7-sURVIVAL STRATEGIES

Biomedicine & Pharmacotherapy 176 (2024) 116783
Contents lists available at ScienceDirect
Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha
Review
Survival strategies: How tumor hypoxia microenvironment

orchestrates angiogenesis
Mengrui Yang a, 1, Yufeng Mu b, Xiaoyun Yu a, Dandan Gao a, Wenfeng Zhang a, Ye Li c,
Jingyang Liu c, Changgang Sun a, d, *, Jing Zhuang d, **
a
College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang 261053, China
b
First School of Clinical Medicine, Shandong University of Traditional Chinese Medicine, Jinan 250014, China
c
Faculty of Chinese Medicine and State Key Laboratory of Quality Research in Chinese Medicines, Macau University of Science and Technology, 999078, Macao Special
Administrative Region of China
d
Department of Oncology, Weifang Traditional Chinese Hospital, Weifang 261000, China
A R T I C L E I N F O A B S T R A C T
Keywords: During tumor development, the tumor itself must continuously generate new blood vessels to meet their growth
tumor microenvironment needs while also allowing for tumor invasion and metastasis. One of the most common features of tumors is
hypoxia, angiogenesis hypoxia, which drives the process of tumor angiogenesis by regulating the tumor microenvironment, thus
VEGF
adversely affecting the prognosis of patients. In addition, to overcome unsuitable environments for growth, such
non-VEGF-dependent angiogenesis
as hypoxia, nutrient deficiency, hyperacidity, and immunosuppression, the tumor microenvironment (TME)
coordinates angiogenesis in several ways to restore the supply of oxygen and nutrients and to remove metabolic
wastes. A growing body of research suggests that tumor angiogenesis and hypoxia interact through a complex
interplay of crosstalk, which is inextricably linked to the TME. Here, we review the TME’s positive contribution
to angiogenesis from an angiogenesis-centric perspective while considering the objective impact of hypoxic
phenotypes and the status and limitations of current angiogenic therapies.
Abbreviations: TME, Tumor microenvironment; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor; SDPP, stroma-
derived prognostic predictor; ECM, extracellular matrix; ROS, reactive oxygen species; HIF-1, hypoxia inducible factor-1; HRE, hypoxia-response element; PlGF,
placental growth factor; MT-MMP, membrane type-matrix metalloproteinase; MMP, matrix metalloproteinase; NF-κb, nuclear factor kappa-B; OS, overall survival;
FGF, fibroblast growth factor; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; Ang, Angiopoietin; TNF-α, tumor necrosis factor-α; IL-1p, interleukin-1p;
VSMC, vascular smooth muscle cells; Tie2, endothelial cell specific tyrosine kinase receptor-2; OC, ovarian cancer; NSCLC, non-small cell lung cancer; HCC, he
patocellular carcinoma; TGF-β, transforming growth factor-β; FGFR, fibroblast growth factor receptor; BFGF, basic fibroblast growth factor; HSPG, heparan sulfate
proteoglycan; TAMs, tumor-associated macrophages; IL-1, interleukin-1; IL-6, interleukin-6; IL-8, interleukin-8; NO, nitric oxide; COX2, cyclooxygenase-2; COX6,
cyclooxygenase-6; MTOR, mammalian target of rapamycin; REDD1, regulated in development and DNA damage responses 1; MM, multiple myeloma; GBM, glio
blastoma; EndMT, endothelial-mesenchymal transition; ADM, adrenomedullin; Sema4D, semaphorin 4D; CAFs, cancer-associated fibroblasts; SKCM, skin cutaneous
melanoma; PDAC, pancreatic ductal adenocarcinoma; PHD, prolyl hydroxylase; EVs, extracellular vesicles; MRNA, messenger RNA; LncRNA, long non-coding RNA;
TSPN, tetraspanin; HUVECs, human umbilical vein endothelial cells; CRC, colorectal cancer; EFNA3, Ephrin A3; CXCL12, stromal cell-derived factor-1; CXCR4, CXC
chemokine receptor 4; ZO-1, zonula occludens-1; IFP, interstitial fluid pressure; FDA, Flight Data Analysis; AADs, anti-angiogenic drugs; ICI, immune checkpoint
inhibitors; NRP1, neuropilin 1; OXPHOS, oxidative phosphorylation; NFAT, nuclear factor of activated T cells; ALK1, activin receptor-like kinase 1; CCL19, C-C Motif
Chemokine Ligand 19; PVHL, von Hippel–Lindau tumor suppressor protein; RCC, renal cell carcinoma; MTC, medullary thyroid carcinoma; TC, thyroid carcinoma;
DTC, differentiated thyroid cancer; GIST, gastrointestinal stromal tumors; NET, neuroendocrine tumor; STC, soft tissue cancer; PPC, primary peritoneal carcinoma;
GAC, gastric adenocarcinoma; FTC, fallopian tube cancer; CC, cervical cancer; OEC, ovarian epithelial carcinoma; BC, Breast cancer; PC, pancreatic cancer; SEGA,
subependymal giant cell astrocytoma.
