Cyramza®) is a fully humanized IgG1 antibody
with a weight of 147 kDa, which targets the extracellular binding and VEGF165 (Table 1). Ranibizumab is a prevalent anti-angiogenic
domain of VEGFR-2 to disturb the potent VEGF signal in tumor agent in treating oculopathy (Table 1).
angiogenesis (Table 1).382,383 As the first antibody targeted VEGFR-
2, ramucirumab significantly improved the median OS (5.2 months Anti-angiogenic oligonucleotide derivatives. Oligonucleotides are
vs. placebo 3.8 months) and PFS (2.1 months vs. placebo nucleic acid polymers that regulates gene expression and have
1.3 months) rates of patients (adults with advanced or unresect- specially designed sequences, including antisense oligonucleo-
tides (ASOs), siRNA (small interfering RNA), microRNA and
able gastric and gastroesophageal junction adenocarcinoma) in a
prospective, double-blind and placebo-controlled a phase III aptamers. Pegaptanib (Macugen®) is a 50 kDa VEGF-A targeted
REGARD clinical trial. Furthermore, it prolonged the median OS RNA aptamer, which has been approved for angiogenic age-
related macular degeneration in December 2004, leading to good
(9.6 months vs. 7.4 months) and PFS (4.4 months vs. 2.86 months)
tolerability and negligible local adverse effects of AMD patients
rates of homogeneous patients in a randomized, double-blind and
placebo-controlled a phase III RAINBOW trial through a combina- through intravitreous injections (Table 1).390
tion with paclitaxel.382 In 2014, ramucirumab was approved by
Anti-angiogenic recombinant fusion proteins. Fusion proteins are
FDA for previously treated advanced gastric or gastroesophageal
junction (GEJ) adenocarcinoma. Additionally, the first-line therapy complexes from binding the Fc segment of immunoglobulin to a
for metastatic CRC is a combination of ramucirumab and a biologically active functional protein molecule through genetic
modified FOLFOX-6 regimen (mFOLFOX-6), which demonstrated engineering technology. Aflibercept (Eylea®) is a recombinant
decoy receptor targeted VEGF, which is combined of the
gratifying safety and efficacy in a phase II clinical trial
(NCT00862784).384 extracellular VEGFR domain (VEGFR-1 Ig2 region and VEGFR-2
Olaratumab (Lartruvo®) is a 154 kDa fully recombinant human Ig3 region) and the Fc segment of human immunoglobulin G1
IgG1 monoclonal antibody with high affinity to PDGFRα, which is (IgG1) and has long half-life in anti-angiogenesis (Table 1).
Aflibercept inhibits the binding and activation of the VEGF family
the first-line drug approved by FDA for soft tissue sarcoma (STS)
(Table 1).385 STS is a relatively rare malignancy that occurs in and natural VEGFR by specifically blocking VEGF-A and most
connective tissue. In a randomized ANNOUNCE clinical trial among proangiogenic cytokines, thereby inhibiting division and prolifera-
tion of ECs, reducing vascular permeability, and is commonly used
509 patients, the addition of olaratumab did not significantly
improve the OS rate (doxorubicin plus olaratumab 20.4 months vs. in non-neoplastic angiogenic disease like AMD, DR, and
doxorubicin plus placebo 19.7 months) of advanced STS DME.380,391 Ziv-aflibercept is an adaptive variant of aflibercept,
patients.386,387 which has lower pH and higher osmolality (Table 1). It has been

Liu et al.
21
approved by FDA for the treatment of metastatic CRC patients step structural modification.406,407 Sorafenib (Table 1) is an orally
who are resistant to or have progressed following an oxaliplatin- available type II multi-targeted angiogenic inhibitor with pyridine
containing regimen.392–394 carboxamide (Raf1 IC50 = 6 nM, bRaf IC50 = 22 nM, bRafV600E
IC50 = 38 nM, VEGFR-1/-2/-3 IC50 = 26/90/20 nM, PDGFR-β
Anti-angiogenic mTOR inhibitor. Everolimus (RAD001) is an oral IC50 = 57 nM), which deactivates downstream Ras/Raf/MEK/ERK
analog of rapamycin that inhibits proliferation and induces pathway by blocking Raf and the autophosphorylation of kinase
apoptosis and autophagy of tumor cells through indirectly receptors including VEGFR, PDGFR, c-Kit, and RET, subsequently
blocked mTOR (Table 1). mTOR is a serine/threonine (Ser/Thr) inhibiting proliferation, invasion, metastasis, and angiogenesis of
kinase, which plays a pivotal role in tumor cell proliferation and the tumor.408,409 In December 2005, sorafenib was approved by
angiogenesis through cooperating with PI3K/AKT signaling path- FDA for patients with advanced RCC according to a phase II
way.395 Everolimus forms a complex with cyclophilin FKBP-12 to TARGET clinical trial, in which sorafenib improved PFS rate
specifically bind mTOR, and then inhibits downstream signals (5.5 months) of advanced clear-cell RCC patients compared with
through composing the mTORC1 with raptor and mLST8.396 In a a placebo (2.8 months) alone (NCT00073307).410 However, the
phase II clinical trial in predominantly clear cell RCC patients who toxicity increased a lot due to the pan-inhibition of multiple
had received pre-treatment or less, and had progressive measur- kinases. As the first anti-angiogenic small molecule tyrosine kinase
able metastatic disease, everolimus achieved some surprising inhibitor, sorafenib remarkably promoted the subsequent devel-
results with a median PFS of 11.2 months and a median OS of opment and clinical research of anti-angiogenic small molecule
22.1 months.397 In a randomized, double-blind, and placebo- agents, in order to enhance the selectivity and efficacy of the
controlled phase III trial (NCT00410124), everolimus prolonged PFS drugs and reduce toxicity.
rate of metastatic CRC patients whose disease had deteriorated Sunitinib is an indole-2-one multi-targeted kinase inhibitor from
after being treated with VEGFR-2 inhibitors sorafenib or sunitinib, HTS that targets VEGFR-1/-2/-3 (VEGFR-2 IC50 = 80 nM), Flt-3, c-Kit,
contributing to the launch of everolimus.397 RET, PDGFR-α/-β (PDGFR-β IC50 = 2 nM) (Table 1), and it was the
Temsirolimus (Table 1) is the other small molecule inhibitors of first TKI approved for treating patients with advanced pancreatic
mTOR, and part of the PI3K/AKT pathway involved in tumor cell neuroendocrine tumors (pNET) based on a randomized phase III
proliferation and angiogenesis approved by FDA for advanced trial (NCT00428597).411 Besides, sunitinib became the first and
RCC. And it also approved for relapsed or refractory mantle cell only adjuvant treatment approved by FDA in 2017 for adult
lymphoma/non-Hodgkins lymphoma by European Union. patients with high-risk recurrent RCC after nephrectomy because
the median disease-free survival (DFS) was increased by 1.2 years
Anti-angiogenic immunosuppressants. Thalidomide (Thalomid®) in a double-blind phase III clinical trial (NCT00375674).412
was synthesized by the CIBA pharmaceutical company in 1954 Pazopanib (Table 1) is an oral angiogenic inhibitor that primarily
and was initially used for mitigating morning sickness as a non- inhibits VEGFR-1 (IC50 = 10 nM), VEGFR-2 (IC50 = 30 nM), VEGFR-3
addictive and non-barbiturate tranquilizer (Table 1).398 However, it (IC50 = 47 nM), PDGFR-α (IC50 = 71 nM), PDGFR-β (IC50 = 84 nM),
was withdrawn by FDA due to serious teratogenic events and the stem-cell factor receptor c-Kit (IC50 = 74 nM).413,414
(fundamentally attributed to chiral isomers) reported in the early Pazopanib was firstly enrolled in clinical treatment by FDA for
1960s. But the research on thalidomide was not terminated, in patients with advanced RCC on a basis of a randomized and
1998, thalidomide was approved for erythema nodosum leprosum double-blind phase III trial (NCT00334282), in which PFS rate was
(ENL) after a series of pharmacological studies.399 Concurrently, increased five months compared with placebo.415 However, the
the metabolite of thalidomide was shown to have anti-microvessel advantage of pazopanib was not shown in patients with advanced
formation activity both in human and rabbit models.400 And it was NSCLC in a phase III clinical trial (NCT01208064).416 The OS and
not until 2006 that thalidomide received approval from FDA for PFS rates of patients who had received standard first-line
multiple myeloma (MM) based on a phase III clinical trial platinum-based chemotherapy were not conspicuously improved,
combined with dexamethasone.401 Another unexpected harvest but several serious adverse events were increased obviously like
is that thalidomide sensitizes icotinib to increase apoptosis and hypertension.
prevent migration in humanized NSCLC cell lines PC9 and A549, Vandetanib (Table 1), a derivative of 4-anilinoquinazoline, which
indicating that it has the potential to treat lung cancer.402 is an orally active angiogenic inhibitor with potent inhibitory
Lenalidomide (Revlimid®) was invented to reduce toxicity and efficacy against VEGFR-2 (IC50 = 40 nM), VEGFR-3 (IC50 = 10 nM),
enhance efficiency of thalidomide, which can specifically inhibit EGFR (IC50 = 0.5 μM), and Ret (IC50 = 0.1 μM) and other tyrosine
the growth of mature B cell lymphomas (like MM) and induce IL-2 kinases.417,418 However, vandetanib was initially marketed for
release from T cells (Table 1).403,404 In addition to anti-MM NSCLC, which was withdrawn by the FDA due to disappointing
treatment, lenalidomide has been approved by FDA for mantle phase III clinical trial results in 2009.419–421 Fortunately, vandetanib
cell lymphoma (MCL) in 2013, because it demonstrated consistent was approved for patients with unresectable locally advanced or
efficacy and safety of heavily pretreated patients with advanced- metastatic MTC in 2011 based on moderate clinical results of
stage relapsed/refractory MCL in multiple phase II trials.405 enhancive median rates of OS and PFS (NCT00410761).422
Regorafenib is a potent VEGFR-2 inhibitor with pyridine
Angiogenic small molecule TKIs. Since the first kinase inhibitor carboxamide derived from sorafenib structural modifications
imatinib significantly reduced adverse events and improved the (Table 1).423,424 In the kinase inhibition assay, regorafenib exhibits
prognosis of patients with chronic myeloid leukemia (CML) in multiple kinase inhibition capabilities (VEGFR-1 IC50 = 13 nM,
2001,381 the importance of kinases in tumorigenesis has attracted VEGFR-2 IC50 = 4.2 nM, VEGFR-3 IC50 = 46 nM, PDGFR-β
wide attention. In the early years, tyrosine kinase inhibitors IC50 = 22 nM, FGFR-1 IC50 = 202 nM, c-Kit IC50 = 7 nM, Ret
approved for anti-angiogenesis were developed with different IC50 = 1.5 nM, Raf1 IC50 = 2.5 nM).425 Regorafenib was firstly
spectrums of tyrosine kinases (Table 1), which block receptors marketed in 2012 and approved by FDA for patients with
phosphorylation and suppress transduction of downstream metastatic CRC because it dramatically stabilized the disease of
signaling pathways (PI3K/AKT/mTOR, Ras/Raf/MEK/ERK, p38 MAPK, 207 patients (41%) in a crucial phase III clinical trial
and JAK/STAT, shown in Fig. 4) by specifically blocking transmem- (NCT01103323).426 In 2017, the FDA expanded another indication
brane receptors, inhibiting angiogenesis and progression of of regorafenib for the treatment of HCC patients who had been
the tumor. treated with sorafenib (NCT01774344).427 In a latest study, the
Originally defined as a Raf inhibitor, sorafenib was obtained researcher reported that regorafenib could regulate macrophage
from a long period of high-throughput screening (HTS) and four- polarization through the p38 kinase/Creb1/Klf4 pathway,

Liu et al.
22
enhancing anti-tumor immunity independent of the angiogenic cells (NK cells) and macrophages. Owing to this natural property of
process.428 lacking the FUT8 gene, bemarituzumab can enhance antibody-
Cabozantinib is a selective angiogenic inhibitor with a high independent cell-mediated cytotoxicity (ADCC) against tumor
affinity to VEGFR-2 (IC50 = 0.035 nM), c-Met (IC50 = 1.3 nM), c-Kit models with FGFR-2b over-expression. In the early phase I clinical
(IC50 = 4.6 nM), Tie-2 (IC50 = 14.3 nM), Flt-3 (IC50 = 11.3 nM), and trials (NCT02318329, NCT03343301), the desirable safety, tolerance
Ret (IC50 = 5.2 nM), which is a bismethoxyquinoline analog (Table and pharmacokinetic characterization of bemarituzumab was
1).429,430 Because of the ability to inhibit autophosphorylation of demonstrated in gastrointestinal adenocarcinoma (GEA) and GC
VEGFR-2 and c-Met, cabozantinib exhibited decent anti-tumor, patients with FGFR-2b over-expression, leading to phase II clinical
anti-metastatic, and anti-angiogenic activities in preclinical trial of bemarituzumab.452,453 In a randomized, double-blind, and
models. Up to now, cabozantinib has been ratified for several placebo-controlled phase II trial (NCT03694522), the overall
most common angiogenic carcinomas (NCT01908426, efficacy of bemarituzumab is satisfactory, although the median
NCT01865747).431,432 A randomized and open-label phase III PFS rate only prolonged 2.1 months in patients with FGFR2b-
clinical trial has shown that combination of immune checkpoint selected GC or GEJ adenocarcinoma compared with the placebo
inhibitors with cabozantinib significantly improved the OS and group.454 The statistical significance of bemarituzumab will be
PFS rates of patients with clear-cell and advanced RCC rather than testified in the randomized and double-blind phase III clinical trial
sunitinib (NCT03141177).433 in GC and GEJ patients with untreated advanced diseases
Lenvatinib, an oral quinoline multi-targeted kinase inhibitor (NCT05052801).
against VEGFRs (VEGFR-2, IC50 = 4.0 nM and VEGFR-3, Avapritinib (BLU-285) is a selective and oral kinase inhibitor that
IC50 = 5.2 nM), PDGFRs, c-Kit (IC50 = 0.1 μM), RET, and FGFRs, targets PDGFR-α and c-Kit (Table 2), which has been approved by
inhibits angiogenesis induced by Ret mutation and lymphogen- FDA for GIST, systemic mastocytosis, and solid tumors, especially
esis mediated by VEGFR-3 (Table 1).434,435 In 2016, the combina- for adult patients with metastatic or unresectable GIST carrying
tion of lenvatinib with mTOR inhibitor everolimus (Table 1) was PDGFR-α 18 exon mutations.455 In xenograft models of GIST, the
approved for advanced RCC (NCT01136733).436,437 In 2021, the anti-tumor effects of avapritinib were significantly better than
combination of lenvatinib with pembrolizumab (PD-1 antibody) imatinib or regorafenib because avapritinib could potently
became the first-line treatment for adult patients with advanced obstruct the autophosphorylation of Kit D816V and PDGFR-α
RCC due to the significantly enhanced PFS and OS rates compared D842V, and activation of downstream signals like AKT and
to sunitinib in a randomized phase III clinical trial with 1069 STAT3.456 In a two-part and open-label NAVIGATOR clinical trial
patients (NCT02811861).438 Whether the combination of lenvati- (NCT02508532), avapritinib exhibited excellent anti-tumor efficacy,
nib and other immune checkpoint inhibitors can be used for HCC safety, and tolerance in unresectable GIST patients with PDGFR-α
is in evaluation through several phases III clinical trials D842V mutation. The launch of avapritinib resulted in an
(NCT03713593, NCT04039607).439 unprecedented, durable clinical benefit to GIST patients with
Axitinib (Table 1) is a novel selective angiogenic inhibitor PDGFRA D842V-mutation.457–459 However, the overall effects of
targeted VEGFR-1 (IC50 = 0.1 nM), VEGFR-2 (IC50 = 0.2 nM), VEGFR- avapritinib were not superior to regorafenib in patients with
3 (IC50 = 0.2 nM), PDGFR-α (IC50 = 5 nM), PDGFR-β (IC50 = 1.6 nM), locally advanced unresectable or metastatic GIST in a randomized
and c-Kit (IC50 = 1.7 nM), which is currently only approved for RCC, VOYAGER phase III study (NCT02508532).460 The phase IV clinical
and other indications are still in a exploratory stage.440 Ponatinib trial has been planned to assess the effect of avapritinib on a
(Table 1) was originally designed as an ABL inhibitor targeted ALL larger group of participants. The most common adverse events
and CML patients with T315I mutation (ABL, IC50 = 0.37 nM; include nausea, vomiting, decreased appetite, diarrhea, fatigue,
ABLT315I, IC50 = 2 nM).441,442 It also potently inhibits angiogenesis- cognitive impairment, hair color changes, lacrimation, abdominal
related kinases, such as VEGFR-1 (IC50 = 3.7 nM), VEGFR-2 pain, constipation, rash, and dizziness.
(IC50 = 1.5 nM), VEGFR-3 (IC50 = 2.3 nM), PDGFR-α (IC50 = 1.1 nM), Erdafitinib (JNJ-42756493) (Table 2), a selective angiogenic TKI
PDGFR-β (IC50 = 7.7 nM), FGFR-1 (IC50 = 2 nM), FGFR-2 with high affinity to FGFR-1 (IC50 = 1.2 nM), FGFR-2 (IC50 = 2.5 nM),
(IC50 = 2 nM), FGFR-4 (IC50 = 8 nM), and others.443,444 Relevant FGFR-3 (IC50 = 3.0 nM), and FGFR-4 (IC50 = 5.7 nM).461,462 As an
research of ponatinib for other angiogenic cancers have not FDA-accelerated drug, erdafitinib primarily aims to adult patients
reported.445 Apatinib and nintedanib (VEGFR-2, IC50 = 13 nM) are with locally advanced or metastatic urothelial cancer who carrying
potent angiogenic inhibitors with encouraging preclinical and FGFR-2 or FGFR-3 gene mutations after platinum chemother-
clinical data in the treatment of various solid tumors through a apy.463 Up to now, several phase II and phase III clinical trials in
high kinase inhibitory level (Table 1).446–450 patients with bladder cancer are still ongoing (NCT03390504,
Other inhibitors with anti-angiogenesis approved by FDA NCT04172675, NCT02365597, NCT02465060, NCT03473743). The
including: Interferon α (Intron® A and Roferon®), TAS-102 (Lonsurf®) clinical potency of erdafitinib in NSCLC, lymphoma, cholangio-
and rhEndostatin (Endostar®/Endu-available only in China) from carcinoma, liver cancer, prostate cancer, esophageal cancer, or
https://angio.org/. other carcinomas is undergoing investigation. Common adverse
events include hyponatremia, oral mucosal disease, and weakness,
Potential anti-angiogenic agents in the clinical evaluation in the but no treatment-related deaths.461,464 Similar to erdafitinib,
latest three years pemigatinib, futibatinib and rogaratinib are also pan-FGFR
In recent years, research on highly selective targeted drugs has tyrosine kinase inhibitors, which play a role in angiogenesis
also made considerable progress in anti-angiogenic therapy (Table inhibition (Table 2). Moreover, these FGFR inhibitors inhibits cell
2). Individual drugs have successfully passed preliminary clinical proliferation in FGFR-addicted cancer cells with FGFR aberrations
trials about the safety, tolerability and effectiveness of drugs, and such as gene amplification, activating mutations and chromoso-
entered into phase III or even phase IV clinical evaluation, such as mal translocations.465
bemarituzumab (FPA144), avapritinib and erdafitinib. (All of the
drug information is from https://clinicaltrials.gov.) Potential anti-angiogenic small molecules reported in the latest
Bemarituzumab (FPA144) is the first recombinant humanized three years
IgG1 monoclonal antibody (Table 2), which obstructs ligand In addition to the marketed and clinically evaluated anti-
binding and downstream signaling activation by blocking the IgG angiogenic drugs described previously, some novel TKIs have
III region of the FGFR-2b isoform.451 As a glycosylated derivative, shown potent biological activity in the initial evaluation in kinase
bemarituzumab has a higher affinity for Fc γ receptor IIIa (FcγRIIIa), assay, which may be promising to become clinical candidates. Like
which is commonly expressed on immune cells like natural killer compounds 23, 24, and 25, are selective inhibitors with good

Liu et al.
23
Table 3. Selected small molecules with excellent kinase inhibition activity
Compounds Chemical Structures Targets IC50 References

471
1 VEGFR-2 0.19 nM
472
2 VEGFR-2 2.6 nM
473
3 VEGFR-2 3.2 nM
474
4 VEGFR-2 3.2 nM
475
5 VEGFR-2 27 nM
476
6 VEGFR-2 66 nM
7 VEGFR-2 0.12 μM 477
8 VEGFR-2 0.12 μM 478
9 VEGFR-2 0.23 μM 479

Liu et al.
24
Table 3. continued
10 VEGFR-2 0.29 μM 480
11 VEGFR-2 0.31 μM 481
481
12 VEGFR-2 24.7 nM
PDGFR-β 16.1 nM
482
13 VEGFR-2 7 nM
FGFR-1 69 nM
PDGFR-β 31 nM
14 VEGFR-2 0.18 μM 481
FGFR-1 0.23 μM
PDGFR-β 0.1 μM
481,483
15 VEGFR-2 435 nM
c-Met 654 nM
PDGFR-β 371 nM
484,485
16 VEGFR-2 1.05 nM
Tie-2 2.47 nM
EphB4 0.27 nM
486
17 VEGFR-2 1.85 nM
Tie-2 0.73 nM
EphB4 2.99 nM

Liu et al.
25
Table 3. continued
487
18 VEGFR-2 2.35 nM
Tie-2 5.63 nM
EphB4 3.87 nM
19 VEGFR-2 5 μM 488
HDAC4 0.36 μM
489
20 FGFR-4 5.4 nM
490
21 FGFR-1 1.0 nM
FGFR-2 4.5 nM
VEGFR-2 2.9 nM
22 FGFR-1 0.6 μM 491
FGFR-2 1.3 μM
FGFR-3 4.1 μM
23 HIF-1α 0.6 μM 492

Liu et al.
26
Table 3. continued
24 HIF-1α 0.32 μM 493
25 HIF-1α 0.6 μM 494
inhibitory activity targeted HIF-α. TME is a highly complex of other angiogenic modalities, genetic or phenotypic mutations,
ecosystem of cellular and noncellular components, which is stromal autophagy and induction of EMT.
broadly related to tumor invasion and recurrence.466,467 In recent
years, research on tumor microenvironment and targeted therapy Drug resistance
has indicated that limiting tumor deterioration and angiogenesis Drug resistance is a dominant difficulty that consistently limits the
by inhibiting HIF expression to downregulate the level of some clinical outcomes in targeted anti-angiogenic therapy, which can be
angiogenic factors may be a valuable strategy.468–470 Table 3 divided into congenital resistance and acquired resistance (Fig. 8).503
summarizes the structures of reported molecules and related Congenital drug resistance is defined as the inherent insensitivity to
references, which could be beneficial to the research on drugs of patients, which may be related to the genes of patients and
angiogenic inhibitors. tumors. Acquired drug resistance has been comprehensively
analyzed by researchers through cytological and molecular studies.
These unique mechanisms include: (a) upregulation of compensa-
LIMITATIONS AND CHALLENGES OF ANTI-ANGIOGENIC tory pro-angiogenic signaling pathways in tumor tissue (HGF, bFGF,
THERAPY VEGF-C, PlGF, angiopoietins, and Dll-4 have been widely testified
Angiogenic inhibitors used in cancer therapy by affecting the that upregulated in various tumors with drug resistance);133,504,505
formation of new blood vessels in tumors, which have expended a (b) recruiting bone marrow-derived endothelial progenitor cells,506
new field for the treatment of a wide range of solid tumors. pericyte progenitor cells,507 tumor-associated macrophages,508 and
However, there are still some shortcomings in anti-angiogenic immature monocytic cells, which can maintain the formation of
therapy due to the complex mechanisms of tumor angiogenesis blood vessels; (c) recruitment of perivascular cells (like pericytes),
and limited research, including tumor relapse,495 drug resis- which can cover immature tumor blood vessels to prevent
tance,496,497 lack of bio-markers,496 short-acting efficacy,27,28 and destruction by anti-angiogenic drugs;509 (d) unconventional angio-
several serious adverse events.498,499 genic processes like vessel co-option,510–513 vessel mimicry and
intussusceptive angiogenesis.77,514,515 Additionally, drug resistance
Limited therapeutic efficacy also involves high heterogeneity of tumor tissue and TME,
It was initially assumed that anti-angiogenic therapy might not be endothelial heterogeneity,516 autophagy of tumor cells, differentia-
toxic compared with other chemotherapeutic agents owing to tion of cancer stem cells,517 infiltration of stromal cells,518 tumor
genetic stability and quiescence of ECs under normal physiological types, gene mutations of tumors or targets, development stage of
conditions and the selectivity of targeted drugs. However, this was the tumor, medication history of patients, and other factors, all of
proved to be a miscalculation. Common serious adverse events which can affect the response and tolerance of patients to anti-
such as hypertension, proteinuria, lymphopenia, thrombocytope- tumor therapy.
nia, leukopenia, neutropenia, and some physical abnormalities
caused by different drugs have appeared in a number of different Lack of valid biomarkers
clinical treatments (Table 1), which may affect the tolerance of The application of biomarkers is a powerful adjuvant means which
patients and even lead to treatment termination.45,54,500 This are essential for disease identification, early diagnosis and
requires further optimization of the structures of angiogenic prevention, and drug treatment monitoring. Biomarkers refer to
inhibitors to better target selectivity, or other techniques to biochemical indicators of normal physiological or pathogenic
increase drug delivery to tumor tissue while bypassing normal processes to furnish the structural or functional changes of
tissue, such as nano-preparations. systems, organs, tissues, cells and subcells, and can also be used
In addition, angiogenic inhibitors have a result on controlling for disease diagnosis, disease stage, or evaluating the safety and
growth and spread of tumor in the short term by blocking the blood efficacy of a drug or regimen among targeted population.519 In
supply (which is manifested in clinical treatment as increased PFS), clinical practice, there are at least six categories of biomarkers
but the long-term result is an increased risk of tumor local invasion including diagnostic, predictive, prognostic, pharmacodynamic,
and distant metastasis induced by hypoxia, as well as the probability safety and monitoring biomarkers owing to different bio-functions.
of revascularization and tumor resurgence after discontinuation of For example, HER2 is a diagnostic indicator for breast cancer typing,
sustained treatment (which manifests as an insignificant or even and levels of PD-L1 is used to predict the efficacy of immune
unchanged increase in OS).501,502 Some molecular events under- checkpoint inhibitors (ICIs). Despite considerable efforts, there are
stood by researchers within the past few decades could be the few biomarkers responding to angiogenesis approved for clinical
activation of alternative pro-angiogenic molecules, the development application.172,519,520 Given the variable results from anti-angiogenic

Liu et al.
27
Fig. 8 Mechanisms of drug resistance in anti-angiogenic therapy. Some patients are intrinsically non-responsive to anti-angiogenic therapy
while other patients who are initially responsive acquire adaptive resistance. The mechanisms that manifest acquired resistance to anti-
angiogenic therapy include: compensatory upregulation of alternative pro-angiogenic factors such as bFGF, PDGF, and PlGF within the tumor;
recruitment of bone marrow-derived endothelial progenitor cells to facilitate neovascularization; increased pericyte coverage protects tumor
blood vessels; autophagy helps tumor cells thrive in a hypoxic environment; increased invasiveness of the tumor promotes the distant
metastasis and invasion of tumor cells through blood and lymphatic circulation. In addition, genetic mutations, vessel mimicry, vessel co-
option, and intussusception angiogenesis also contribute to drug resistance
treatments in the clinic, there is a need to characterize changes in characteristically synergistic or an additive manner targeting
the blood vessels and tumor microenvironment to detect and important signaling pathway. Diversified methods in anti-cancer
prevent tumor escape, and to monitor the patients’ response to therapy provide more options for clinical treatment and make
drugs and the advances in treatment.521,522 It is an inevitable trend strong alliances possible.
to explore effective cancer-specific biomarkers responding to In recent several years, one of the prevalent research direction is
angiogenic system to enhance the efficacy of anti-angiogenic the combination of angiogenic inhibitors and immune checkpoint
regime and anti-cancer therapy. With the advancement in bio- inhibitors, in which better clinical benefits from HCC and RCC
analytical technology and clinical bio-chemistry, tissue and cell patients treated with programmed cell death 1 (PD-1) and VEGFR-
concentrations of some angiogenic mediators, circulating ECs, 2 inhibitors than with monotherapy.467,525,526 Tumors can induce
circulating progenitor cells, CT imaging of blood flow and blood immune tolerance and limit proliferation and activation of T cells
volume have been shown to have potential as biomarkers, but more during growth and metastasis by using immune checkpoints (ICs)
clinical trials are needed to validate their prospective. Developing produced on T cells to accomplish immune escape. Blockade with
efficient biomarkers for diagnosing the progression and stage of different immune checkpoint inhibitors may activate the body’s
cancer and identifying mechanisms of tumor angiogenesis and drug immune system and weaken immunosuppression in TME against
resistance, in order to benefit drug selection, balance efficacy and tumor cells by promoting the activation and proliferation of
toxicity, and simplify anti-cancer therapy. Actually, due to numerous T cells, including PD-1, programmed cell death-ligand 1 (PD-L1)
factors such as the complexity of tumor angiogenesis, heterogeneity and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibi-
and variability of tumors, the unpredictability of response or toxicity, tors.525 As mentioned before, the tumor microenvironment is
and limitations of preclinical and clinical trials, the development of composed of tumor cells, cancer stem cells, immune cells,
biomarkers will be a great challenge. fibroblasts and other cells and their secretions, as well as non-
cellular components such as extracellular matrix. High levels of
VEGF in TME are not only crucial factors in inducing abnormaliza-
EMERGING APPROCHES TO FURTHER IMPROVE ANTI- tion and increasing permeability of tumor vessels, but also weaken
ANGIOGENIC THERAPY the anti-tumor effect of immune cells through multiple pathways
Combination therapy including: a) immune-activating cells and immune effector cells
Since the first angiogenic inhibitor bevacizumab approved for can be effectively blocked by VEGF, such as inhibiting maturation
treatment, combination therapy based on anti-angiogenic agents of dendritic cells (DCs), and inducing the failure and apoptosis of
has infiltrated anti-tumor field.523 Combination therapy is a cytotoxic T cells; b) the aggregation and activity of immunosup-
modality aiming to enhance anti-tumor efficacy through combin- pressive cells including regulatory T cells (Tregs), myeloid-derived
ing two or more therapeutic agents, including anti-angiogenic suppressor cells (MDSCs), M2-like tumor-associated macrophages
therapy combined with surgery, immunotherapy, chemotherapy, (M2 TAM) can be up-regulated by intratumoral VEGF; c) by
radiotherapy, genetherapy or (and) other targeted anti-tumor elevating the production of endothelial adhesion molecules and
agents.524 Compared with monotherapy, the combination of anti- up-regulating immune checkpoints, VEGF can generate a selective
tumor drugs improves the therapeutic efficacy in a endothelial barrier for cytotoxic T cells to prevent infiltration while

28
Table 4. Selected clinical trials of combination therapy
Interventions Cancers Phase Results NCT numbers
Successful clinical trials

ABI-007 plus bevacizumab vs. ABI-007 Metastatic BC II Promising PFS and an acceptable safety profile with no unanticipated NCT00394082
toxicities (combination vs. ABI-007: PFS 11.4 vs. 6.11 months, ORR 30%
vs. 14%)a
Docetaxel plus ramucirumab vs. plus placebo Locally advanced or metastatic urothelial III This combination significantly prolongs PFS with no unexpected toxic NCT02426125
carcinoma effects; PFS 4.07 vs. 2.76 monthsa.
Cisplatin or carboplatin, and etoposide plus sunitinib Extensive-stage small cell lung cancer I/II The addition of sunitinib prolongs PFS and OS; median OS (9.0 vs. 6.9 NCT00453154
months) and median PFS (3.7 vs. 2.1 months)a.
Docetaxel plus vandetanib vs. plus placebo Advanced NSCLC III This combination significantly improves PFS, median PFS 4.0 vs. 3.2 NCT00312377
monthsa.
Bevacizumab, carboplatin, paclitaxel plus Stage IV non-squamous NSCLC III The addition of atezolizumab to bevacizumab plus chemotherapy is NCT02366143
atezolizumab (ABCP) vs. BCP significant: median PFS 8.3 vs. 6.8 months; median OS 19.2 vs.
14.7 monthsa.
Atezolizumab plus bevacizumab vs. sorafenib Untreated locally advanced or metastatic III Atezolizumab-bevacizumab is better than sorafenib: OS at 12 months NCT03434379
HCC 67.2% vs. 54.6%; median PFS 6.8 vs. 4.3 monthsa.
Different chemotherapies (nab-paclitaxel; paclitaxel; Untreated locally recurrent inoperable or III The addition of pembrolizumab resulted in significantly longer PFS and NCT02819518
gemcitabine/carboplatin) plus pembrolizumab metastatic TNBC OS than chemotherapy-placebo in twice interim analysisb.
Lenvatinib plus pembrolizumab vs. doxorubicin Advanced endometrial cancer after failure of III The combination has significantly longer PFS and OS: median PFS 6.6 NCT03517449
platinum-based chemotherapy vs. 3.8 months; median OS 17.4 vs. 12.0 monthsb.
Liu et al.
Atezolizumab with or without cobimetinib vs. Metastatic CRC II Positive results in median OS: atezolizumab 7.10 months, atezolizumab NCT02788279
regorafenib plus cobimetinib 8.87 months, regorafenib 8.51 monthsa.
Unsuccessful or terminated clinical trials
Irinotecan and temozolomide plus bevacizumab Relapsed or refractory neuroblastoma II Expected and transient toxicities, but the addition of bevacizumab did NCT01114555
not improve response rates compared to irinotecan plus
temozolomidea.
FOLFOX6 plus bevacizumab Biliary system carcinoma II 1/8 patient with perforation of colon; impossible to get insurance NCT00881504
companies to cover bevacizumabc.
Ixabepilone plus bevacizumab Metastatic RCC II Well tolerated, with modest activity in second - or later-line mRCC, not NCT00923130
recommendeda.
Docetaxel plus sorafenib Advanced non-squamous cell NSCLC II Preliminary efficacy data was not encouraging, 4/5 patients with serious NCT00801801
adverse eventsc.
Temozolomide plus sorafenib Recurrent GBM II Well tolerated, but limited activity for recurrent GBMa. NCT00597493
Paclitaxel and carboplatin plus axitinib vs. plus Advanced lung cancer II Axitinib plus paclitaxel and carboplatin is worse than bevacizumab plus NCT00600821
bevacizumab paclitaxel and carboplatin: PFS 11.0 vs. 15.9 months; OS 18.1 vs.
21.6 monthsa.
Modified FOLFOX6 plus axitinib and/or bevacizumab Metastatic CRC II No improvements in combination with axitinib or axitinib/bevacizumab NCT00460603
compared to bevacizumab plus FOLFOX6: PFS 11.0 vs. 12.5 vs.15.9
months; OS 18.1 vs. 19.7 vs. 21.6 monthsa.
Chemotherapy (capecitabine or docetaxel) vs. TNBC II No improvements of sunitinib in median OS (9.4 vs. 10.5 months), NCT00246571
sunitinib objective response rates (3% vs. 7%)a.

Docetaxel plus vandetanib vs. plus placebo Transitional bladder cancer II The additional of vandetanib not significantly improve the outcomes: NCT00880334
median PFS 2.56 vs. 1.58 months; OS and ORR with no differencea.
Azacitidine plus durvalumab vs. azacitidine Untreated adults with higher-risk MDS or II More toxicities and without significant improvement in clinical NCT02775903
elder patients with AML outcomes than azacitidinea.
Metastatic pancreatic adenocarcinoma II NCT02879318
Liu et al.
29
Similar safety; non-statistically significant gain in OS than gemcitabine NCT00219557

NCT numbers facilitating the transport of immunosuppressive Tregs; d) redun-
AML acute myeloid leukemia, BC breast cancer, CRC colorectal cancer, FOLFOX6 oxaliplatin, calcium folinate and 5-fluorouracil, GBM glioblastoma, MDS myelodysplastic syndromes, NSCLC non-small cell lung
dant VEGF derived from tumor cells lead to disordered and leaky
vascular networks, which seriously affects the blood transport of
cytotoxic drugs and immunosuppressants.525,527,528 If immu-
notherapy is accompanied by anti-angiogenic drugs targeting
VEGF pathway, it reverses these immunosuppression caused by
VEGF and enhances the immune function of patients. At the same
time, it can neutralize excess VEGF, reconstruct the vascular
system of tumor tissue, normalize vascular network, promote the
No significant benefits from the addition of durvalumab and
blood transport of immunosuppressant, inhibit excessive angio-

genesis, reduce microvascular density, and limit tumor growth,
invasion and metastasis.529 Additionally, ICIs activate intratumoral
effector T cells, reshape the TME, improve immunity of host, and
up-regulate expression of γ-interferon,529 all of which are
conducive to vascular normalization. Some optimistic results of
combination therapy have been achieved in recent years (shown
in Table 4). For example, in a phase III clinical trial (NCT03434379),
the combination of bevacizumab with PD-1 inhibitor atezolizumab
significantly improved the OS and PFS rates of unresectable HCC
patients compared to sorafenib.530 And in multiple clinical trials of
combination therapy, the efficiency of PD-1 inhibitors (such as
cancer, ORR overall response rate, OS overall survival, PFS progression-free survival, RCC renal cell carcinoma, TNBC triple-negative breast cancer
alone: 6.9 vs. 5.6 monthsa.
nivolumab and pembrolizumab) combined with cabozantinib,

axitinib, or bevacizumab was much better than a single use of
sunitinib in patients with RCC, NSCLC, CRC and GIST.526 The
combination of anti-angiogenic and immune therapy has a
tremelimumabb.
positive significance to anti-cancer treatment according to

majority of clinical trials, especially patients with advanced
malignant tumors who are not sensitive, willing, or tolerant to
Phase Results
chemotherapy.526 But some common problems like effectiveness,

toxicity and tolerability of this combination modality need to be
optimized through further research on therapeutic dosage, time
and sequence among different patients.531–533 And mechanisms
II
of the positive loops between angiogenic inhibitors and ICIs

should be performed in a more in-depth and interconnected
manner to help develop new formulation and design clinical
studies, in order to encourage this promising strategy into one of
the most standard cancer therapeutic modality.
As mentioned before, although it has more damage to normal
cells, blood vessels and immune system due to the administration
Metastatic pancreatic cancer
with maximum tolerated dosage and poor tissue selectivity,

chemotherapy is an irreplaceable method for many advanced
patients with cancer metastasis to prolong the survival.534 With
the advancement of medical technology, clinical medicine and
pharmacy, it has been proven that the addition of anti-angiogenic
therapy or (and) emerging immunotherapy to chemotherapy may
win more benefits for patients. Angiogenic inhibitors normalize
Cancers
tumor blood vessels, reduce osmolality, alleviate local hypoxia,

restore the penetration and delivery of the drugs into tumor cells,
and also reduce the dose of administration and improve patient
Gemcitabine and nab-paclitaxel vs. gemcitabine, nab-
tolerance under the premise of effective chemotherapy, while ICIs

improve the immune system of patients and prevent “immune
escape” of tumors. Some relevant clinical trials with positive
paclitaxel plus durvalumab and tremelimumab
outcomes have been shown in Table 4. For example, a phase III