* Corresponding author at: College of Traditional Chinese Medicine, Shandong Second Medical University, Weifang 261053, China
** Corresponding author.
E-mail addresses: [email protected] (C. Sun), [email protected] (J. Zhuang).
1
These authors have contributed equally to this work and share the first authorship.
https://doi.org/10.1016/j.biopha.2024.116783
Received 15 March 2024; Received in revised form 7 May 2024; Accepted 17 May 2024
Available online 25 May 2024
0753-3322/© 2024 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/).
M. Yang et al. Biomedicine & Pharmacotherapy 176 (2024) 116783
1. Introduction “antiangiogenic therapy”, and restricted our search to articles published

since 2019.
In the human body, to maintain the homeostasis of the immune
system, body temperature and pH, oxygen, nutrients, metabolites, and 3. Hypoxia and angiogenesis in tumors: Positive correlations
other substances can be transported through the blood vessels between that crosstalk each other
cells, thus ensuring proper bodily function [1]. Neovascularization not
only plays an important role in embryonic development, organ growth, The expression profiles of genes associated with angiogenic and
and wound healing but also is the basis for tumor growth and spread. hypoxic responses are highly predictive in terms of cancer prognosis
Some studies have shown that when the tumor grows more than 2–3 mm [13,14]. Greg Finak et al. [15]proposed a new stroma-derived prog
in diameter, it becomes reliant on the neovascularization formed by the nostic predictor (SDPP) by using laser capture microdissection to
tumor itself to provide nutrients and oxygen [2]. Tumor cells do not exist compare the gene expression profiles of tumor stroma from 53 primary
in isolation in the body; their cancerous transformation depends on the breast tumors as well as derived signatures that were strongly correlated
surrounding tumor microenvironment (TME), which consists of many with clinical outcomes. The genes represented in the SDPP reveal a
different cell types as well as biophysical and biochemical components robust prognostic capacity for differential immune responses as well as
[3]. TME is an active promoter of cancer progression [4], and it forms a angiogenic and hypoxic responses. A bidirectional cross-link between
dynamic and reciprocal relationship with cancer cells at an early stage of hypoxia and angiogenesis has now been identified, indicating a positive
tumor growth. This complex interaction provides a favorable "breeding correlation between the two in crosstalk [16]. Hypoxia and angiogenesis
ground" for tumor cell survival, local invasion, and metastatic spread. In are not simply two important phenotypes that characterize tumor ma
addition, oxygen supply plays an essential role in tumor development, lignancy, but more importantly, hypoxia can act as an "upstream factor"
and to overcome the prevalent hypoxia, the TME coordinates angio for a number of pro-angiogenic factors, triggering their increased
genesis on multiple fronts to restore oxygen and nutrient supply and to expression. It has been shown that HIF-1α directly upregulates VEGF and
remove metabolic wastes [5]. Neovascularization in solid tumors begins activates stromal fibroblasts via PDGF-BB thereby creating a cascade of
with excessive pro-angiogenic signaling due to hypoxia, which is a effects, and these activated fibroblasts become hubs for the production
critical step in tumor growth, invasion, and metastasis and a hallmark of of PDGF-CC, and FGF, among others, which together promote
cancer progression [6,7]. Hypoxia, a typical feature of the tumor non-VEGF-dependent tumor angiogenesis [17]. At the same time, solid
microenvironment, is present in 90 % of solid tumors [8] and is essen tumors begin the process of generating a large number of pathological
tially a contradiction between the oxygen demand of cancer cells and the blood vessels, driven by the combination of higher nutritional re
insufficient supply of oxygen due to tumor vascular dysfunction [9]. The quirements of the tumor itself and the high expression of pro-angiogenic
rapid proliferation of tumor cells consumes large amounts of oxygen, factors. The newly generated pathological blood vessels have unstable
which is the main cause of the hypoxic microenvironment [10]. The and immature vascular structure, which makes them unable to reach the
presence of a hypoxic microenvironment alters the expression levels of "ideal state" of energy and oxygen supply at the early stage of angio
genes that regulate metabolism and other processes, making intercel genesis, and this, on the contrary, leads to extensive hypoxia in the