Gemcitabine plus axitinib vs. gemcitabine
clinical trial (NCT02366143) have shown that the addition of

atezolizumab (anti-PD-L1) greatly extended the OS (19.2 vs. 14.7
months), PFS (8.3 vs. 6.8 months) and OR (63.5% vs. 48.0%) rates of
NSCLC patients treated with bevacizumab, carboplatin and
paclitaxel.535 Although many optimistic results have been
reported, some failures cannot be neglected (shown in Table 4),
which underlines suitable drugs for compatibility, suitable primary
or auxiliary drugs, dosage and sequence of administration,
continued
individual differences in patients, and different stages and types

of tumors.533
Interventions
Another notable therapeutic method is an emerging adjuvant

Terminated
Completed
strategy - neoadjuvant chemotherapy (NACT), aiming to reduce

Ongoing
Table 4.
the tumor and kill invisible metastatic tumor cells through

systemic chemotherapy to facilitate subsequent surgery, radio-
b
a
therapy, and other treatments. Up to now, various NACT regimens

Liu et al.
30
(SOX, XELOX, FOLFOX) have been suggested with satisfactory administration, in order to break the “treatment deadlock” and
clinical results in primary or advanced tumors and lower risk of strive more opportunities for cancer patients.
progression, but some discouraging clinical evidence of NACT also With an in-depth understanding of tumor angiogenesis, tumor
observed in recent years (especially breast cancer).536–539 A review microenvironment, and drug resistance, these problems may be
from Perelmuter et al. summarized a number of potential solved in the near future. As an emerging strategy, anti-
mechanisms of chemoresistance in NACT, wherein, it is reported angiogenic therapy will achieve more clinical benefits for cancer
that NACT could stimulate cancer metastasis through inducing patients and anti-tumor therapy, and facilitate the clinical
angiogenesis, lymphangiogenesis and inflammatory infiltration, treatment of non-neoplastic angiogenesis-related diseases as well.
altering immune responses and worsening TME, and these
changes may induce secondary chemoresistance.540 Can addition
of angiogenic inhibitors and ICIs against this resistance? Theore- ACKNOWLEDGEMENTS
tically, it is promising, but massive efforts are also necessary, some This work was supported by the National Natural Science Foundation of China
clinical trials are already underway (NCT05554276, NCT04294511, (21102182), the Natural Science Foundation of Jiangsu Province (BK2012760, China),
NCT04606108, NCT05468242, NCT05202314). Fundamental Research Funds for the Central Universities (2632018ZD09, China), and
Excellent Science and Technology Innovation Team of Jiangsu Province Universities
in 2015 (China).
Multi-targeted anti-angiogenic agents
Apart from the means above, exploiting novel selective multi-
targeted kinase inhibitors is one of the current trendy research
AUTHOR CONTRIBUTIONS
directions. In tumor angiogenesis, various angiogenic tyrosine L.S. designed the review and revised the draft. Z.L.L., H.H.C., and L.L.Z. drafted the
kinases act synergistically to induce an array of intracellular manuscript and prepared the tables and figures. L.P.S. revised the manuscript. All
signaling cascades instead of working individually.541,542 So, authors have read and approved the article.
selective multi-targeted angiogenic TKIs might be used to
overcome compensatory angiogenesis and cross-talk of alter-
native angiogenic signals.543,544 The advantages of selective multi- ADDITIONAL INFORMATION
targeted kinase inhibitors include: (a) avoiding adverse events Competing interests: The authors declare no competing interests.
from broad-spectrum inhibitors; (b) exerting multiple anti-
angiogenic effects; (c) avoiding drug interactions; (d) forming
more stable pharmacokinetic characterization.545 REFERENCES
1. Larionova, I., Kazakova, E., Gerashchenko, T. & Kzhyshkowska, J. New angiogenic
Exploring endogenous biomolecules with anti-angiogenesis regulators produced by TAMs: perspective for pargeting tumor angiogenesis.
In normal tissue, anti-angiogenic molecules can balance the pro- Cancers 13, 3253 (2021).
angiogenic factors to maintain the homeostasis of the internal 2. Duran, C. L. et al. Molecular regulation of sprouting angiogenesis. Compr. Physiol.
8, 153–235 (2017).
environment. The active angiogenesis in tumor tissue is related to
3. Teleanu, R. I., Chircov, C., Grumezescu, A. M. & Teleanu, D. M. Tumor angio-
the over-activation of pro-angiogenic factors and the over- genesis and anti-angiogenic strategies for cancer treatment. J. Clin. Med. 9, 84
inhibition of anti-angiogenic mediators. Hence, endogenous (2019).
anti-angiogenic components or their derivatives may be con- 4. Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nat. Rev.
ducive to vascular normalization and therapeutic efficiency. For Drug Discov. 6, 273–286 (2007).
instance, endostatin is an enzymatic fragment of XVIII collagen 5. Smolen, J. S., Aletaha, D., Koeller, M., Weisman, M. H. & Emery, P. New therapies
with a molecular weight of about 20 kDa that was identified by O’ for treatment of rheumatoid arthritis. Lancet 370, 1861–1874 (2007).
Reilly and his colleagues in 1997.546 Endostatin can not only 6. Creamer, D., Jaggar, R., Allen, M., Bicknell, R. & Barker, J. Overexpression of the
regulate more than 12% of angiogenesis-related genes in the angiogenic factor platelet-derived endothelial cell growth factor/thymidine
phosphorylase in psoriatic epidermis. Br. J. Dermatol. 137, 851–855 (1997).
human genome but can also compete with FGFs to limit ECs
7. Costa, C., Incio, J. & Soares, R. Angiogenesis and chronic inflammation: cause or
proliferation and tumor development. Recombinant human consequence? Angiogenesis 10, 149–166 (2007).
endostatin is an angiogenic inhibitor with no cytotoxicity 8. Caldwell, R. B. et al. Vascular endothelial growth factor and diabetic retinopathy:
approved by the Chinese FDA for treating various cancers, pathophysiological mechanisms and treatment perspectives. Diabetes Metab.
including NSCLC.337,546 However, the clinical application of Res. Rev. 19, 442–455 (2003).
endostatin is not very accessible due to poor stability and 9. Ng, E. W. M. & Adamis, A. P. Targeting angiogenesis, the underlying disorder in
solubility, short half-lives, and difficult production problems. neovascular age-related macular degeneration. Can. J. Ophthalmol. 40, 352–368
According to current studies, other molecules also have anti- (2005).
angiogenic activities like angiostatin, thrombospondin-1/-2, TIMP, 10. Khosravi Shahi, P., Soria Lovelle, A. & Pérez Manga, G. Tumoral angiogenesis and
breast cancer. Clin. Transl. Oncol. 11, 138–142 (2009).
tumstatin, interferon, platelet factor 4, vasohibin, interleukin,
11. Zhong, M. et al. TIPE regulates VEGFR2 expression and promotes angiogenesis
chondromodulin, chemokines, pigment epithelial-derived factor, in colorectal cancer. Int. J. Biol. Sci. 16, 272–283 (2020).
isthmin1 (ISM1), carboxy-terminus of Hsc70 interacting protein 12. Hall, R. D., Le, T. M., Haggstrom, D. E. & Gentzler, R. D. Angiogenesis inhibition as
(CHIP), multimerin-2, and G-protein coupled receptor 56 a therapeutic strategy in non-small cell lung cancer (NSCLC). Transl. Lung Cancer
(GPR56).359,547–555 Res. 4, 515–523 (2015).
13. Zimna, A. & Kurpisz, M. Hypoxia-inducible factor-1 in physiological and patho-
physiological angiogenesis: applications and therapies. BioMed. Res. Int. 2015,
CONCLUSION 549412 (2015).
Angiogenesis is one of the key conditions for the proliferation, 14. Conway, E. M., Collen, D. & Carmeliet, P. Molecular mechanisms of blood vessel
growth. Cardiovasc. Res. 49, 507–521 (2001).
invasion, and metastasis of carcinomas and anti-angiogenic
15. Kalluri, R. Basement membranes: structure, assembly and role in tumour
treatment has gradually become a prevalent anti-tumor strategy angiogenesis. Nat. Rev. Cancer 3, 422–433 (2003).
with a criterion of vascular optimization. But some common issues 16. Gasparini, G., Longo, R., Toi, M. & Ferrara, N. Angiogenic inhibitors: a new
that cannot be ignored remain to be solved such as insufficient therapeutic strategy in oncology. Nat. Rev. Pract. Oncol. 2, 562–577 (2005).
therapeutic efficacy, reproducibility and popularization of treat- 17. Adams, R. H. & Alitalo, K. Molecular regulation of angiogenesis and lym-
ment modalities. These limitations encourage researchers to phangiogenesis. Nat. Rev. Mol. Cell Biol. 8, 464–478 (2007).
develop novel angiogenic inhibitor, explore the druggability of 18. Jain, R. K. Molecular regulation of vessel maturation. Nat. Med. 9, 685–693
more targets, validate specific biomarkers and optimize treatment (2003).

Liu et al.
31
19. Rowley, D. R. What might a stromal response mean to prostate cancer pro- 53. Chauhan, V. P. et al. Normalization of tumour blood vessels improves the
gression? Cancer Metastasis Rev. 17, 411–419 (1998). delivery of nanomedicines in a size-dependent manner. Nat. Nanotechnol. 7,
20. Liakouli, V. et al. The role of extracellular matrix components in angiogenesis 383–388 (2012).
and fibrosis: possible implication for Systemic Sclerosis. Mod. Rheumatol. 28, 54. Martin, J. D., Seano, G. & Jain, R. K. Normalizing function of tumor vessels:
922–932 (2018). progress, opportunities, and challenges. Annu. Rev. Physiol. 81, 505–534 (2019).
21. Shiga, K. et al. Cancer-associated fibroblasts: their characteristics and their roles 55. Yang, T. et al. Vascular normalization: a new window opened for cancer
in tumor growth. Cancers 7, 2443–2458 (2015). therapies. Front. Oncol. 11, 719836 (2021).
22. Roland, C. L. et al. Inhibition of vascular endothelial growth factor reduces 56. Stylianopoulos, T., Munn, L. L. & Jain, R. K. Reengineering the physical micro-
angiogenesis and modulates immune cell infiltration of orthotopic breast can- environment of tumors to improve drug delivery and efficacy: from mathe-
cer xenografts. Mol. Cancer Ther. 8, 1761–1771 (2009). matical modeling to bench to bedside. Trends Cancer 4, 292–319 (2018).
23. Ribatti, D. & Crivellato, E. Immune cells and angiogenesis. J. Cell. Mol. Med 13, 57. Jain, R. K., Martin, J. D. & Stylianopoulos, T. The role of mechanical forces in
2822–2833 (2009). tumor growth and therapy. Annu. Rev. Biomed. Eng. 16, 321–346 (2014).
24. Parmar, D. & Apte, M. Angiopoietin inhibitors: a review on targeting tumor 58. Stylianopoulos, T. & Jain, R. K. Combining two strategies to improve perfusion
angiogenesis. Eur. J. Pharmacol. 899, 174021 (2021). and drug delivery in solid tumors. Proc. Natl Acad. Sci. USA 110, 18632–18637
25. Deyell, M., Garris, C. S. & Laughney, A. M. Cancer metastasis as a non-healing (2013).
wound. Br. J. Cancer 124, 1491–1502 (2021). 59. Jain, R. K. & Stylianopoulos, T. Delivering nanomedicine to solid tumors. Nat. Rev.
26. Viallard, C. & Larrivée, B. Tumor angiogenesis and vascular normalization: Clin. Oncol. 7, 653–664 (2010).
alternative therapeutic targets. Angiogenesis 20, 409–426 (2017). 60. Hamzah, J. et al. Vascular normalization in Rgs5-deficient tumours promotes
27. Bellou, S., Pentheroudakis, G., Murphy, C. & Fotsis, T. Anti-angiogenesis in cancer immune destruction. Nature 453, 410–414 (2008).
therapy: hercules and hydra. Cancer Lett. 338, 219–228 (2013). 61. Vaupel, P. & Mayer, A. Hypoxia in cancer: significance and impact on clinical
28. Ebos, J. M. L. & Kerbel, R. S. Antiangiogenic therapy: impact on invasion, disease outcome. Cancer Metastasis Rev. 26, 225–239 (2007).
progression, and metastasis. Nat. Rev. Clin. Oncol. 8, 210–221 (2011). 62. Stubbs, M., McSheehy, P. M. J., Griffiths, J. R. & Bashford, C. L. Causes and
29. Pirker, R. Chemotherapy remains a cornerstone in the treatment of nonsmall cell consequences of tumour acidity and implications for treatment. Mol. Med. Today
lung cancer. Curr. Opin. Oncol. 32, 63–67 (2020). 6, 15–19 (2000).
30. Biller, L. H. & Schrag, D. Diagnosis and treatment of metastatic colorectal cancer: 63. Lee, E. S., Oh, K. T., Kim, D., Youn, Y. S. & Bae, Y. H. Tumor pH-responsive flower-
a review. JAMA 325, 669 (2021). like micelles of poly(l-lactic acid)-b-poly(ethylene glycol)-b-poly(l-histidine). J.
31. Luqmani, Y. A. Mechanisms of drug resistance in cancer chemotherapy. Med. Control. Release 123, 19–26 (2007).
Princ. Pract. 14, 35–48 (2005). 64. Zhang, Z. et al. Rational design of nanoparticles with deep tumor penetration
32. Saeki, T., Tsuruo, T., Sato, W. & Nishikawsa, K. Drug resistance in chemotherapy for effective treatment of tumor metastasis. Adv. Funct. Mater. 28, 1801840
for breast cancer. Cancer Chemother. Pharmacol. 56, 84–89 (2005). (2018).
33. Salgia, R. & Kulkarni, P. The genetic/non-genetic duality of drug ‘resistance’ in 65. Khawar, I. A., Kim, J. H. & Kuh, H. J. Improving drug delivery to solid tumors:
cancer. Trends Cancer 4, 110–118 (2018). Priming the tumor microenvironment. J. Control. Release 201, 78–89 (2015).
34. Turner, N. C. & Reis-Filho, J. S. Genetic heterogeneity and cancer drug resistance. 66. Zhu, L. et al. Angiogenesis and immune checkpoint dual blockade in combi-
Lancet Oncol. 13, e178–e185 (2012). nation with radiotherapy for treatment of solid cancers: opportunities and
35. Duesberg, P. et al. Cancer drug resistance: the central role of the karyotype. Drug challenges. Oncogenesis 10, 47 (2021).
Resist. Updat. 10, 51–58 (2007). 67. Li, X. et al. The immunological and metabolic landscape in primary and meta-
36. Lahiry, P., Torkamani, A., Schork, N. J. & Hegele, R. A. Kinase mutations in human static liver cancer. Nat. Rev. Cancer 21, 541–557 (2021).
disease: interpreting genotype-phenotype relationships. Nat. Rev. Genet. 11, 68. Provenzano, P. P. et al. Enzymatic targeting of the stroma ablates physical
60–74 (2010). barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21,
37. Claesson-Welsh, L. Vascular permeability—the essentials. Ups. J. Med. Sci. 120, 418–429 (2012).
135–143 (2015). 69. Milosevic, M., Fyles, A., Hedley, D. & Hill, R. The human tumor microenvironment:
38. De Bock, K., Cauwenberghs, S. & Carmeliet, P. Vessel abnormalization: another invasive (needle) measurement of oxygen and interstitial fluid pressure. Semin.
hallmark of cancer? Molecular mechanisms and therapeutic implications. Curr. Radiat. Oncol. 14, 249–258 (2004).
Opin. Genet. Dev. 21, 73–79 (2011). 70. Chun, C. Z., Sood, R. & Ramchandran, R. in Vascular Tumors and Developmental
39. Mortezaee, K. Immune escape: a critical hallmark in solid tumors. Life Sci. 258, Malformations (eds. North, P. E. & Sander, T.) 77–99 (Springer, 2016).
118110 (2020). 71. Hillen, F. & Griffioen, A. W. Tumour vascularization: sprouting angiogenesis and
40. Igney, F. H. & Krammer, P. H. Immune escape of tumors: apoptosis resistance beyond. Cancer Metastasis Rev. 26, 489–502 (2007).
and tumor counterattack. J. Leukoc. Biol. 71, 907–920 (2002). 72. Gianni-Barrera, R., Bartolomeo, M., Vollmar, B., Djonov, V. & Banfi, A. Split for the
41. Majidpoor, J. & Mortezaee, K. Angiogenesis as a hallmark of solid tumors— cure: VEGF, PDGF-BB and intussusception in therapeutic angiogenesis. Biochem.
clinical perspectives. Cell. Oncol. 44, 715–737 (2021). Soc. Trans. 42, 1637–1642 (2014).
42. Choi, S. H., Yoo, S. S., Lee, S. Y. & Park, J. Y. Anti-angiogenesis revisited: reshaping 73. Burri, P. H. & Djonov, V. Intussusceptive angiogenesis—the alternative to
the treatment landscape of advanced non-small cell lung cancer. Arch. Pharm. capillary sprouting. Mol. Asp. Med. 23, 1–27 (2002).
Res. 45, 263–279 (2022). 74. Ratajska, A. et al. Vasculogenesis and its cellular therapeutic applications. Cells
43. Zhong, L. et al. Small molecules in targeted cancer therapy: advances, chal- Tissues Organs 203, 141–152 (2017).
lenges, and future perspectives. Signal Transduct. Target. Ther. 6, 201 (2021). 75. Shi, L. in Burger’s Medicinal Chemistry and Drug Discovery (ed. Abraham, D. J.)
44. Huinen, Z. R., Huijbers, E. J. M., van Beijnum, J. R., Nowak-Sliwinska, P. & Griffioen, 1–66 (Wiley, 2021).
A. W. Anti-angiogenic agents—overcoming tumour endothelial cell anergy and 76. Teuwen, L. A. et al. Tumor vessel co-option probed by single-cell analysis. Cell
improving immunotherapy outcomes. Nat. Rev. Clin. Oncol. 18, 527–540 (2021). Rep. 35, 109253 (2021).
45. Gacche, R. N. & Meshram, R. J. Angiogenic factors as potential drug target: 77. Wei, X. et al. Mechanisms of vasculogenic mimicry in hypoxic tumor micro-
efficacy and limitations of anti-angiogenic therapy. Biochim. Biophys. Acta 1846, environments. Mol. Cancer 20, 7 (2021).
161–179 (2014). 78. Potente, M., Gerhardt, H. & Carmeliet, P. Basic and therapeutic aspects of
46. Bergers, G. & Hanahan, D. Modes of resistance to anti-angiogenic therapy. Nat. angiogenesis. Cell 146, 873–887 (2011).
Rev. Cancer 8, 592–603 (2008). 79. Melincovici, C. S. et al. Vascular endothelial growth factor (VEGF)—key factor in
47. Ansari, M. J. et al. Cancer combination therapies by angiogenesis inhibitors; a normal and pathological angiogenesis. Rom. J. Morphol. Embryol. 59, 455–467 (2018).
comprehensive review. Cell Commun. Signal. 20, 49 (2022). 80. Kazlauskas, A. PDGFs and their receptors. Gene 614, 1–7 (2017).
48. Bergers, G. & Song, S. The role of pericytes in blood-vessel formation and 81. Sang, Q. X. A. Complex role of matrix metalloproteinases in angiogenesis. Cell
maintenance. Neuro Oncol. 7, 452–464 (2005). Res. 8, 171–177 (1998).
49. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 82. Ferrara, N., Hillan, K. J., Gerber, H. P. & Novotny, W. Discovery and development
249–257 (2000). of bevacizumab, an anti-VEGF antibody for treating cancer. Nat. Rev. Drug Dis-
50. Goel, S. et al. Normalization of the vasculature for treatment of cancer and other cov. 3, 391–400 (2004).
diseases. Physiol. Rev. 91, 1071–1121 (2011). 83. Shibuya, M. & Claesson-Welsh, L. Signal transduction by VEGF receptors in
51. Kim, C. et al. Vascular RhoJ is an effective and selective target for tumor regulation of angiogenesis and lymphangiogenesis. Exp. Cell Res. 312, 549–560
angiogenesis and vascular disruption. Cancer Cell 25, 102–117 (2014). (2006).
52. Jain, R. K. Normalizing tumor microenvironment to treat cancer: bench to 84. Senger, D. R. et al. Vascular permeability factor (VPF, VEGF) in tumor biology.
bedside to biomarkers. J. Clin. Oncol. 31, 2205–2218 (2013). Cancer Metast Rev. 12, 303–324 (1993).

Liu et al.
32
85. Bao, P. et al. The role of vascular endothelial growth factor in wound healing. J. 115. Valtola, R. et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis
Surg. Res. 153, 347–358 (2009). in breast cancer. Am. J. Pathol. 154, 1381–1390 (1999).
86. Shibuya, M. Vascular endothelial growth factor (VEGF) and its receptor (VEGFR) 116. Saintigny, P. et al. Vascular endothelial growth factor-C and its receptor VEGFR-3
signaling in angiogenesis: a crucial target for anti- and pro-angiogenic thera- in non-small-cell lung cancer: concurrent expression in cancer cells from pri-
pies. Genes Cancer 2, 1097–1105 (2011). mary tumour and metastatic lymph node. Lung Cancer 58, 205–213 (2007).
87. Carmeliet, P. VEGF as a key mediator of angiogenesis in cancer. Oncology 69, 117. Yonemura, Y. et al. Lymphangiogenesis and the vascular endothelial growth
4–10 (2005). factor receptor (VEGFR)-3 in gastric cancer. Eur. J. Cancer 37, 918–923 (2001).
88. Peach, C. J. et al. Molecular pharmacology of VEGF-A isoforms: binding and 118. Su, J. L. et al. The role of the VEGF-C/VEGFR-3 axis in cancer progression. Br. J.
signalling at VEGFR2. Int. J. Mol. Sci. 19, 1264 (2018). Cancer 96, 541–545 (2007).
89. Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of 119. Simiantonaki, N. et al. Hypoxia-induced epithelial VEGF-C/VEGFR-3 upregulation
angiogenesis. Nature 473, 298–307 (2011). in carcinoma cell lines. Int. J. Oncol. 32, 589–592 (2008).
90. Ji, R. C. Characteristics of lymphatic endothelial cells in physiological and 120. Goel, H. L. & Mercurio, A. M. VEGF targets the tumour cell. Nat. Rev. Cancer 13,
pathological conditions. Histol. Histopathol. 20, 155–175 (2005). 871–882 (2013).
91. He, Y. et al. Suppression of tumor lymphangiogenesis and lymph node 121. Wang, H. et al. Over-expression of PDGFR-β promotes PDGF-induced prolifera-
metastasis by blocking vascular endothelial growth factor receptor 3 signaling. tion, migration, and angiogenesis of EPCs through PI3K/Akt signaling pathway.
J. Natl Cancer Inst. 94, 819–825 (2002). PLoS ONE 7, e30503 (2012).
92. Luttun, A., Autiero, M., Tjwa, M. & Carmeliet, P. Genetic dissection of tumor 122. Manzat Saplacan, R. M. et al. The role of PDGFs and PDGFRs in colorectal cancer.
angiogenesis: are PlGF and VEGFR-1 novel anti-cancer targets? Biochim. Biophys. Mediators Inflamm. 2017, 1–9 (2017).
Acta 1654, 79–94 (2004). 123. Kalra, K., Eberhard, J., Farbehi, N., Chong, J. J. & Xaymardan, M. Role of PDGF-A/B
93. McDonald, N. Q. & Hendrickson, W. A. A structural superfamily of growth factors ligands in cardiac repair after myocardial infarction. Front. Cell Dev. Biol. 9,
containing a cystine knot motif. Cell 73, 421–424 (1993). 669188 (2021).
94. Luttun, A. et al. Revascularization of ischemic tissues by PlGF treatment, and 124. Balamurugan, K. et al. Structural insights into the modulation of PDGF/PDGFR-β
inhibition of tumor angiogenesis, arthritis and atherosclerosis by anti-Flt1. Nat. complexation by hyaluronan derivatives. Biol. Chem. 402, 1441–1452 (2021).
Med. 8, 831–840 (2002). 125. Cenciarelli, C. et al. PDGFRα depletion attenuates glioblastoma stem cells fea-
95. Iyer, S. & Acharya, K. R. Role of placenta growth factor in cardiovascular health. tures by modulation of STAT3, RB1 and multiple oncogenic signals. Oncotarget
Trends Cardiovasc. Med. 12, 128–134 (2002). 7, 53047–53063 (2016).
96. Beck, H. et al. Cell type-specific expression of neuropilins in an MCA-occlusion 126. Chabot, V. et al. Urokinase-type plasminogen activator receptor interaction with
model in mice suggests a potential role in post-ischemic brain remodeling. J. β1 integrin is required for platelet-derived growth factor-AB-induced human
Neuropathol. Exp. Neurol. 61, 339–350 (2002). mesenchymal stem/stromal cell migration. Stem Cell Res. Ther. 6, 188 (2015).
97. Donnini, S., Machein, M. R., Plate, K. H. & Weich, H. A. Expression and localization 127. Li, H. et al. Development of monoclonal anti-PDGF-CC antibodies as tools for
of placenta growth factor and PlGF receptors in human meningiomas. J. Pathol. investigating human tissue expression and for blocking PDGF-CC induced
189, 66–71 (1999). PDGFRα signalling in vivo. PLoS ONE 13, e0201089 (2018).
98. Lacal, P. M. et al. Human melanoma cells secrete and respond to placenta 128. Dardik, A., Yamashita, A., Aziz, F., Asada, H. & Sumpio, B. E. Shear stress-
growth factor and vascular endothelial growth factor. J. Invest. Dermatol. 115, stimulated endothelial cells induce smooth muscle cell chemotaxis via platelet-
1000–1007 (2000). derived growth factor-BB and interleukin-1α. J. Vasc. Surg. 41, 321–331 (2005).
99. Ribatti, D., Conconi, M. T. & Nussdorfer, G. G. Nonclassic endogenous novel 129. Muratoglu, S. C., Mikhailenko, I., Newton, C., Migliorini, M. & Strickland, D. K. Low
regulators of angiogenesis. Pharmacol. Rev. 59, 185–205 (2007). density lipoprotein receptor-related protein 1 (LRP1) forms a signaling complex
100. Byrne, A. M., Bouchier-Hayes, D. J. & Harmey, J. H. Angiogenic and cell survival with platelet-derived growth factor receptor-β in endosomes and regulates
functions of vascular endothelial growth factor (VEGF). J. Cell. Mol. Med. 9, activation of the MAPK pathway. J. Biol. Chem. 285, 14308–14317 (2010).
777–794 (2005). 130. Wang, J. C. et al. Metformin inhibits metastatic breast cancer progression and
101. Barleon, B. et al. Migration of human monocytes in response to vascular improves chemosensitivity by inducing vessel normalization via PDGF-B
endothelial growth factor (VEGF) is mediated via the VEGF receptor flt-1. Blood downregulation. J. Exp. Clin. Cancer Res. 38, 235 (2019).
87, 3336–3343 (1996). 131. Li, M. et al. Integrins as attractive targets for cancer therapeutics. Acta Pharm.
102. Shibuya, M. Vascular endothelial growth factor receptor-1 (VEGFR-1/Flt-1): a dual Sin. B 11, 2726–2737 (2021).
regulator for angiogenesis. Angiogenesis 9, 225–230 (2006). 132. Zou, X. et al. Targeting the PDGF/PDGFR signaling pathway for cancer therapy: a
103. Ferrara, N., Gerber, H. P. & LeCouter, J. The biology of VEGF and its receptors. review. Int. J. Biol. Macromol. 202, 539–557 (2022).
Nat. Med. 9, 669–676 (2003). 133. Gacche, R. N. & Assaraf, Y. G. Redundant angiogenic signaling and tumor drug
104. Ishida, A. et al. Expression of vascular endothelial growth factor receptors in resistance. Drug Resist. Updat. 36, 47–76 (2018).
smooth muscle cells. J. Cell. Physiol. 188, 359–368 (2001). 134. Lee, C. & Li, X. Platelet-derived growth factor-C and -D in the cardiovascular
105. Ghosh, S. et al. High levels of vascular endothelial growth factor and its system and diseases. Mol. Asp. Med. 62, 12–21 (2018).
receptors (VEGFR-1, VEGFR-2, neuropilin-1) are associated with worse outcome 135. Berthod, F., Symes, J., Tremblay, N., Medin, J. A. & Auger, F. A. Spontaneous
in breast cancer. Hum. Pathol. 39, 1835–1843 (2008). fibroblast-derived pericyte recruitment in a human tissue-engineered angio-
106. Ceci, C., Atzori, M. G., Lacal, P. M. & Graziani, G. Role of VEGFs/VEGFR-1 signaling genesis model in vitro. J. Cell. Physiol. 227, 2130–2137 (2012).
and its inhibition in modulating tumor invasion: experimental evidence in dif- 136. Ribatti, D., Nico, B. & Crivellato, E. The role of pericytes in angiogenesis. Int. J.
ferent metastatic cancer models. Int. J. Mol. Sci. 21, 1388 (2020). Dev. Biol. 55, 261–268 (2011).
107. Ioannidou, E. et al. Angiogenesis and anti-angiogenic treatment in prostate 137. Chatterjee, S. & Naik, U. P. Pericyte-endothelial cell interaction: a survival
cancer: mechanisms of action and molecular targets. Int. J. Mol. Sci. 22, 9926 mechanism for the tumor vasculature. Cell Adh. Migr. 6, 157–159 (2012).
(2021). 138. Luk, K. et al. Influence of morphine on pericyte-endothelial interaction: impli-
108. Simons, M., Gordon, E. & Claesson-Welsh, L. Mechanisms and regulation of cations for antiangiogenic therapy. J. Oncol. 2012, 1–10 (2012).
endothelial VEGF receptor signalling. Nat. Rev. Mol. Cell Biol. 17, 611–625 (2016). 139. Cavalcanti, E., Ignazzi, A., De Michele, F. & Caruso, M. L. PDGFRα expression as a
109. Molhoek, K. R. et al. VEGFR-2 expression in human melanoma: revised assess- novel therapeutic marker in well-differentiated neuroendocrine tumors. Cancer
ment. Int. J. Cancer 129, 2807–2815 (2011). Biol. Ther. 20, 423–430 (2019).
110. Spannuth, W. A. et al. Functional significance of VEGFR-2 on ovarian cancer cells. 140. Burger, R. A. Overview of anti-angiogenic agents in development for ovarian
Int. J. Cancer 124, 1045–1053 (2009). cancer. Gynecol. Oncol. 121, 230–238 (2011).
111. Capp, C. et al. Increased expression of vascular endothelial growth factor and its 141. Raica, M. & Cimpean, A. M. Platelet-derived growth factor (PDGF)/PDGF recep-
receptors, VEGFR-1 and VEGFR-2, in medullary thyroid carcinoma. Thyroid 20, tors (PDGFR) axis as target for antitumor and antiangiogenic therapy. Pharma-
863–871 (2010). ceuticals 3, 572–599 (2010).
112. Modi, S. J. & Kulkarni, V. M. Vascular endothelial growth factor receptor (VEGFR- 142. Heindryckx, F. Targeting the tumor stroma in hepatocellular carcinoma. World J.
2)/KDR inhibitors: medicinal chemistry perspective. Med. Drug Discov. 2, 100009 Hepatol. 7, 165–176 (2015).
(2019). 143. Cornellà, H., Alsinet, C. & Villanueva, A. Molecular pathogenesis of hepatocellular
113. Padró, T. et al. Overexpression of vascular endothelial growth factor (VEGF) and carcinoma. Alcohol. Clin. Exp. Res. 35, 821–825 (2011).
its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute 144. Brahmi, M. et al. Expression and prognostic significance of PDGF ligands and
myeloid leukemia. Leukemia 16, 1302–1310 (2002). receptors across soft tissue sarcomas. ESMO Open 6, 100037 (2021).
114. Sun, W. Angiogenesis in metastatic colorectal cancer and the benefits of tar- 145. Rao, L. et al. HB-EGF-EGFR signaling in bone marrow endothelial cells mediates
geted therapy. J. Hematol. Oncol. 5, 63 (2012). angiogenesis associated with multiple myeloma. Cancers 12, 173 (2020).

Liu et al.
33
146. Hu, L. et al. Dual target inhibitors based on EGFR: promising anticancer agents 175. Mulcahy, E. Q. X., Colόn, R. R. & Abounader, R. HGF/MET signaling in malignant
for the treatment of cancers (2017-). Eur. J. Med. Chem. 227, 113963 (2022). brain tumors. Int. J. Mol. Sci. 21, 7546 (2020).
147. Larsen, A. K., Ouaret, D., El Ouadrani, K. & Petitprez, A. Targeting EGFR and 176. Nakamura, T. & Mizuno, S. The discovery of hepatocyte growth factor (HGF) and
VEGF(R) pathway cross-talk in tumor survival and angiogenesis. Pharmacol. Ther. its significance for cell biology, life sciences and clinical medicine. Proc. Jpn.
131, 80–90 (2011). Acad. B: Phys. Biol. Sci. 86, 588–610 (2010).
148. Holbro, T. & Hynes, N. E. ErbB receptors: directing key signaling networks 177. Bottaro, D. P. et al. Identification of the hepatocyte growth factor receptor as the
throughout life. Annu. Rev. Pharmacol. Toxicol. 44, 195–217 (2004). c- met proto-oncogene product. Science 251, 802–804 (1991).
149. Ellis, L. M. Epidermal growth factor receptor in tumor angiogenesis. Hematol. 178. Dean, M. et al. The human met oncogene is related to the tyrosine kinase
Oncol. Clin. North Am. 18, 1007–1021 (2004). oncogenes. Nature 318, 385–388 (1985).
150. De Luca, A. et al. The role of the EGFR signaling in tumor microenvironment. J. 179. Ono, K., Matsumori, A., Shioi, T., Furukawa, Y. & Sasayama, S. Enhanced
Cell. Physiol. 214, 559–567 (2008). expression of hepatocyte growth factor/c-Met by myocardial ischemia and
151. Albadari, N., Deng, S. & Li, W. The transcriptional factors HIF-1 and HIF-2 and reperfusion in a rat model. Circulation 95, 2552–2558 (1997).
their novel inhibitors in cancer therapy. Expert Opin. Drug Discov. 14, 667–682 180. Cai, W., Rook, S. L., Jiang, Z. Y., Takahara, N. & Aiello, L. P. Mechanisms of
(2019). hepatocyte growth factor–induced retinal endothelial cell migration and
152. Bos, R. et al. Hypoxia-inducible factor-1α is associated with angiogenesis, and growth. Invest. Ophthalmol. Vis. Sci. 41, 1885–1893 (2000).
expression of bFGF, PDGF-BB, and EGFR in invasive breast cancer. Histopathol- 181. Ankoma-Sey, V. et al. Coordinated induction of VEGF receptors in mesenchymal
ogy 46, 31–36 (2005). cell types during rat hepatic wound healing. Oncogene 17, 115–121 (1998).
153. Salomon, D. S., Brandt, R., Ciardiello, F. & Normanno, N. Epidermal growth factor- 182. Nagashima, M. et al. Hepatocyte growth factor (HGF), HGF activator, and c-Met
related peptides and their receptors in human malignancies. Crit. Rev. Oncol. in synovial tissues in rheumatoid arthritis and osteoarthritis. J. Rheumatol. 28,
Hematol. 19, 183–232 (1995). 1772–1778 (2001).
154. Yu, H. A. et al. Poor response to erlotinib in patients with tumors containing 183. Hughes, P. E. et al. In vitro and in vivo activity of AMG 337, a potent and
baseline EGFR T790M mutations found by routine clinical molecular testing. selective MET kinase inhibitor, in MET-dependent cancer models. Mol. Cancer
Ann. Oncol. 25, 423–428 (2014). Ther. 15, 1568–1579 (2016).
155. Raj, S. et al. Molecular mechanism(s) of regulation(s) of c-MET/HGF signaling in 184. Leung, E. et al. Blood vessel endothelium-directed tumor cell streaming in
head and neck cancer. Mol. Cancer 21, 31 (2022). breast tumors requires the HGF/C-Met signaling pathway. Oncogene 36,
156. Acevedo, V. D., Ittmann, M. & Spencer, D. M. Paths of FGFR-driven tumorigenesis. 2680–2692 (2017).
Cell Cycle 8, 580–588 (2009). 185. Kuang, W. et al. Hepatocyte growth factor induces breast cancer cell invasion via
157. Chen, M., Bao, L., Zhao, M., Cao, J. & Zheng, H. Progress in research on the role of the PI3K/Akt and p38 MAPK signaling pathways to up-regulate the expression of
FGF in the formation and treatment of corneal neovascularization. Front. COX2. Am. J. Transl. Res. 9, 3816–3826 (2017).
Pharmacol. 11, 111 (2020). 186. Hartmann, S., Bhola, N. E. & Grandis, J. R. HGF/Met signaling in head and neck
158. Montesano, R., Vassalli, J. D., Baird, A., Guillemin, R. & Orci, L. Basic fibroblast cancer: impact on the tumor microenvironment. Clin. Cancer Res. 22, 4005–4013
growth factor induces angiogenesis in vitro. Proc. Natl Acad. Sci. USA 83, (2016).
7297–7301 (1986). 187. Demuth, C., Andersen, M. N., Jakobsen, K. R., Madsen, A. T. & Sørensen, B. S.
159. Giacomini, A. et al. The FGF/FGFR system in the physiopathology of the prostate Increased PD-L1 expression in erlotinib-resistant NSCLC cells with MET gene
gland. Physiol. Rev. 101, 569–610 (2021). amplification is reversed upon MET-TKI treatment. Oncotarget 8, 68221–68229
160. Hui, Q. et al. FGF family: from drug development to clinical application. Int. J. (2017).
Mol. Sci. 19, 1875 (2018). 188. Kwon, M. J. et al. Frequent hepatocyte growth factor overexpression and low
161. Presta, M. et al. Fibroblast growth factor/fibroblast growth factor receptor sys- frequency of c-Met gene amplification in human papillomavirus-negative ton-
tem in angiogenesis. Cytokine Growth Factor Rev. 16, 159–178 (2005). sillar squamous cell carcinoma and their prognostic significances. Hum. Pathol.
162. Fons, P. et al. Tumor vasculature is regulated by FGF/FGFR signaling-mediated 45, 1327–1338 (2014).
angiogenesis and bone marrow-derived cell recruitment: this mechanism is 189. Miranda, O., Farooqui, M. & Siegfried, J. M. Status of agents targeting the HGF/c-
inhibited by SSR128129E, the first allosteric antagonist of FGFRs. J. Cell. Physiol. Met axis in lung cancer. Cancers 10, 280 (2018).
230, 43–51 (2015). 190. Wang, Q., Yang, S., Wang, K. & Sun, S. Y. MET inhibitors for targeted therapy of
163. Katoh, M. & Nakagama, H. FGF receptors: cancer biology and therapeutics. Med. EGFR TKI-resistant lung cancer. J. Hematol. Oncol. 12, 63 (2019).
Res. Rev. 34, 280–300 (2014). 191. Wu, J. C. et al. Heteronemin is a novel c-Met/STAT3 inhibitor against advanced
164. Kopetz, S. et al. Phase II trial of infusional fluorouracil, irinotecan, and bev- prostate cancer cells. Prostate 76, 1469–1483 (2016).
acizumab for metastatic colorectal cancer: efficacy and circulating angiogenic 192. Imura, Y. et al. Functional and therapeutic relevance of hepatocyte growth
biomarkers associated with therapeutic resistance. J. Clin. Oncol. 28, 453–459 factor/c‐MET signaling in synovial sarcoma. Cancer Sci. 107, 1867–1876 (2016).
(2010). 193. Birchmeier, C., Birchmeier, W., Gherardi, E. & Vande Woude, G. F. Met, metastasis,
165. Batchelor, T. T. et al. AZD2171, a pan-VEGF receptor tyrosine kinase inhibitor, motility and more. Nat. Rev. Mol. Cell Biol. 4, 915–925 (2003).
normalizes tumor vasculature and alleviates edema in glioblastoma patients. 194. Zhang, Y. et al. Function of the c-Met receptor tyrosine kinase in carcinogenesis
Cancer Cell 11, 83–95 (2007). and associated therapeutic opportunities. Mol. Cancer 17, 45 (2018).
166. Katoh, M. Cancer genomics and genetics of FGFR2 (Review). Int. J. Oncol. 33, 195. Scalia, P., Giordano, A. & Williams, S. J. The IGF-II-insulin receptor isoform-A
233–237 (2008). autocrine signal in cancer: actionable perspectives. Cancers 12, 366 (2020).
167. Turner, N. & Grose, R. Fibroblast growth factor signalling: from development to 196. Bach, L. A. Endothelial cells and the IGF system. J. Mol. Endocrinol. 54, R1–R13
cancer. Nat. Rev. Cancer 10, 116–129 (2010). (2014).
168. Greulich, H. & Pollock, P. M. Targeting mutant fibroblast growth factor receptors 197. Clemmons, D. R. Modifying IGF1 activity: an approach to treat endocrine dis-
in cancer. Trends Mol. Med. 17, 283–292 (2011). orders, atherosclerosis and cancer. Nat. Rev. Drug Discov. 6, 821–833 (2007).
169. Cross, M. J. & Claesson-Welsh, L. FGF and VEGF function in angiogenesis: sig- 198. van Beijnum, J. R., Pieters, W., Nowak-Sliwinska, P. & Griffioen, A. W. Insulin-like
nalling pathways, biological responses and therapeutic inhibition. Trends Phar- growth factor axis targeting in cancer and tumour angiogenesis—the missing
macol. Sci. 22, 201–207 (2001). link: IGF signaling in tumor angiogenesis. Biol. Rev. Camb. Philos. Soc. 92,
170. García-Caballero, M. et al. Angioprevention of urologic cancers by plant-derived 1755–1768 (2017).
foods. Pharmaceutics 14, 256 (2022). 199. Chantelau, E. Evidence that upregulation of serum IGF-1 concentration can trigger
171. Aviles, R. J., Annex, B. H. & Lederman, R. J. Testing clinical therapeutic angio- acceleration of diabetic retinopathy. Br. J. Ophthalmol. 82, 725–730 (1998).
genesis using basic fibroblast growth factor (FGF-2): Clinical angiogenesis using 200. Wilkinson-Berka, J. L., Wraight, C. & Werther, G. The role of growth hormone,
FGF-2. Br. J. Pharm. 140, 637–646 (2003). insulin-like growth factor and somatostatin in diabetic retinopathy. Curr. Med.
172. Vasudev, N. S. & Reynolds, A. R. Anti-angiogenic therapy for cancer: current Chem. 13, 3307–3317 (2006).
progress, unresolved questions and future directions. Angiogenesis 17, 471–494 201. Higashi, Y., Sukhanov, S., Anwar, A., Shai, S. Y. & Delafontaine, P. Aging, ather-
(2014). osclerosis, and IGF-1. J. Gerontol. A: Biol. Sci. Med. Sci. 67, 626–639 (2012).
173. Ding, S., Merkulova-Rainon, T., Han, Z. C. & Tobelem, G. HGF receptor up- 202. Hellstrom, A. et al. Low IGF-I suppresses VEGF-survival signaling in retinal
regulation contributes to the angiogenic phenotype of human endothelial cells endothelial cells: direct correlation with clinical retinopathy of prematurity. Proc.
and promotes angiogenesis in vitro. Blood 101, 4816–4822 (2003). Natl Acad. Sci. USA 98, 5804–5808 (2001).
174. Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in devel- 203. Smith, L. E. H. Pathogenesis of retinopathy of prematurity. Acta Paediatr. Suppl.
opment and disease. Nat. Rev. Mol. Cell Biol. 15, 786–801 (2014). 91, 26–28 (2002).