lular communication more frequent and complex [11] and shaping a tumor area where they are located [18], which aggravates the malignant
tumor-promoting and metastatic TME. From this perspective, a close manifestation of the tumor. These evidences suggest a crosstalk between
interactive link exists between tumor angiogenesis, hypoxia, and TME, hypoxia and tumor angiogenesis, and the two are mutually malignant
collectively promoting tumorigenesis and progression. outcomes. Three main factors contribute to tumor hypoxia: (1) High
Given the importance of angiogenesis in the biological process of proliferation rate of cancer cells, which are not only metabolically active
tumors, Judah Folkman introduced the idea of anti-angiogenic therapy but also consume a lot of energy, and when the metabolic oxygen de
as early as 1970 [12]. Despite the widespread use of anti-angiogenic in mand exceeds the supply, the hypoxic area of cancer cells will be
the clinical treatment of many solid tumors, the survival benefit of aggravated. (2) Dysregulation of angiogenesis leads to abnormal
cancer patients is still limited. Moreover, various limitations persist in vascular structure (chaotic arrangement and formation of many
anti-angiogenic treatment, which has prompted further research into the non-functional blood vessels) and vascular pattern (rapid growth of
signaling behind tumor angiogenesis to improve the clinical effect cancer cells, and cancerous areas become hypoxic due to the lack of a
through the development of multi-agent and combination therapies. vasculature system). (3) Activation and proliferation of stromal cells and
Previous studies have focused on the conclusion that hypoxia and an increase in stromal components lead to enhanced compression of
angiogenesis are both malignant manifestations of tumors, and have blood vessels by the extracellular matrix (ECM), resulting in impaired
emphasized the impact of typical angiogenic factors such as VEGF on circulation and insufficient oxygen supply, further leading to tissue
tumor angiogenesis. Whereas the authors of this paper argue that hyp hypoxia [19]. For these reasons, cancer hypoxia has been categorized
oxia and angiogenesis should be discussed more as triggers for each into three main types: chronic, acute, and cyclic hypoxia [20](Fig. 1).
other by integrating existing studies and literature. Therefore, in this Changes in the redox status of tumor cells and the associated
paper, starting from hypoxic TME, we integrate the complex microenvironment (e.g., due to the production of reactive oxygen spe
pro-angiogenic factors (such as non-VEGF-dependent angiogenic fac cies, ROS) regulate the transcriptional control of hypoxia inducible
tors, tumor-associated macrophages, cancer-associated fibroblasts, factor-1 (HIF-1) mediated angiogenic factors and also influence down
exosomes, etc.) in TME, and explore the effects of hypoxia on angio stream angiogenic signaling. When ROS are produced in excess or due to
genesis, especially on the effects produced by these easy-to-overlook defective antioxidant defenses, ROS levels rise dramatically, leading to
pro-angiogenic factors. To further elucidate the crosstalk between hyp the prolyl hydroxylase (PHD) inactivation and HIF-1α stabilization [21]
oxia and angiogenesis, and then to provide feasible theoretical refer (Fig. 2a). HIFs, as core factors responding to the low partial pressure of
ences for clinical anti-angiogenic multi-target combination therapy and oxygen within solid tumors, interact with other signaling pathways,
the development of new target drugs from multiple perspectives. such as JAK/STAT3 signaling pathway, Notch signaling pathway, etc,
[22–29] (Fig. 2b) and exert pro-angiogenic effects by mediating the
2. Methods expression of downstream genes, which can have a malignant impact on
the prognosis of tumor patients. Under hypoxic conditions, HIF-α pro
We used “Pubmed” to search for literature related to tumor angio teins are stable and can translocate into the nucleus, where they heter
genesis and tumor hypoxia. We used keyword“Tumor angiogenesis”, odimerize with HIF-1β proteins to form functional HIF transcription
“Tumor hypoxia”, “angiogenic factor”, “VEGF”, “angiopoietin”, “PDGF”, factor complexes. Upon recruitment of transcriptional co-activators, the
“TGF-β”, “FGF”, “TAMs”, “CAFs”, “Extracellular vesicles”, HIF-α/HIF-1β complex responds to the expression of tumor
2
Fig. 1. Different types of tumor hypoxia: Chronic hypoxia: duration > 24 hours, mainly caused by excessive proliferation of cancer cells; Acute hypoxia: duration
< 24 hours, caused by sudden obstruction of small vessels; Cyclic hypoxia: variable in duration due to immature, dysfunctional structural closure of the neovascular
system. Created with www.figdraw.com.