Liu et al.
34
204. Moschos, S. J. & Mantzoros, C. S. The role of the IGF system in cancer: from basic 235. Mazzocca, A., Fransvea, E., Lavezzari, G., Antonaci, S. & Giannelli, G. Inhibition of
to clinical studies and clinical applications. Oncology 63, 317–332 (2002). transforming growth factor β receptor I kinase blocks hepatocellular carcinoma
205. Sachdev, D. & Yee, D. The IGF system and breast cancer. Endocr. Relat. Cancer 8, growth through neo-angiogenesis regulation. Hepatology 50, 1140–1151 (2009).
197–209 (2001). 236. Bhagyaraj, E. et al. TGF-β induced chemoresistance in liver cancer is modulated
206. Samani, A. A., Yakar, S., LeRoith, D. & Brodt, P. The role of the IGF system in by xenobiotic nuclear receptor PXR. Cell Cycle 18, 3589–3602 (2019).
cancer growth and metastasis: overview and recent insights. Endocr. Rev. 28, 237. Yang, Y. et al. GP73 promotes epithelial–mesenchymal transition and invasion
20–47 (2007). partly by activating TGF-β1/Smad2 signaling in hepatocellular carcinoma. Car-
207. Baserga, R., Peruzzi, F. & Reiss, K. The IGF-1 receptor in cancer biology. Int. J. cinogenesis 39, 900–910 (2018).
Cancer 107, 873–877 (2003). 238. Chiechi, A. et al. Role of TGF-β in breast cancer bone metastases. Adv. Biosci.
208. Azar, W. J. et al. IGFBP-2 enhances VEGF gene promoter activity and consequent Biotechnol. 4, 15–30 (2013).
promotion of angiogenesis by neuroblastoma cells. Endocrinology 152, 239. Masoud, G. N. & Li, W. HIF-1α pathway: role, regulation and intervention for
3332–3342 (2011). cancer therapy. Acta Pharm. Sin. B 5, 378–389 (2015).
209. Png, K. J., Halberg, N., Yoshida, M. & Tavazoie, S. F. A microRNA regulon that 240. Yang, Y., Sun, M., Wang, L. & Jiao, B. HIFs, angiogenesis, and cancer. J. Cell.
mediates endothelial recruitment and metastasis by cancer cells. Nature 481, Biochem. 114, 967–974 (2013).
190–194 (2011). 241. Konisti, S., Kiriakidis, S. & Paleolog, E. M. Hypoxia—a key regulator of angio-
210. Liu, B. et al. Insulin-like growth factor-binding protein-3 inhibition of prostate cancer genesis and inflammation in rheumatoid arthritis. Nat. Rev. Rheumatol. 8,
growth involves suppression of angiogenesis. Oncogene 26, 1811–1819 (2007). 153–162 (2012).
211. Wu, M. Y. & Hill, C. S. TGF-β superfamily signaling in embryonic development 242. Ahluwalia, A. & Tarnawski, A. S. Critical role of hypoxia sensor—HIF-1 in VEGF
and homeostasis. Dev. Cell 16, 329–343 (2009). gene activation. Implications for angiogenesis and tissue injury healing. Curr.
212. Yang, Y. et al. The role of TGF-β signaling pathways in cancer and its potential as Med. Chem. 19, 90–97 (2012).
a therapeutic target. Evid. Based Complement Altern. Med. 2021, 6675208 (2021). 243. Tanaka, T. & Nangaku, M. Angiogenesis and hypoxia in the kidney. Nat. Rev.
213. Zhang, Y. E. Non-Smad signaling pathways of the TGF-β family. Cold Spring Harb. Nephrol. 9, 211–222 (2013).
Perspect. Biol. 9, a022129 (2017). 244. Chen, L., Endler, A. & Shibasaki, F. Hypoxia and angiogenesis: regulation of
214. Santoro, R., Carbone, C., Piro, G., Chiao, P. J. & Melisi, D. TAK-ing aim at che- hypoxia-inducible factors via novel binding factors. Exp. Mol. Med. 41, 849–857
moresistance: the emerging role of MAP3K7 as a target for cancer therapy. Drug (2009).
Resist. Updat. 33–35, 36–42 (2017). 245. Ikeda, H. & Kakeya, H. Targeting hypoxia-inducible factor 1 (HIF-1) signaling with
215. Colak, S. & Ten Dijke, P. Targeting TGF-β signaling in cancer. Trends Cancer 3, natural products toward cancer chemotherapy. J. Antibiot. 74, 687–695 (2021).
56–71 (2017). 246. Pugh, C. W. & Ratcliffe, P. J. Regulation of angiogenesis by hypoxia: role of the
216. Platten, M., Wick, W. & Weller, M. Malignant glioma biology: Role for TGF-β in HIF system. Nat. Med. 9, 677–684 (2003).
growth, motility, angiogenesis, and immune escape. Microsc. Res. Tech. 52, 247. Semenza, G. L. Targeting hypoxia-inducible factor 1 to stimulate tissue vascu-
401–410 (2001). larization. J. Investig. Med. 64, 361–363 (2016).
217. Sabbadini, F. et al. The multifaceted role of TGF-β in gastrointestinal tumors. 248. Vleugel, M. M. et al. Differential prognostic impact of hypoxia induced and
Cancers 13, 3960 (2021). diffuse HIF-1 expression in invasive breast cancer. J. Clin. Pathol. 58, 172–177
218. Massagué, J. TGFβ signalling in context. Nat. Rev. Mol. Cell Biol. 13, 616–630 (2005).
(2012). 249. Dales, J. P. et al. Overexpression of hypoxia-inducible factor HIF-1α predicts early
219. Horiguchi, K. et al. Role of Ras signaling in the induction of snail by transforming relapse in breast cancer: retrospective study in a series of 745 patients. Int. J.
growth factor-β. J. Biol. Chem. 284, 245–253 (2009). Cancer 116, 734–739 (2005).
220. Korc, M. Role of growth factors in pancreatic cancer. Surg. Oncol. Clin. N. Am. 7, 250. Yatabe, N. et al. HIF-1-mediated activation of telomerase in cervical cancer cells.
25–41 (1998). Oncogene 23, 3708–3715 (2004).
221. Nolan-Stevaux, O. et al. GLI1 is regulated through Smoothened-independent 251. Pezzuto, A. et al. A close relationship between HIF-1α expression and bone
mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and metastases in advanced NSCLC, a retrospective analysis. Oncotarget 10,
transformation. Genes Dev. 23, 24–36 (2009). 7071–7079 (2019).
222. Budi, E. H., Mamai, O., Hoffman, S., Akhurst, R. J. & Derynck, R. Enhanced TGF-β 252. Jackson, A. L., Zhou, B. & Kim, W. Y. HIF, hypoxia and the role of angiogenesis in
signaling contributes to the insulin-induced angiogenic responses of endo- non-small cell lung cancer. Expert Opin. Ther. Targets 14, 1047–1057 (2010).
thelial cells. iScience 11, 474–491 (2019). 253. Liu, K. et al. The changes of HIF-1α and VEGF expression after TACE in patients
223. Darland, D. C. & D’Amore, P. A. TGFβ is required for the formation of capillary- with hepatocellular carcinoma. J. Clin. Med. Res. 8, 297–302 (2016).
like structures in three-dimensional cocultures of 10T1/2 and endothelial cells. 254. Zheng, S. S., Chen, X. H., Yin, X. & Zhang, B. H. Prognostic significance of HIF-1α
Angiogenesis 4, 11–20 (2001). expression in hepatocellular carcinoma: a meta-analysis. PLoS ONE 8, e65753 (2013).
224. Huynh, L. K., Hipolito, C. J. & Ten Dijke, P. A perspective on the development of 255. Semenza, G. L. Targeting HIF-1 for cancer therapy. Nat. Rev. Cancer 3, 721–732
TGF-β inhibitors for cancer treatment. Biomolecules 9, 743 (2019). (2003).
225. Katz, L. H. et al. TGF-β signaling in liver and gastrointestinal cancers. Cancer Lett. 256. Schöning, J. P., Monteiro, M. & Gu, W. Drug resistance and cancer stem cells: the
379, 166–172 (2016). shared but distinct roles of hypoxia‐inducible factors HIF 1α and HIF 2α. Clin.
226. Tsubakihara, Y. & Moustakas, A. Epithelial-mesenchymal transition and metas- Exp. Pharmacol. Physiol. 44, 153–161 (2017).
tasis under the control of transforming growth factor β. Int. J. Mol. Sci. 19, 3672 257. Rohwer, N. & Cramer, T. Hypoxia-mediated drug resistance: Novel insights on
(2018). the functional interaction of HIFs and cell death pathways. Drug Resist. Updat.
227. Fu, M., Peng, D., Lan, T., Wei, Y. & Wei, X. Multifunctional regulatory protein 14, 191–201 (2011).
connective tissue growth factor (CTGF): a potential therapeutic target for 258. Zhang, Q., Lenardo, M. J. & Baltimore, D. 30 years of NF-κB: a blossoming of
diverse diseases. Acta Pharm. Sin. B 12, 1740–1760 (2022). relevance to human pathobiology. Cell 168, 37–57 (2017).
228. Pepper, M. S. Transforming growth factor-β: vasculogenesis, angiogenesis, and 259. Iosef, C. et al. Inhibiting NF-κB in the developing lung disrupts angiogenesis and
vessel wall integrity. Cytokine Growth Factor Rev. 8, 21–43 (1997). alveolarization. Am. J. Physiol. Lung Cell. Mol. Physiol. 302, L1023–L1036 (2012).
229. Fang, L. et al. TGF-β1 induces VEGF expression in human granulosa-lutein cells: a 260. Sakamoto, K. et al. Constitutive NF-κB activation in colorectal carcinoma plays a
potential mechanism for the pathogenesis of ovarian hyperstimulation syn- key role in angiogenesis, promoting tumor growth. Clin. Cancer Res. 15,
drome. Exp. Mol. Med. 52, 450–460 (2020). 2248–2258 (2009).
230. Wang, H. et al. Methyl-CpG-binding protein 2 drives the Furin/TGF-β1/Smad axis 261. Huang, S., Pettaway, C. A., Uehara, H., Bucana, C. D. & Fidler, I. J. Blockade of NF-
to promote epithelial–mesenchymal transition in pancreatic cancer cells. kappaB activity in human prostate cancer cells is associated with suppression of
Oncogenesis 9, 76 (2020). angiogenesis, invasion, and metastasis. Oncogene 20, 4188–4197 (2001).
231. Melisi, D. et al. Modulation of pancreatic cancer chemoresistance by inhibition 262. Davis, S. et al. Angiopoietins have distinct modular domains essential for
of TAK1. J. Natl Cancer Inst. 103, 1190–1204 (2011). receptor binding, dimerization and superclustering. Nat. Struct. Biol. 10, 38–44
232. Zhang, H. et al. TGFβ signaling in pancreatic ductal adenocarcinoma. Tumor Biol. (2003).
36, 1613–1618 (2015). 263. Saharinen, P., Eklund, L. & Alitalo, K. Therapeutic targeting of the angiopoietin-
233. Santoro, R. et al. Modulating TAK1 expression inhibits YAP and TAZ oncogenic TIE pathway. Nat. Rev. Drug Discov. 16, 635–661 (2017).
functions in pancreatic cancer. Mol. Cancer Ther. 19, 247–257 (2020). 264. Partanen, J. et al. A novel endothelial cell surface receptor tyrosine kinase with
234. Gladilin, E. et al. TGFβ-induced cytoskeletal remodeling mediates elevation of extracellular epidermal growth factor homology domains. Mol. Cell. Biol. 12,
cell stiffness and invasiveness in NSCLC. Sci. Rep. 9, 7667 (2019). 1698–1707 (1992).

Liu et al.
35
265. Fagiani, E. & Christofori, G. Angiopoietins in angiogenesis. Cancer Lett. 328, 295. Sahlgren, C., Gustafsson, M. V., Jin, S., Poellinger, L. & Lendahl, U. Notch signaling
18–26 (2013). mediates hypoxia-induced tumor cell migration and invasion. Proc. Natl Acad.
266. Shim, W. S. N., Ho, I. A. W. & Wong, P. E. H. Angiopoietin: a TIE(d) balance in Sci. USA 105, 6392–6397 (2008).
tumor angiogenesis. Mol. Cancer Res 5, 655–665 (2007). 296. Surawska, H., Ma, P. C. & Salgia, R. The role of ephrins and Eph receptors in
267. Gillen, J., Richardson, D. L. & Moore, K. N. Angiopoietin-1 and angiopoietin-2 cancer. Cytokine Growth Factor Rev. 15, 419–433 (2004).
inhibitors: clinical development. Curr. Oncol. Rep. 21, 22 (2019). 297. Zozulya, S. A. & Udovichenko, I. P. Eph family receptors as therapeutic targets.
268. Eklund, L., Kangas, J. & Saharinen, P. Angiopoietin–Tie signalling in the cardio- Bioorg. Khim. 38, 267–279 (2012).
vascular and lymphatic systems. Cancer Sci. 131, 87–103 (2016). 298. Zhang, J. & Hughes, S. Role of the ephrin and Eph receptor tyrosine kinase
269. Takahama, M. et al. Enhanced expression of Tie2, its ligand angiopoietin-1, families in angiogenesis and development of the cardiovascular system. J.
vascular endothelial growth factor, and CD31 in human non-small cell lung Pathol. 208, 453–461 (2006).
carcinomas1. Clin. Cancer Res. 5, 2506–2510 (1999). 299. Batlle, E. & Wilkinson, D. G. Molecular mechanisms of cell segregation and
270. Tangkeangsirisin, W., Hayashi, J. & Serrero, G. PC Cell-derived growth factor boundary formation in development and tumorigenesis. Cold Spring Harb.
mediates tamoxifen resistance and promotes tumor growth of human breast Perspect. Biol. 4, a008227 (2012).
cancer cells. Cancer Res 64, 1737–1743 (2004). 300. Pasquale, E. B. Eph receptor signalling casts a wide net on cell behaviour. Nat.
271. Shirakawa, K. et al. Absence of endothelial cells, central necrosis, and fibrosis are Rev. Mol. Cell Biol. 6, 462–475 (2005).
associated with aggressive inflammatory breast cancer. Cancer Res. 61, 445–451 301. Pasquale, E. B. Eph-ephrin bidirectional signaling in physiology and disease. Cell
(2001). 133, 38–52 (2008).
272. Martoglio, A. M. et al. Changes in tumorigenesis- and angiogenesis-related gene 302. Du, E., Li, X., He, S., Li, X. & He, S. The critical role of the interplays of EphrinB2/
transcript abundance profiles in ovarian cancer detected by tailored high EphB4 and VEGF in the induction of angiogenesis. Mol. Biol. Rep. 47, 4681–4690
density cDNA arrays. Mol. Med. 6, 750–765 (2000). (2020).
273. Ding, H. et al. Expression and hypoxic regulation of angiopoietins in human 303. Yuan, C. et al. Overexpression of ephrinB2 in stem cells from apical papilla
astrocytomas. Neuro Oncol. 3, 1–10 (2001). accelerates angiogenesis. Oral. Dis. 25, 848–859 (2019).
274. Stratmann, A., Risau, W. & Plate, K. H. Cell type-specific expression of 304. You, C. et al. EphB4 forward signalling mediates angiogenesis caused by CCM3/
angiopoietin-1 and angiopoietin-2 suggests a role in glioblastoma angiogenesis. PDCD10-ablation. J. Cell. Mol. Med. 21, 1848–1858 (2017).
Am. J. Pathol. 153, 1459–1466 (1998). 305. Yang, D. et al. EphrinB2/EphB4 pathway in postnatal angiogenesis: a potential
275. Udani, V. et al. Differential expression of angiopoietin-1 and angiopoietin-2 may therapeutic target for ischemic cardiovascular disease. Angiogenesis 19, 297–309
enhance recruitment of bone marrow-derived endothelial precursor cells into (2016).
brain tumors. Neurol. Res. 27, 801–806 (2005). 306. Pierscianek, D. et al. Study of angiogenic signaling pathways in hemangio-
276. Thurston, G. & Daly, C. The complex role of angiopoietin-2 in the blastoma. Neuropathology 37, 3–11 (2017).
angiopoietin-Tie signaling pathway. Cold Spring Harb. Perspect. Med. 2, 307. Avraamides, C. J., Garmy-Susini, B. & Varner, J. A. Integrins in angiogenesis and
a006650 (2012). lymphangiogenesis. Nat. Rev. Cancer 8, 604–617 (2008).
277. Eklund, L. & Saharinen, P. Angiopoietin signaling in the vasculature. Exp. Cell Res. 308. Bergonzini, C., Kroese, K., Zweemer, A. J. M. & Danen, E. H. J. Targeting integrins
319, 1271–1280 (2013). for cancer therapy - disappointments and opportunities. Front. Cell Dev. Biol. 10,
278. Bolós, V., Grego-Bessa, J. & de la Pompa, J. L. Notch signaling in development 863850 (2022).
and cancer. Endocr. Rev. 28, 339–363 (2007). 309. Takada, Y., Ye, X. & Simon, S. The integrins. Genome Biol. 8, 215 (2007).
279. Ranganathan, P., Weaver, K. L. & Capobianco, A. J. Notch signalling in solid 310. Hynes, R. O. Integrins. Cell 110, 673–687 (2002).
tumours: a little bit of everything but not all the time. Nat. Rev. Cancer 11, 311. Mezu-Ndubuisi, O. J. & Maheshwari, A. The role of integrins in inflammation and
338–351 (2011). angiogenesis. Pediatr. Res. 89, 1619–1626 (2021).
280. Takeshita, K. et al. Critical role of endothelial notch1 signaling in postnatal 312. Huveneers, S. & Danen, E. H. Adhesion signaling – crosstalk between integrins,
Angiogenesis. Circ. Res. 100, 70–78 (2007). Src and Rho. J. Cell Sci. 122, 1059–1069 (2009).
281. Blanco, R. & Gerhardt, H. VEGF and Notch in tip and stalk cell selection. Cold 313. Łasiñska, I. & Mackiewicz, J. Integrins as a new target for cancer treatment.
Spring Harb. Perspect. Med. 3, a006569 (2013). Anticancer Agents Med. Chem. 19, 580–586 (2019).
282. Radtke, F. & Raj, K. The role of Notch in tumorigenesis: oncogene or tumour 314. Trikha, M. et al. CNTO 95, a fully human monoclonal antibody that inhibits? αv
suppressor? Nat. Rev. Cancer 3, 756–767 (2003). integrins, has antitumor and antiangiogenic activityin vivo. Int. J. Cancer 110,
283. Gustafsson, M. V. et al. Hypoxia requires Notch signaling to maintain the 326–335 (2004).
undifferentiated cell state. Dev. Cell 9, 617–628 (2005). 315. Mitjans, F. et al. In vivo therapy of malignant melanoma by means of antago-
284. Sainson, R. C. & Harris, A. L. Hypoxia-regulated differentiation: let’s step it up a nists of αv integrins. Int. J. Cancer 87, 716–723 (2000).
Notch. Trends Mol. Med. 12, 141–143 (2006). 316. Khalili, P. et al. A non–RGD-based integrin binding peptide (ATN-161) blocks
285. Diez, H. et al. Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in breast cancer growth and metastasis in vivo. Mol. Cancer Ther. 5, 2271–2280
endothelial progenitor cells and adoption of arterial cell fate. Exp. Cell Res. 313, (2006).
1–9 (2007). 317. Garmy-Susini, B. et al. Integrin α4β1–VCAM-1–mediated adhesion between
286. Patel, N. S. et al. Up-regulation of delta-like 4 ligand in human tumor vasculature endothelial and mural cells is required for blood vessel maturation. J. Clin. Invest.
and the role of basal expression in endothelial cell function. Cancer Res. 65, 115, 1542–1551 (2005).
8690–8697 (2005). 318. Kim, S., Bell, K., Mousa, S. A. & Varner, J. A. Regulation of angiogenesis in vivo by
287. Reedijk, M. et al. High-level coexpression of JAG1 and NOTCH1 is observed in ligation of integrin α5β1 with the central cell-binding domain of fibronectin. Am.
human breast cancer and is associated with poor overall survival. Cancer Res. 65, J. Pathol. 156, 1345–1362 (2000).
8530–8537 (2005). 319. Vlahakis, N. E. et al. Integrin α9β1 directly binds to vascular endothelial growth
288. Tschaharganeh, D. F. et al. Yes-associated protein up-regulates Jagged-1 and factor (VEGF)-A and contributes to VEGF-A-induced angiogenesis. J. Biol. Chem.
activates the NOTCH pathway in human hepatocellular carcinoma. Gastro- 282, 15187–15196 (2007).
enterology 144, 1530–1542 (2013). 320. Rooprai, H. K., Rucklidge, G. J., Panou, C. & Pilkington, G. J. The effects of exo-
289. Yousif, N. G. et al. Notch1 ligand signaling pathway activated in cervical cancer: genous growth factors on matrix metalloproteinase secretion by human brain
poor prognosis with high-level JAG1/Notch1. Arch. Gynecol. Obstet. 292, tumour cells. Br. J. Cancer 82, 52–55 (2000).
899–904 (2015). 321. Laronha, H. & Caldeira, J. Structure and function of human matrix metallopro-
290. Che, L. et al. Jagged 1 is a major Notch ligand along cholangiocarcinoma teinases. Cells 9, 1076 (2020).
development in mice and humans. Oncogenesis 5, e274 (2016). 322. Quintero-Fabián, S. et al. Role of matrix metalloproteinases in angiogenesis and
291. Bellon, M., Moles, R., Chaib-Mezrag, H., Pancewicz, J. & Nicot, C. JAG1 over- cancer. Front. Oncol. 9, 1370 (2019).
expression contributes to Notch1 signaling and the migration of HTLV-1- 323. Kessenbrock, K., Plaks, V. & Werb, Z. Matrix metalloproteinases: regulators of the
transformed ATL cells. J. Hematol. Oncol. 11, 119 (2018). tumor microenvironment. Cell 141, 52–67 (2010).
292. Sethi, N., Dai, X., Winter, C. G. & Kang, Y. Tumor-derived JAGGED1 promotes 324. Chantrain, C. F. et al. Stromal matrix metalloproteinase-9 regulates the vascular
osteolytic bone metastasis of breast cancer by engaging notch signaling in architecture in neuroblastoma by promoting pericyte recruitment. Cancer Res.
bone cells. Cancer Cell 19, 192–205 (2011). 64, 1675–1686 (2004).
293. Sjölund, J. et al. Suppression of renal cell carcinoma growth by inhibition of 325. Lafleur, M. A., Handsley, M. M., Knäuper, V., Murphy, G. & Edwards, D. R. Endo-
Notch signaling in vitro and in vivo. J. Clin. Invest. 118, 217–228 (2008). thelial tubulogenesis within fibrin gels specifically requires the activity of
294. Schneider, M. et al. Inhibition of Delta-induced Notch signaling using fucose membrane-type-matrix metalloproteinases (MT-MMPs). J. Cell Sci. 115,
analogs. Nat. Chem. Biol. 14, 65–71 (2018). 3427–3438 (2002).

Liu et al.
36
326. Huang, H. Matrix metalloproteinase-9 (MMP-9) as a cancer biomarker and MMP- 358. Boehm, T., Folkman, J., Browder, T. & O’Reilly, M. S. Antiangiogenic therapy of
9 biosensors: recent advances. Sensors 18, 3249 (2018). experimental cancer does not induce acquired drug resistance. Nature 390,
327. Itoh, T. et al. Reduced angiogenesis and tumor progression in gelatinase 404–407 (1997).
A-deficient mice1. Cancer Res. 58, 1048–1051 (1998). 359. O’Reilly, M. S. et al. Endostatin: an endogenous inhibitor of angiogenesis and
328. Gálvez, B. G., Matı ́as-Román, S., Albar, J. P., Sánchez-Madrid, F. & Arroyo, A. G. tumor growth. Cell 88, 277–285 (1997).
Membrane type 1-matrix metalloproteinase is activated during migration of 360. Denekamp, J. Review article: angiogenesis, neovascular proliferation and vascular
human endothelial cells and modulates endothelial motility and matrix remo- pathophysiology as targets for cancer therapy. Br. J. Radiol. 66, 181–196 (1993).
deling. J. Biol. Chem. 276, 37491–37500 (2001). 361. Weidner, N., Semple, J. P., Welch, W. R. & Folkman, J. Tumor angiogenesis and
329. Hiraoka, N., Allen, E., Apel, I. J., Gyetko, M. R. & Weiss, S. J. Matrix metallopro- metastasis—correlation in invasive breast carcinoma. N. Engl. J. Med. 324, 1–8
teinases regulate neovascularization by acting as pericellular fibrinolysins. Cell (1991).
95, 365–377 (1998). 362. Folkman, J. Successful treatment of an angiogenic disease. N. Engl. J. Med. 320,
330. Huo, N. et al. MMP-7 (matrilysin) accelerated growth of human umbilical vein 1211–1212 (1989).
endothelial cells. Cancer Lett. 177, 95–100 (2002). 363. Ingber, D. et al. Synthetic analogues of fumagillin that inhibit angiogenesis and
331. Whitelock, J. M., Murdoch, A. D., Iozzo, R. V. & Underwood, P. A. The degradation suppress tumour growth. Nature 348, 555–557 (1990).
of human endothelial cell-derived perlecan and release of bound basic fibro- 364. Senger, D. R. et al. Tumor cells secrete a vascular permeability factor that pro-
blast growth factor by stromelysin, collagenase, plasmin, and heparanases. J. motes accumulation of ascites fluid. Science 219, 983–985 (1983).
Biol. Chem. 271, 10079–10086 (1996). 365. Liu, K. et al. Targeting the vasculature in hepatocellular carcinoma treatment:
332. Horejs, C. M. Basement membrane fragments in the context of the epithelial-to- Starving versus normalizing blood supply. Clin. Transl. Gastroenterol. 8, e98
mesenchymal transition. Eur. J. Cell Biol. 95, 427–440 (2016). (2017).
333. Nieto, M. A. The ins and outs of the epithelial to mesenchymal transition in 366. Jain, R. K. Antiangiogenesis strategies revisited: from starving tumors to alle-
health and disease. Annu. Rev. Cell Dev. Biol. 27, 347–376 (2011). viating hypoxia. Cancer Cell 26, 605–622 (2014).
334. Seo, D. W. et al. TIMP-2 mediated inhibition of angiogenesis: an MMP- 367. Gupta, K. & Zhang, J. Angiogenesis: a curse or cure? Postgrad. Med. J. 81,
independent mechanism. Cell 114, 171–180 (2003). 236–242 (2005).
335. Schnaper, H. W. et al. Type IV collagenase(s) and TIMPs modulate endothelial 368. Shchors, K. & Evan, G. Tumor angiogenesis: cause or consequence of cancer?
cell morphogenesis in vitro. J. Cell. Physiol. 156, 235–246 (1993). Cancer Res. 67, 7059–7061 (2007).
336. Murphy, A. N., Unsworth, E. J. & Stetler-Stevenson, W. G. Tissue inhibitor of 369. Goel, S., Wong, A. H. & Jain, R. K. Vascular normalization as a therapeutic strategy
metalloproteinases-2 inhibits bFGF-induced human microvascular endothelial for malignant and nonmalignant disease. Cold Spring Harb. Perspect. Med. 2,
cell proliferation. J. Cell. Physiol. 157, 351–358 (1993). a006486 (2012).
337. Hutzen, B. et al. Treatment of medulloblastoma with oncolytic measles viruses 370. Jain, R. K. Normalization of tumor vasculature: an emerging concept in anti-
expressing the angiogenesis inhibitors endostatin and angiostatin. BMC Cancer angiogenic therapy. Science 307, 58–62 (2005).
14, 206 (2014). 371. Jain, R. K. Normalizing tumor vasculature with anti-angiogenic therapy: a new
338. Egeblad, M. & Werb, Z. New functions for the matrix metalloproteinases in paradigm for combination therapy. Nat. Med. 7, 987–989 (2001).
cancer progression. Nat. Rev. Cancer 2, 161–174 (2002). 372. He, L. et al. Antiangiogenic effects of recombinant human endostatin in lung
339. Frisch, A. et al. Apelin controls angiogenesis-dependent glioblastoma growth. cancers. Mol. Med. Rep. 17, 79–86 (2018).
Int. J. Mol. Sci. 21, 4179 (2020). 373. Wang, J. & Zhu, C. Anticoagulation in combination with antiangiogenesis and
340. Tong, M., Jun, T., Nie, Y., Hao, J. & Fan, D. The role of the Slit/Robo signaling chemotherapy for cancer patients: evidence and hypothesis. Onco Targets Ther.
pathway. J. Cancer 10, 2694–2705 (2019). 9, 4737–4746 (2016).
341. Nikitenko, L. L., Fox, S. B., Kehoe, S., Rees, M. C. & Bicknell, R. Adrenomedullin and 374. Sato, Y. Persistent vascular normalization as an alternative goal of anti-
tumour angiogenesis. Br. J. Cancer 94, 1–7 (2006). angiogenic cancer therapy. Cancer Sci. 102, 1253–1256 (2011).
342. Ribatti, D., Nico, B., Spinazzi, R., Vacca, A. & Nussdorfer, G. G. The role of adre- 375. Wong, P. P., Bodrug, N. & Hodivala-Dilke, K. M. Exploring novel methods for
nomedullin in angiogenesis. Peptides 26, 1670–1675 (2005). modulating tumor blood vessels in cancer treatment. Curr. Biol. 26,
343. Gately, S. & Li, W. W. Multiple roles of COX-2 in tumor angiogenesis: a target for R1161–R1166 (2016).
antiangiogenic therapy. Semin. Oncol. 31, 2–11 (2004). 376. Li, W., Quan, Y. Y., Li, Y., Lu, L. & Cui, M. Monitoring of tumor vascular normal-
344. Toomey, D. P., Murphy, J. F. & Conlon, K. C. COX-2, VEGF and tumour angio- ization: the key points from basic research to clinical application. Cancer Manag.
genesis. Surgeon 7, 174–180 (2009). Res. 10, 4163–4172 (2018).
345. Belperio, J. A. et al. CXC chemokines in angiogenesis. J. Leukoc. Biol. 68, 1–8 377. Zheng, R., Li, F., Li, F. & Gong, A. Targeting tumor vascularization: promising
(2000). strategies for vascular normalization. J. Cancer Res. Clin. Oncol. 147, 2489–2505
346. Strieter, R. M., Belperio, J. A., Phillips, R. J. & Keane, M. P. CXC chemokines in (2021).
angiogenesis of cancer. Semin. Cancer Biol. 14, 195–200 (2004). 378. Luo, X. et al. Inducing vascular normalization: a promising strategy for immu-
347. Ribatti, D. Interleukins as modulators of angiogenesis and anti-angiogenesis in notherapy. Int. Immunopharmacol. 112, 109167 (2022).
tumors. Cytokine 118, 3–7 (2019). 379. Kerr, D. J. Targeting angiogenesis in cancer: clinical development of bev-
348. Indraccolo, S. Interferon-α as angiogenesis inhibitor: learning from tumor acizumab. Nat. Clin. Pract. Oncol. 1, 39–43 (2004).
models. Autoimmunity 43, 244–247 (2010). 380. Kim, E. S. et al. Potent VEGF blockade causes regression of coopted vessels in a
349. Xiao, H. B. et al. Interferon-β efficiently inhibited endothelial progenitor cell- model of neuroblastoma. Proc. Natl Acad. Sci. USA 99, 11399–11404 (2002).
induced tumor angiogenesis. Gene Ther. 19, 1030–1034 (2012). 381. Cohen, P., Cross, D. & Jänne, P. A. Kinase drug discovery 20 years after imatinib:
350. Takano, S., Ishikawa, E., Matsuda, M., Yamamoto, T. & Matsumura, A. Interferon-β progress and future directions. Nat. Rev. Drug Discov. 20, 551–569 (2021).
inhibits glioma angiogenesis through downregulation of vascular endothelial 382. Oholendt, A. L. & Zadlo, J. L. Ramucirumab: a new therapy for advanced gastric
growth factor and upregulation of interferon inducible protein 10. Int. J. Oncol. cancer. J. Adv. Pract. Oncol. 6, 71–75 (2015).
45, 1837–1846 (2014). 383. Lowery, C. D. et al. Anti-VEGFR2 therapy delays growth of preclinical pediatric
351. Murohara, T. et al. Nitric oxide synthase modulates angiogenesis in response to tumor models and enhances anti-tumor activity of chemotherapy. Oncotarget
tissue ischemia. J. Clin. Invest. 101, 2567–2578 (1998). 10, 5523–5533 (2019).
352. Perez-Pinera, P., Berenson, J. R. & Deuel, T. F. Pleiotrophin, a multifunctional 384. Garcia-Carbonero, R. et al. An open-label phase II study evaluating the safety
angiogenic factor: mechanisms and pathways in normal and pathological and efficacy of ramucirumab combined with mFOLFOX-6 as first-line therapy for
angiogenesis. Curr. Opin. Hematol. 15, 210–214 (2008). metastatic colorectal cancer. Oncologist 19, 350–351 (2014).
353. Albrecht, E. D. & Pepe, E. J. Steroid hormone regulation of angiogenesis in the 385. Shirley, M. Olaratumab: first global approval. Drugs 77, 107–112 (2017).
primate endometrium. Front. Biosci. 8, d416–d429 (2003). 386. Tap, W. D. et al. Effect of doxorubicin plus olaratumab vs doxorubicin plus
354. DiPietro, L. A. & Polverini, P. J. in Molecular, Cellular, and Clinical Aspects of placebo on survival in patients with advanced soft tissue sarcomas: the
Angiogenesis (ed. Maragoudakis, M. E.) 105–113 (Springer, 1996). ANNOUNCE randomized clinical trial. JAMA 323, 1266–1276 (2020).
355. Huang, T., Sun, L., Yuan, X. & Qiu, H. Thrombospondin-1 is a multifaceted player 387. Tap, W. D. et al. Olaratumab and doxorubicin versus doxorubicin alone for
in tumor progression. Oncotarget 8, 84546–84558 (2017). treatment of soft-tissue sarcoma: an open-label phase 1b and randomised
356. Marshall, E. The roadblocks to angiogenesis blockers. Science 280, 997 (1998). phase 2 trial. Lancet 388, 488–497 (2016).
357. Marshall, E. The power of the front page of The New York Times. Science 280, 388. Casak, S. J. et al. FDA’s approval of the first biosimilar to bevacizumab. Clin.
996–997 (1998). Cancer Res. 24, 4365–4370 (2018).