angiogenesis-related genes (e.g., VEGFA, TGF-β [7]) and induces the tumor microenvironment. Solid tumors try to compensate for their
secretion of cytokines from the relevant cells (e.g., macrophages, qualitative deficiencies by increasing the number of blood vessels in the
tumor-associated fibroblasts [30]) by binding to hypoxia-response face of harsh microenvironmental conditions [37], and this reciprocal
element (HRE), which are located in the promoter regions of a large relationship promotes the development of a hypoxic tumor microenvi
number of target genes. ronment and further stimulates more pathological tumor angiogenesis.
In normal tissues, the vascular system is quiescent and tightly
regulated by the balance between pro- and anti-angiogenic factors, 4. Hypoxic conditions in the TME radicalize angiogenic
whereas, in tumors, the angiogenic switch shifts the balance towards processes
angiogenesis, leading to tumor development and progression. Neo
vascularization in solid tumors begins with excessive pro-angiogenic TME, as a self-sufficient ecological structure of cancer, mainly con
signaling due to hypoxia, which is a critical step in tumor growth, in sists of tumor cells, immune cells, stromal cells, extracellular matrix, and
vasion, and metastasis and a hallmark of cancer development [31]. various growth factors and EVs [38]. Growing evidence indicates that
Tumor angiogenesis can occur in many ways, such as vasculogenesis, cellular and non-cellular components of the TME can reprogram
sprouting angiogenesis, intussusceptive angiogenesis, coalescent tumorigenesis, growth, invasion, metastasis, and response to therapy
angiogenesis, vessel elongation/cooption, and vasculogenic mimicry [39], with angiogenesis being no exception. This section focuses on how
(Fig. 3). When pro-angiogenic signals, such as VEGF, are predominant, individual components of the TME exert pro-angiogenic effects under
the onset of angiogenesis is induced, a process known as the "angiogenic the influence of a hypoxic ecological niche (Table 1).
switch" in tumors. Activation of the "angiogenic switch" results in
aberrant capillary sprouting, tortuous and excessive vascular branching, 4.1. Hypoxia microenvironment regulates growth factor-altered
vascular enlargement, unstable flow, microhemorrhages, leakage, and angiogenic pathways
proliferation of aberrant endothelial cells, among other outcomes [6].
Although the blood vessels generated in this case are beneficial to the Growth factors in the tumor microenvironment are secreted and
tumor’s vascular supply, they also result in the tumor’s vasculature regulated by various cell types, and a significant correlation exists be
becoming functionally and morphologically heterogeneous, which dif tween their expression levels and hypoxia. In addition to regulating cell
fers fundamentally from the normal vasculature [32]. Twisted and dis proliferation, differentiation, and apoptosis, these growth factors play
torted hyperpermeable neovascularization has a large share in the an important role in the coordination of signaling responses during
vascular system of tumor tissues [33,34]. The high permeability of blood angiogenesis. (Fig. 4)
vessel walls helps tumor cells enter the circulatory system and then
metastasize and spread to other tissues throughout the body [35]. 4.1.1. VEGF-dependent angiogenesis
Furthermore, structural abnormalities of the tumor vascular system that VEGF, originally called “vascular permeability factor,” is an extra
are dysfunctional, chaotically distributed, and highly leaky often result cellular signaling protein that is produced and secreted by tumor cells
in blood passing through the same vessel but following different paths and the surrounding matrix in cancer, stimulates angiogenesis [67], and
[36], which, together with deficiencies such as inadequate perfusion, is associated with tumor progression, invasion, metastasis, and tumor
make the tumor vasculature unable to efficiently transport nutrients and recurrence. The VEGF family consists of five secreted proteins: VEGF
remove harmful metabolic wastes, thus exacerbating hypoxia in the (also known as VEGF-A), VEGF-B, VEGF-C, VEGF-D, and placental
3
Fig. 2. Fundamentals of hypoxia and the interaction of HIF signaling with multiple pathways: a. In normoxia, PHD and pVHL mediate the ubiquitination
degradation of HIF, which results in the inhibition of the HIF signaling pathway. Under hypoxia, HIF stabilizes its accumulation and binds to the constitutively
expressed protein ARNT (aryl hydrocarbon receptor nuclear translocator protein, or HIF-1β) and to the coactivator p300/CBP to form an active transcription
complex. coactivator p300/CBP to form an active transcription complex to promote the transcription of downstream genes. b. Interaction between HIF signaling and
multiple signaling pathways. Created with www.figdraw.com.