Liu et al.
37
389. Rhodes, W. et al. Real-world use of bevacizumab-awwb, a bevacizumab biosi- 419. de Boer, R. H. et al. Vandetanib plus pemetrexed for the second-line treatment
milar, in US patients with metastatic colorectal cancer. Future Oncol. 17, of advanced non-small-cell lung cancer: a randomized, double-blind phase III
5119–5127 (2021). trial. J. Clin. Oncol. 29, 1067–1074 (2011).
390. Ng, E. W. et al. Pegaptanib, a targeted anti-VEGF aptamer for ocular vascular 420. Natale, R. B. et al. Phase III trial of vandetanib compared with erlotinib in
disease. Nat. Rev. Drug Discov. 5, 123–132 (2006). patients with previously treated advanced non-small-cell lung cancer. J. Clin.
391. Holash, J. et al. VEGF-Trap: a VEGF blocker with potent antitumor effects. Proc. Oncol. 29, 1059–1066 (2011).
Natl Acad. Sci. USA 99, 11393–11398 (2002). 421. Lee, J. S. et al. Vandetanib versus placebo in patients with advanced non-small-
392. Mansour, A. M., Al-Ghadban, S. I., Yunis, M. H. & El-Sabban, M. E. Ziv-aflibercept cell lung cancer after prior therapy with an epidermal growth factor receptor
in macular disease. Br. J. Ophthalmol. 99, 1055–1059 (2015). tyrosine kinase inhibitor: a randomized, double-blind phase III trial (ZEPHYR). J.
393. Malik, D. et al. Safety profiles of anti-VEGF drugs: bevacizumab, ranibizumab, Clin. Oncol. 30, 1114–1121 (2012).
aflibercept and ziv-aflibercept on human retinal pigment epithelium cells in 422. Wells, S. A. et al. Vandetanib in patients with locally advanced or metastatic
culture. Br. J. Ophthalmol. 98, i11–i16 (2014). medullary thyroid cancer: a randomized, double-blind phase III trial. J. Clin.
394. de Oliveira Dias, J. R., de Andrade, G. C., Novais, E. A., Farah, M. E. & Rodrigues, E. Oncol. 30, 134–141 (2012).
B. Fusion proteins for treatment of retinal diseases: aflibercept, ziv-aflibercept, 423. Strumberg, D. & Schultheis, B. Regorafenib for cancer. Expert Opin. Investig.
and conbercept. Int. J. Retin Vitreous 2, 3 (2016). Drugs 21, 879–889 (2012).
395. O’Reilly, T. & McSheehy, P. M. Biomarker development for the clinical activity of 424. Ettrich, T. J. & Seufferlein, T. Regorafenib. Recent Results Cancer Res. 211, 45–56
the mTOR inhibitor everolimus (RAD001): processes, limitations, and further (2018).
proposals. Transl. Oncol. 3, 65–79 (2010). 425. Wilhelm, S. M. et al. Regorafenib (BAY 73-4506): A new oral multikinase inhibitor
396. Kawata, T. et al. Dual inhibition of the mTORC1 and mTORC2 signaling pathways of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent
is a promising therapeutic target for adult T-cell leukemia. Cancer Sci. 109, preclinical antitumor activity. Int. J. Cancer 129, 245–255 (2011).
103–111 (2018). 426. Grothey, A. et al. Regorafenib monotherapy for previously treated metastatic
397. Houghton, P. J. Everolimus. Clin. Cancer Res. 16, 1368–1372 (2010). colorectal cancer (CORRECT): an international, multicentre, randomised, pla-
398. Vargesson, N. Thalidomide‐induced teratogenesis: history and mechanisms. cebo-controlled, phase 3 trial. Lancet 381, 303–312 (2013).
Birth Defects Res. C: Embryo Today 105, 140–156 (2015). 427. Bruix, J. et al. Regorafenib for patients with hepatocellular carcinoma who
399. Melchert, M. & List, A. The thalidomide saga. Int. J. Biochem. Cell Biol. 39, progressed on sorafenib treatment (RESORCE): a randomised, double-blind,
1489–1499 (2007). placebo-controlled, phase 3 trial. Lancet 389, 56–66 (2017).
400. Bauer, K. S., Dixon, S. C. & Figg, W. D. Inhibition of angiogenesis by thalidomide 428. Ou, D. L. et al. Regorafenib enhances antitumor immunity via inhibition of p38
requires metabolic activation, which is species-dependent. Biochem. Pharmacol. kinase/Creb1/Klf4 axis in tumor-associated macrophages. J. Immunother. Cancer
55, 1827–1834 (1998). 9, e001657 (2021).
401. Rajkumar, S. V., Blood, E., Vesole, D., Fonseca, R. & Greipp, P. R. Phase III clinical 429. You, W. K. et al. VEGF and c-Met blockade amplify angiogenesis inhibition in
trial of thalidomide plus dexamethasone compared with dexamethasone alone pancreatic islet cancer. Cancer Res. 71, 4758–4768 (2011).
in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern 430. Yakes, F. M. et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor,
Cooperative Oncology Group. J. Clin. Oncol. 24, 431–436 (2006). simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol.
402. Sun, X. et al. Synergistic inhibition of thalidomide and icotinib on human non- Cancer Ther. 10, 2298–2308 (2011).
small cell lung carcinomas through ERK and AKT signaling. Med. Sci. Monit. 24, 431. Abou-Alfa, G. K. et al. Cabozantinib in patients with advanced and progressing
3193–3203 (2018). hepatocellular carcinoma. N. Engl. J. Med. 379, 54–63 (2018).
403. Krönke, J., Hurst, S. N. & Ebert, B. L. Lenalidomide induces degradation of IKZF1 432. Choueiri, T. K. et al. Cabozantinib versus everolimus in advanced renal-cell
and IKZF3. OncoImmunology 3, e941742 (2014). carcinoma. N. Engl. J. Med. 373, 1814–1823 (2015).
404. Kotla, V. et al. Mechanism of action of lenalidomide in hematological malig- 433. Choueiri, T. K. et al. Nivolumab plus cabozantinib versus sunitinib for advanced
nancies. J. Hematol. Oncol. 2, 36 (2009). renal-cell carcinoma. N. Engl. J. Med. 384, 829–841 (2021).
405. Witzig, T. E. et al. Long-term analysis of phase II studies of single-agent lenali- 434. Suyama, K. & Iwase, H. Lenvatinib: a promising molecular targeted agent for
domide in relapsed/refractory mantle cell lymphoma. Am. J. Hematol. 92, multiple cancers. Cancer Control 25, 107327481878936 (2018).
E575–E583 (2017). 435. Kudo, M. et al. Lenvatinib versus sorafenib in first-line treatment of patients with
406. Smith, R. A. et al. Discovery of heterocyclic ureas as a new class of raf kinase unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority
inhibitors: identification of a second generation lead by a combinatorial trial. Lancet 391, 1163–1173 (2018).
chemistry approach. Bioorg. Med. Chem. Lett. 11, 2775–2778 (2001). 436. Motzer, R. J. et al. Lenvatinib, everolimus, and the combination in patients with
407. Lowinger, T. B., Riedl, B., Dumas, J. & Smith, R. A. Design and discovery of small metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre
molecules targeting raf-1 kinase. Curr. Pharm. Des. 8, 2269–2278 (2002). trial. Lancet Oncol. 16, 1473–1482 (2015).
408. Wilhelm, S. M. et al. BAY 43-9006 exhibits broad spectrum oral antitumor activity 437. Matsuki, M. et al. Targeting of tumor growth and angiogenesis underlies the
and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved enhanced antitumor activity of lenvatinib in combination with everolimus.
in tumor progression and angiogenesis. Cancer Res. 64, 7099–7109 (2004). Cancer Sci. 108, 763–771 (2017).
409. Kamal, M. A., Mandour, Y. M., Abd El-Aziz, M. K., Stein, U. & El Tayebi, H. M. Small 438. Motzer, R. et al. Lenvatinib plus pembrolizumab or everolimus for advanced
molecule inhibitors for hepatocellular carcinoma: advances and challenges. renal cell carcinoma. N. Engl. J. Med. 384, 1289–1300 (2021).
Molecules 27, 5537 (2022). 439. Rizzo, A. et al. Lenvatinib plus pembrolizumab: the next frontier for the treat-
410. Escudier, B. et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. ment of hepatocellular carcinoma? Expert Opin. Investig. Drug 31, 371–378
Med. 356, 125–134 (2007). (2022).
411. Raymond, E. et al. Sunitinib malate for the treatment of pancreatic neu- 440. Hu-Lowe, D. D. et al. Nonclinical antiangiogenesis and antitumor activities of
roendocrine tumors. N. Engl. J. Med. 364, 501–513 (2011). axitinib (AG-013736), an oral, potent, and selective inhibitor of vascular endo-
412. Ravaud, A. et al. Adjuvant sunitinib in high-risk renal-cell carcinoma after thelial growth factor receptor tyrosine kinases 1, 2, 3. Clin. Cancer Res 14,
nephrectomy. N. Engl. J. Med. 375, 2246–2254 (2016). 7272–7283 (2008).
413. Schutz, F. A., Choueiri, T. K. & Sternberg, C. N. Pazopanib: clinical development of 441. Huang, W. S. et al. Discovery of 3-[2-(imidazo[1,2- b]pyridazin-3-yl)ethynyl]-4-
a potent anti-angiogenic drug. Crit. Rev. Oncol. Hematol. 77, 163–171 (2011). methyl- N -{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benza-
414. Miyamoto, S. et al. Drug review: pazopanib. Jpn. J. Clin. Oncol. 48, 503–513 mide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster
(2018). region-abelson (BCR-ABL) kinase including the T315I gatekeeper mutant. J. Med.
415. Sternberg, C. N. et al. Pazopanib in locally advanced or metastatic renal cell Chem. 53, 4701–4719 (2010) .
carcinoma: results of a randomized phase III trial. J. Clin. Oncol. 28, 1061–1068 442. Miller, G. D., Bruno, B. J. & Lim, C. S. Resistant mutations in CML and Ph+ALL—
(2010). role of ponatinib. Biologics 8, 243–254 (2014).
416. O’Brien, M. E. et al. Maintenance pazopanib versus placebo in non-small cell 443. O’Hare, T. et al. AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia,
lung cancer patients non-progressive after first line chemotherapy: a double potently inhibits the T315I mutant and overcomes mutation-based resistance.
blind randomised phase III study of the lung cancer group, EORTC 08092 Cancer Cell 16, 401–412 (2009).
(EudraCT: 2010-018566-23, NCT01208064). Eur. J. Cancer 51, 1511–1528 (2015). 444. Gozgit, J. M. et al. Ponatinib (AP24534), a multitargeted pan-FGFR inhibitor with
417. Frampton, J. E. Vandetanib: in medullary thyroid cancer. Drugs 72, 1423–1436 activity in multiple FGFR-amplified or mutated cancer models. Mol. Cancer Ther.
(2012). 11, 690–699 (2012).
418. Commander, H., Whiteside, G. & Perry, C. Vandetanib: first global approval. Drugs 445. Gainor, J. F. & Chabner, B. A. Ponatinib: accelerated disapproval. Oncologist 20,
71, 1355–1365 (2011). 847–848 (2015).

Liu et al.
38
446. Zhang, H. Apatinib for molecular targeted therapy in tumor. Drug Des. Dev. Ther. 475. Zeidan, M. A. et al. Design, synthesis and docking study of novel picolinamide
9, 6075–6081 (2015). derivatives as anticancer agents and VEGFR-2 inhibitors. Eur. J. Med. Chem. 168,
447. Scott, L. J. Apatinib: a review in advanced gastric cancer and other advanced 315–329 (2019).
cancers. Drugs 78, 747–758 (2018). 476. Jiang, Z. et al. Discovery of a highly selective VEGFR2 kinase inhibitor CHMFL-
448. Roviello, G. et al. Apatinib: a novel receptor tyrosine kinase inhibitor for the VEGFR2-002 as a novel anti-angiogenesis agent. Acta Pharm. Sin. B 10, 488–497
treatment of gastric cancer. Cancer Lett. 372, 187–191 (2016). (2020).
449. Roth, G. J. et al. Design, synthesis, and evaluation of indolinones as triple 477. El‐Adl, K., Sakr, H., Nasser, M., Alswah, M. & Shoman, F. M. A. 5‐(4‐Methox-
angiokinase inhibitors and the discovery of a highly specific 6- ybenzylidene)thiazolidine‐2,4‐dione‐derived VEGFR‐2 inhibitors: design, synthesis,
methoxycarbonyl-substituted indolinone (BIBF 1120). J. Med. Chem. 52, molecular docking, and anticancer evaluations. Arch. Pharm. 353, e2000079 (2020).
4466–4480 (2009). 478. El‐Adl, K., El‐Helby, A. A., Sakr, H. & El‐Hddad, S. S. A. Design, synthesis, molecular
450. Hilberg, F. et al. BIBF 1120: triple angiokinase inhibitor with sustained receptor docking, and anticancer evaluations of 1‐benzylquinazoline‐2,4(1 H, 3 H)‐dione
blockade and good antitumor efficacy. Cancer Res. 68, 4774–4782 (2008). bearing different moieties as VEGFR‐2 inhibitors. Arch. Pharm. 353, e2000068 (2020).
451. Catenacci, D. V. et al. Bemarituzumab with modified FOLFOX6 for advanced 479. Sun, W., Hu, S., Fang, S. & Yan, H. Design, synthesis and biological evaluation of
FGFR2-positive gastroesophageal cancer: FIGHT phase III study design. Future pyrimidine-based derivatives as VEGFR-2 tyrosine kinase inhibitors. Bioorg.
Oncol. 15, 2073–2082 (2019). Chem. 78, 393–405 (2018).
452. Xiang, H. et al. Population pharmacokinetic analysis of phase 1 bemarituzumab 480. El-Adl, K. et al. Design, synthesis, and anti-proliferative evaluation of new qui-
data to support phase 2 gastroesophageal adenocarcinoma FIGHT trial. Cancer nazolin-4(3H)-ones as potential VEGFR-2 inhibitors. Bioorg. Med. Chem. 29,
Chemother. Pharmacol. 86, 595–606 (2020). 115872 (2020).
453. Catenacci, D. V. T. et al. Phase I escalation and expansion study of bemar- 481. Dhokne, P., Sakla, A. P. & Shankaraiah, N. Structural insights of oxindole based
ituzumab (FPA144) in patients with advanced solid tumors and FGFR2b-selected kinase inhibitors as anticancer agents: Recent advances. Eur. J. Med. Chem. 216,
gastroesophageal adenocarcinoma. J. Clin. Oncol. 38, 2418–2426 (2020). 113334 (2021).
454. Wainberg, Z. A. et al. Bemarituzumab in patients with FGFR2b-selected gastric or 482. Yao, Y. et al. Design, synthesis and pharmacological evaluation of 4-(3-chloro-4-
gastro-oesophageal junction adenocarcinoma (FIGHT): a randomised, double- (3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carbox-
blind, placebo-controlled, phase 2 study. Lancet Oncol. 23, 1430–1440 (2022). amide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy. Acta
455. Dhillon, S. Avapritinib: first approval. Drugs 80, 433–439 (2020). Pharm. Sin. B 10, 1453–1475 (2020).
456. Gebreyohannes, Y. K. et al. Robust activity of avapritinib, potent and highly 483. Mohamady, S. et al. Dual targeting of VEGFR2 and c-Met kinases via the design
selective inhibitor of mutated KIT, in patient-derived xenograft models of gas- and synthesis of substituted 3-(Triazolo-thiadiazin-3-yl)indolin-2-one derivatives
trointestinal stromal tumors. Clin. Cancer Res. 25, 609–618 (2019). as angiogenesis inhibitors. ACS Omega 5, 18872–18886 (2020).
457. Joseph, C. P. et al. Optimal avapritinib treatment strategies for patients with 484. Zhang, L. et al. Discovery of novel anti-angiogenesis agents. Part 6: multi-
metastatic or unresectable gastrointestinal stromal tumors. Oncologist 26, targeted RTK inhibitors. Eur. J. Med. Chem. 127, 275–285 (2017).
e622–e631 (2021). 485. Sun, Y. et al. Discovery of novel anti-angiogenesis agents. Part 8: diaryl thiourea
458. Jones, R. L. et al. Avapritinib in unresectable or metastatic PDGFRA D842V- bearing 1H-indazole-3-amine as multi-target RTKs inhibitors. Eur. J. Med. Chem.
mutant gastrointestinal stromal tumours: Long-term efficacy and safety data 141, 373–385 (2017).
from the NAVIGATOR phase I trial. Eur. J. Cancer 145, 132–142 (2021). 486. Pan, X. et al. Discovery of novel anti-angiogenesis agents. Part 10: multi-target
459. Heinrich, M. C. et al. Avapritinib in advanced PDGFRA D842V-mutant gastro- inhibitors of VEGFR-2, Tie-2 and EphB4 incorporated with 1,2,3-triazol. Eur. J.
intestinal stromal tumour (NAVIGATOR): a multicentre, open-label, phase 1 trial. Med. Chem. 163, 1–9 (2019).
Lancet Oncol. 21, 935–946 (2020). 487. Li, C. et al. Discovery of novel anti-angiogenesis agents. Part 7: multitarget
460. Kang, Y.-K. et al. Avapritinib versus regorafenib in locally advanced unresectable inhibitors of VEGFR-2, TIE-2 and EphB4. Eur. J. Med. Chem. 141, 506–518 (2017).
or metastatic GI stromal tumor: a randomized, open-label phase III study. J. Clin. 488. Upadhyay, N. et al. Double-edged swords: diaryl pyrazoline thiazolidinediones
Oncol. 39, 3128–3139 (2021). synchronously targeting cancer epigenetics and angiogenesis. Bioorg. Chem.
461. Markham, A. Erdafitinib: first global approval. Drugs 79, 1017–1021 (2019). 116, 105350 (2021).
462. Perera, T. P. S. et al. Discovery and pharmacological characterization of JNJ- 489. Xiaomeng, Zhang et al. Discovery of 1,6-naphthyridin-2(1H)-one derivatives as
42756493 (Erdafitinib), a functionally selective small-molecule FGFR family novel, potent, and selective FGFR4 inhibitors for the treatment of hepatocellular
inhibitor. Mol. Cancer Ther. 16, 1010–1020 (2017). carcinoma. J. Med. Chem. 65, 7595–7618 (2022).
463. Montazeri, K. & Bellmunt, J. Erdafitinib for the treatment of metastatic bladder 490. Wei, M. et al. Design, synthesis and biological evaluation of a series of novel 2-
cancer. Expert Rev. Clin. Pharmacol. 13, 1–6 (2020). benzamide-4-(6-oxy-N-methyl-1-naphthamide)-pyridine derivatives as potent
464. Roubal, K., Myint, Z. W. & Kolesar, J. M. Erdafitinib: a novel therapy for FGFR- fibroblast growth factor receptor (FGFR) inhibitors. Eur. J. Med. Chem. 154, 9–28
mutated urothelial cancer. Am. J. Health Syst. Pharm. 77, 346–351 (2020). (2018).
465. Babina, I. S. & Turner, N. C. Advances and challenges in targeting FGFR signalling 491. Brameld, K. A. et al. Discovery of the irreversible covalent FGFR inhibitor 8-(3-(4-
in cancer. Nat. Rev. Cancer 17, 318–332 (2017). acryloylpiperazin-1-yl)propyl)-6-(2,6-dichloro-3,5-dimethoxyphenyl)-2-(methyla-
466. Bhat, A. A. et al. Tumor microenvironment: an evil nexus promoting aggressive mino)pyrido[2,3- d]pyrimidin-7(8 H)-one (PRN1371) for the treatment of solid
head and neck squamous cell carcinoma and avenue for targeted therapy. tumors. J. Med. Chem. 60, 6516–6527 (2017).
Signal Transduct. Target. Ther. 6, 12 (2021). 492. An, H. et al. Novel hypoxia-inducible factor 1α (HIF-1α) inhibitors for
467. Tang, T. et al. Advantages of targeting the tumor immune microenvironment angiogenesis-related ocular diseases: discovery of a novel scaffold via ring-
over blocking immune checkpoint in cancer immunotherapy. Signal Transduct. truncation strategy. J. Med. Chem. 61, 9266–9286 (2018).
Target. Ther. 6, 72 (2021). 493. Liu, M. et al. Discovery of novel aryl carboxamide derivatives as hypoxia-
468. Tao, J. et al. Targeting hypoxic tumor microenvironment in pancreatic cancer. J. inducible factor 1α signaling inhibitors with potent activities of anticancer
Hematol. Oncol. 14, 14 (2021). metastasis. J. Med. Chem. 62, 9299–9314 (2019).
469. Wang, B. et al. Targeting hypoxia in the tumor microenvironment: a potential 494. Lee, S. et al. Synthesis and biological evaluation of kresoxim-methyl analogues
strategy to improve cancer immunotherapy. J. Exp. Clin. Cancer Res. 40, 24 as novel inhibitors of hypoxia-inducible factor (HIF)-1 accumulation in cancer
(2021). cells. Bioorg. Med. Chem. Lett. 27, 3026–3029 (2017).
470. Li, Y., Zhao, L. & Li, X. F. Hypoxia and the tumor microenvironment. Technol. 495. Jiang, Y. F., Yang, Z. H. & Hu, J. Q. Recurrence or metastasis of HCC: predictors,
Cancer Res. Treat. 20, 153303382110363 (2021). early detection and experimental antiangiogenic therapy. World J. Gastroenterol.
471. AbdelHaleem, A., Mansour, A. O., AbdelKader, M. & Arafa, R. K. Selective VEGFR-2 6, 61–65 (2000).
inhibitors: synthesis of pyridine derivatives, cytotoxicity and apoptosis induction 496. Shojaei, F. Anti-angiogenesis therapy in cancer: current challenges and future
profiling. Bioorg. Chem. 103, 104222 (2020). perspectives. Cancer Lett. 320, 130–137 (2012).
472. Alanazi, M. M. et al. Discovery of new 3-methylquinoxalines as potential anti- 497. Haibe, Y. et al. Resistance mechanisms to anti-angiogenic therapies in cancer.
cancer agents and apoptosis inducers targeting VEGFR-2: design, synthesis, and Front. Oncol. 10, 221 (2020).
in silico studies. J. Enzym. Inhib. Med. Chem. 36, 1732–1750 (2021). 498. Al-Husein, B., Abdalla, M., Trepte, M., DeRemer, D. L. & Somanath, P. R. Anti-
473. Alanazi, M. M. et al. Design, synthesis, docking, ADMET studies, and anticancer angiogenic therapy for cancer: an update. Pharmacotherapy 32, 1095–1111 (2012).
evaluation of new 3-methylquinoxaline derivatives as VEGFR-2 inhibitors and 499. Chen, H. X. & Cleck, J. N. Adverse effects of anticancer agents that target the
apoptosis inducers. J. Enzym. Inhib. Med. Chem. 36, 1760–1782 (2021). VEGF pathway. Nat. Rev. Clin. Oncol. 6, 465–477 (2009).
474. Alanazi, M. M. et al. New bis([1,2,4]triazolo)[4,3-a:3’,4’-c]quinoxaline derivatives 500. Lugano, R., Ramachandran, M. & Dimberg, A. Tumor angiogenesis: causes,
as VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, in silico studies, consequences, challenges and opportunities. Cell. Mol. Life Sci. 77, 1745–1770
and anticancer evaluation. Bioorg. Chem. 112, 104949 (2021). (2020).