growth factor (PlGF) [68]. As a downstream factor of HIF-1α, VEGF will leading to specific endothelial responses such as cell survival, prolifer
continue to be highly expressed under the influence of the hypoxic ation, migration, invasion, vascular permeability, and vascular inflam
microenvironment [69]. A key role in pathological angiogenesis is the mation. Tight coordination of these cellular processes is essential for the
VEGF/VEGF receptor (VEGFR) axis, especially the VEGF-A/VEGFR2 successful establishment of new blood vessels. VEGF secreted by tumor
axis [70,71]. VEGFR-2 activation initiates multiple signaling pathways cells induces endothelial cell proliferation and survival mainly through
4
Fig. 3. Different modalities of tumor angiogenesis. Created with www.figdraw.com.
Table 1
Pro-angiogenic effects of components in hypoxic ecological niches.
Category Mechanisms References
Pro-angiogenic VEGF-dependent VEGF 1. Promote capillary bud formation. [40–44]

factor angiogenesis 2. Promotes VEGFR2 phosphorylation to initiate and maintain angiogenesis.
3. Inducing an inflammatory response.
4. PlGF: triggers crosstalk between VEGFR-1 and VEGFR-2.
Non-VEGF-dependent Ang Ang-1: recruitment of pericytes to achieve vascular homeostasis; Ang-2: Stimulation of new vessel [45–47]
angiogenesis sprouting.
PDGF Recruitment of pericytes to maintain vascular homeostasis. [48]
TGF- Induction of endothelial cell migration and differentiation; Promotes capillary formation and increases [49–53]
β microvessel density; Increased VEGF expression.
FGF Crosstalk with VEGF-A or independent induction of angiogenesis; upregulation of PDGFR expression. [54,55]
TAMs 1. Coordinate factors such as bFGF, VEGF, IL-1, IL-8, TNF-α and NO to promote endothelial cell pro [56–58]
liferation and matrix remodeling.
2. TAMs themselves release pro-angiogenic factors such as MMP-2, MMP-7, MMP-9, MMP-12 and COX2.
3. Hypoxic TAMs upregulate REDD1 expression, leading to excessive abnormal angiogenesis.
4. TAMs are involved in all stages of angiogenesis from early sprouting to late neointimal stabilization.
CAFs 1. CAFs secrete TGF-β, FGF, VEGF, PlGF, MMP and other pro-vascular growth factors. [59–61]
2. CAFs participate in tumor angiogenesis by transdifferentiating into endothelial cells via EndMT.
3. CAFs can produce and organize ECM to promote tumor angiogenesis.
EVs 1. EVs influence angiogenesis by transporting pro-angiogenic biomolecules such as VEGF, MMP, [62–66]
microRNA and others.