Liu et al.
39
501. Ebos, J. M. et al. Accelerated metastasis after short-term treatment with a potent 532. Perdrizet, K. & Leighl, N. B. The role of angiogenesis inhibitors in the era of
inhibitor of tumor angiogenesis. Cancer Cell 15, 232–239 (2009). immune checkpoint inhibitors and targeted therapy in metastatic non-small cell
502. Griffioen, A. W. et al. Rapid angiogenesis onset after discontinuation of sunitinib lung cancer. Curr. Treat. Options Oncol. 20, 21 (2019).
treatment of renal cell carcinoma patients. Clin. Cancer Res. 18, 3961–3971 533. Hilmi, M. et al. Angiogenesis and immune checkpoint inhibitors as therapies for
(2012). hepatocellular carcinoma: current knowledge and future research directions. J.
503. Wang, X., Zhang, H. & Chen, X. Drug resistance and combating drug resistance Immunother. Cancer 7, 333 (2019).
in cancer. Cancer Drug Resist 2, 141–160 (2019). 534. Anderson, T. S., Wooster, A. L., Piersall, S. L., Okpalanwaka, I. F. & Lowe, D. B.
504. Ricci, V., Ronzoni, M. & Fabozzi, T. Aflibercept a new target therapy in cancer Disrupting cancer angiogenesis and immune checkpoint networks for improved
treatment: a review. Crit. Rev. Oncol. Hematol. 96, 569–576 (2015). tumor immunity. Semin. Cancer Biol. 86, 981–996 (2022).
505. Rey, S., Schito, L., Wouters, B. G., Eliasof, S. & Kerbel, R. S. Targeting hypoxia- 535. Lee, W. S., Yang, H., Chon, H. J. & Kim, C. Combination of anti-angiogenic therapy
inducible factors for antiangiogenic cancer therapy. Trends Cancer 3, 529–541 and immune checkpoint blockade normalizes vascular-immune crosstalk to
(2017). potentiate cancer immunity. Exp. Mol. Med. 52, 1475–1485 (2020).
506. Asahara, T. et al. Isolation of putative progenitor endothelial cells for angio- 536. Wang, X. F. et al. Neoadjuvant chemotherapy: practice and thinking for Chinese
genesis. Science 275, 964–967 (1997). patients with early breast cancer. Chin. Med. J. 133, 2368–2369 (2020).
507. Song, S., Ewald, A. J., Stallcup, W., Werb, Z. & Bergers, G. PDGFRβ+ perivascular 537. Ikeda, T., Jinno, H., Matsui, A., Masamura, S. & Kitajima, M. The role of neoad-
progenitor cells in tumours regulate pericyte differentiation and vascular sur- juvant chemotherapy for breast cancer treatment. Breast Cancer 9, 8–14 (2002).
vival. Nat. Cell Biol. 7, 870–879 (2005). 538. Middleton, J. D., Stover, D. G. & Hai, T. Chemotherapy-exacerbated breast cancer
508. Dalton, H. J. et al. Macrophages facilitate resistance to Anti-VEGF therapy by metastasis: a paradox explainable by dysregulated adaptive-response. Int. J. Mol.
altered VEGFR expression. Clin. Cancer Res. 23, 7034–7046 (2017). Sci. 19, 3333 (2018).
509. Greenberg, J. I. et al. A role for VEGF as a negative regulator of pericyte function 539. Ortolan, E. et al. Blood-based genomics of triple-negative breast cancer pro-
and vessel maturation. Nature 456, 809–813 (2008). gression in patients treated with neoadjuvant chemotherapy. ESMO Open 6,
510. Bridgeman, V. L. et al. Vessel co-option is common in human lung metastases 100086 (2021).
and mediates resistance to anti-angiogenic therapy in preclinical lung metas- 540. Perelmuter, V. M. et al. Mechanisms behind prometastatic changes induced by
tasis models. J. Pathol. 241, 362–374 (2017). neoadjuvant chemotherapy in the breast cancer microenvironment. Breast
511. Frentzas, S. et al. Vessel co-option mediates resistance to anti-angiogenic Cancer 11, 209–219 (2019).
therapy in liver metastases. Nat. Med. 22, 1294–1302 (2016). 541. Xiao, L. et al. Anti-vascular endothelial growth factor treatment induces blood
512. Kuczynski, E. A. & Reynolds, A. R. Vessel co-option and resistance to anti- flow recovery through vascular remodeling in high-fat diet induced diabetic
angiogenic therapy. Angiogenesis 23, 55–74 (2020). mice. Microvasc. Res. 105, 70–76 (2016).
513. Rada, M., Lazaris, A., Kapelanski-Lamoureux, A., Mayer, T. Z. & Metrakos, P. Tumor 542. Piperigkou, Z., Mohr, B., Karamanos, N. & Götte, M. Shed proteoglycans in tumor
microenvironment conditions that favor vessel co-option in colorectal cancer stroma. Cell Tissue Res. 365, 643–655 (2016).
liver metastases: a theoretical model. Semin. Cancer Biol. 71, 52–64 (2020). 543. Devisscher, L. et al. Targeting the angio-proteostasis network: combining the
514. Ribatti, D. & Djonov, V. Intussusceptive microvascular growth in tumors. Cancer forces against cancer. Pharmacol. Ther. 167, 1–12 (2016).
Lett. 316, 126–131 (2012). 544. Zhao, Y. & Adjei, A. A. Targeting angiogenesis in cancer therapy: moving beyond
515. Delgado-Bellido, D., Serrano-Saenz, S., Fernández-Cortés, M. & Oliver, F. J. Vas- vascular endothelial growth factor. Oncologist 20, 660–673 (2015).
culogenic mimicry signaling revisited: focus on non-vascular VE-cadherin. Mol. 545. Broekman, F., Giovannetti, E. & Peters, G. J. Tyrosine kinase inhibitors: multi-
Cancer 16, 65 (2017). targeted or single-targeted? World J. Clin. Oncol. 2, 80–93 (2011).
516. Guerrouahen, B. S. et al. Akt-activated endothelium constitutes the niche for 546. Mohajeri, A. et al. Cloning and expression of recombinant human endostatin in
residual disease and resistance to bevacizumab in ovarian cancer. Mol. Cancer periplasm of escherichia coli expression system. Adv. Pharm. Bull. 6, 187–194
Ther. 13, 3123–3136 (2014). (2016).
517. Eyler, C. E. & Rich, J. N. Survival of the fittest: cancer stem cells in therapeutic 547. Rao, N., Lee, Y. F. & Ge, R. Novel endogenous angiogenesis inhibitors and their
resistance and angiogenesis. J. Clin. Oncol. 26, 2839–2845 (2008). therapeutic potential. Acta Pharmacol. Sin. 36, 1177–1190 (2015).
518. McMillin, D. W., Negri, J. M. & Mitsiades, C. S. The role of tumour–stromal 548. Hanahan, D. & Folkman, J. Patterns and emerging mechanisms of the angio-
interactions in modifying drug response: challenges and opportunities. Nat. Rev. genic switch during tumorigenesis. Cell 86, 353–364 (1996).
Drug Discov. 12, 217–228 (2013). 549. Lawler, J. Thrombospondin-1 as an endogenous inhibitor of angiogenesis and
519. Jain, R. K. et al. Biomarkers of response and resistance to antiangiogenic therapy. tumor growth. J. Cell. Mol. Med. 6, 1–12 (2002).
Nat. Rev. Clin. Oncol. 6, 327–338 (2009). 550. Streit, M. et al. Thrombospondin-2: a potent endogenous inhibitor of tumor
520. Pircher, A. et al. Biomarkers in tumor angiogenesis and anti-angiogenic therapy. growth and angiogenesis. Proc. Natl Acad. Sci. USA 96, 14888–14893 (1999).
Int. J. Mol. Sci. 12, 7077–7099 (2011). 551. Watanabe, K. et al. Vasohibin as an endothelium-derived negative feedback
521. Jayson, G. C., Hicklin, D. J. & Ellis, L. M. Antiangiogenic therapy—evolving view regulator of angiogenesis. J. Clin. Invest. 114, 898–907 (2004).
based on clinical trial results. Nat. Rev. Clin. Oncol. 9, 297–303 (2012). 552. Hiraki, Y. et al. Identification of chondromodulin I as a novel endothelial cell
522. Cao, Y. et al. Forty-year journey of angiogenesis translational research. Sci. Transl. growth inhibitor. J. Biol. Chem. 272, 32419–32426 (1997).
Med. 3, 144rv3 (2011). 553. Bikfalvi, A. & Gimenez-Gallego, G. The control of angiogenesis and tumor
523. Hurwitz, H. et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for invasion by platelet factor-4 and platelet factor-4-derived molecules. Semin.
metastatic colorectal cancer. N. Engl. J. Med. 350, 2335–2342 (2004). Thromb. Hemost. 30, 137–144 (2004).
524. Mokhtari, R. B. et al. Combination therapy in combating cancer. Oncotarget 8, 554. O’Reilly, M. S. et al. Angiostatin: a novel angiogenesis inhibitor that mediates the
38022–38043 (2017). suppression of metastases by a lewis lung carcinoma. Cell 79, 315–328 (1994).
525. Song, Y. et al. Anti-angiogenic agents in combination with immune checkpoint 555. Maeshima, Y. et al. Distinct antitumor properties of a type IV collagen domain
Inhibitors: a promising strategy for cancer treatment. Front. Immunol. 11, 1956 derived from basement membrane. J. Biol. Chem. 275, 21340–21348 (2000).
(2020).
526. Ciciola, P., Cascetta, P., Bianco, C., Formisano, L. & Bianco, R. Combining immune
checkpoint inhibitors with anti-angiogenic agents. J. Clin. Med. 9, 675 (2020). Open Access This article is licensed under a Creative Commons
527. Yasuda, S. et al. Simultaneous blockade of programmed death 1 and vascular Attribution 4.0 International License, which permits use, sharing,
endothelial growth factor receptor 2 (VEGFR2) induces synergistic anti-tumour adaptation, distribution and reproduction in any medium or format, as long as you give
effect in vivo. Clin. Exp. Immunol. 172, 500–506 (2013). appropriate credit to the original author(s) and the source, provide a link to the Creative
528. Majidpoor, J. & Mortezaee, K. The efficacy of PD-1/PD-L1 blockade in cold Commons license, and indicate if changes were made. The images or other third party
cancers and future perspectives. Clin. Immunol. 226, 108707 (2021). material in this article are included in the article’s Creative Commons license, unless
529. Yi, M. et al. Synergistic effect of immune checkpoint blockade and anti- indicated otherwise in a credit line to the material. If material is not included in the
angiogenesis in cancer treatment. Mol. Cancer 18, 60 (2019). article’s Creative Commons license and your intended use is not permitted by statutory
530. Cheng, A. L. et al. IMbrave150: Efficacy and safety results from a ph III study regulation or exceeds the permitted use, you will need to obtain permission directly
evaluating atezolizumab (atezo) + bevacizumab (bev) vs sorafenib (Sor) as first from the copyright holder. To view a copy of this license, visit http://
treatment (tx) for patients (pts) with unresectable hepatocellular carcinoma creativecommons.org/licenses/by/4.0/.
(HCC). Ann. Oncol. 30, ix186–ix187 (2019).
531. Neves, K. B., Montezano, A. C., Lang, N. N. & Touyz, R. M. Vascular toxicity
associated with anti-angiogenic drugs. Clin. Sci. 134, 2503–2520 (2020). © The Author(s) 2023

ANGIOGENESIS

Uploaded by

Copyright:

Available Formats

ANGIOGENESIS

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

ANGIOGENESIS

Uploaded by

Copyright:

Available Formats

Signal Transduction and Targeted Therapy www.nature.

REVIEW ARTICLE OPEN

Angiogenic signaling pathways and anti-angiogenic therapy

research of anti-angiogenic therapy.

Signal Transduction and Targeted Therapy (2023)8:198 ; https://doi.org/10.1038/s41392-023-01460-1

INTRODUCTION angiogenesis is locked or limited to a quiescent status owing to

Received: 16 November 2022 Revised: 20 March 2023 Accepted: 20 April 2023

© The Author(s) 2023

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Drugs Targets Indications Companies Adverse effects

Signal Transduction and Targeted Therapy (2023)8:198

Tyrosine kinase inhibitors

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Fig. 7 Timeline of the milestones regarding the research on tumor angiogenesis

Signal Transduction and Targeted Therapy (2023)8:198

Agents Targets Phase Status Conditions or diseases Trial ID

PDGFR-α, c-Kit - Approved Locally advanced unresectable or metastatic GIST NCT03862885

Signal Transduction and Targeted Therapy (2023)8:198

Avapritinib (BLU-285) Active, not

Signal Transduction and Targeted Therapy (2023)8:198

Futibatinib II Recruiting Advanced/metastatic GC or GEJ cancer, myeloid or NCT04189445

Erdaﬁtinib FGFR-1/-2/-3/-4 IV Recruiting Bladder cancer with FGFR mutation NCT05052372

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Compounds Chemical Structures Targets IC50 References

7 VEGFR-2 0.12 μM 477

8 VEGFR-2 0.12 μM 478

9 VEGFR-2 0.23 μM 479

Signal Transduction and Targeted Therapy (2023)8:198

10 VEGFR-2 0.29 μM 480

11 VEGFR-2 0.31 μM 481

14 VEGFR-2 0.18 μM 481

Signal Transduction and Targeted Therapy (2023)8:198

22 FGFR-1 0.6 μM 491

23 HIF-1α 0.6 μM 492

Signal Transduction and Targeted Therapy (2023)8:198

24 HIF-1α 0.32 μM 493

25 HIF-1α 0.6 μM 494

Signal Transduction and Targeted Therapy (2023)8:198

Signal Transduction and Targeted Therapy (2023)8:198

Interventions Cancers Phase Results NCT numbers

Successful clinical trials

Signal Transduction and Targeted Therapy (2023)8:198

Similar safety; non-statistically signiﬁcant gain in OS than gemcitabine NCT00219557

blood transport of immunosuppressant, inhibit excessive angio-

nivolumab and pembrolizumab) combined with cabozantinib,

positive signiﬁcance to anti-cancer treatment according to