2. EVs can induce the formation of vascular lumens by transporting proteins, nucleic acids, and so on.
3. EVs regulate endothelial cell characteristics and promote angiogenesis under hypoxic conditions.
4. EVs promote tumor angiogenesis by affecting vascular permeability.
ERK and PI3K/Akt pathways [72,73]. Endothelial cell migration oxidative phosphorylation (OXPHOS) and induce the production of
downstream of VEGFR2 is induced through multiple signaling path ROS, which further stimulates VEGFR2 phosphorylation and initiates
ways, often involving PI3K stimulation and Rho gtpase activation [74]. and maintains tumor angiogenesis [41]. VEGF-induced angiogenesis is
Alternatively, VEGF-mediated cell invasion is promoted by the expres dependent on vascular permeability, which is considered a prerequisite
sion of membrane type-matrix metalloproteinase (MT-MMP), matrix for VEGF-induced angiogenesis. Vascular permeability is not only
metalloproteinase-2(MMP-2), MMP-9 and urokinase plasminogen acti essential for normal tissue homeostasis but also closely related to
vator, which degrade the basement membrane and extracellular matrix, vascular inflammation. Although VEGF is not an inflammatory cytokine,
allowing endothelial cells to migrate and form capillary buds [75]. In VEGF can induce the nuclear factor of activated T cells (NFAT) in
addition, VEGF has been widely reported to enhance mitochondrial endothelial cells via PLCγ/calcineurin, promoting an inflammatory gene
5
Fig. 4. Growth factors regulated by the hypoxic microenvironment. Created with www.figdraw.com.
expression pattern similar to that of IL-1β [74]. Furthermore, growth factor (FGF), platelet-derived growth factor (PDGF), and
VEGF-mediated activation of nuclear factor kappa-B(NF-κB) down Angiopoietin-2 (Ang2) to promote tumor angiogenesis [81,82]. These
stream of Akt can induce an inflammation-type response and promote VEGF-independent mechanisms represent potential novel mechanisms
leukocyte attraction, thereby contributing to the angiogenic process and therapies that are of high value for inhibiting pathological angio
[76]. As a member of the VEGF family, PlGF enhances pathological genesis in hypoxic tumors.
angiogenesis mainly by triggering crosstalk between VEGFR-1 and
VEGFR-2 [43,44]. 4.1.2.1. Angiopoietin. Angiopoietins are composed of four members,
With the in-depth study of various pro-angiogenic factors, VEGF and namely Ang-1, Ang-2, Ang-3, and Ang-4. Ang-1 and Ang-2, ligands of the
its related receptors have been considered the most relevant regulatory tyrosine kinase receptor Tie2, are widely expressed in many embryonic
pathways for tumor angiogenesis, which has greatly promoted the tissues [83] and play an important role in angiogenesis. Among them,
clinical development of VEGF-targeted drugs. Bevacizumab, a mono Ang-1 is the major ligand of Tie2, while Ang-2 can function as an
clonal antibody targeting VEGF developed in this context, has shown antagonistic ligand [84]. Ang-2 is expressed in cancer cells, while Ang1
encouraging anti-tumor effects in many solid tumors, but multiple is expressed in cells such as the endothelial circumference oxyntic cell,
clinical trials have proved that some patients using bevacizumab have a pericytes, fibroblasts and other non-vascular stromal cells in addition to
median overall survival (OS) prolongation of less than 5 months [77]. cancer cells [32,85,86]. Ang-1 and Ang-2 are associated with the later
This indicates that anti-VEGF antibody therapy only temporarily inhibits stages of vascular development, specifically playing a major role in the
tumor progression, and the initiation of other pathways also provides a process of vascular maturation and remodeling, as a transcriptional
new direction for anti-angiogenesis therapy. regulator of angiopoietin [87], stable expression of HIF results in
up-regulation of angiopoietin expression [88].
4.1.2. Non-VEGF-dependent angiogenesis Under physiological conditions, the Ang-1/Tie2 pathway is tightly
After initial disease stabilization and prolonged VEGFR inhibition, regulated. In tumor tissues, hypoxia and cytokines such as tumor ne
tumor progression is associated with up-regulation of other proangio crosis factor-α (TNF-α) and interleukin-1p (IL-1p) secreted by macro
genic factors, termed VEGF-independent angiogenesis [78], and this phages can cause pericyte apoptosis [89] and induce the increase of
pathway reinitiates tumor growth progression [79]. During tumor pro Ang-1 expression to promote angiogenesis in tumor tissues [90]. Mul
gression, hypoxia causes excessive accumulation of HIF-1 and increases tiple experiments have shown that Ang-1 may play a role in the
the expression of many pro-angiogenic genes that are extremely recruitment of pericyte, including pericytes and vascular smooth muscle
important for new blood vessel sprouting [80]. In the process of HIF-1 cells (VSMC) [45], which are perivascular cells that newly formed blood
participating in the formation of the vascular system, it can bind not vessels need to be covered to achieve vascular stability and vasomotor
only with VEGF, the main angiogenic factor, but also cooperate with control [91]. Ang-1 stimulates the binding of parietal cells to endothelial
other VEGF-independent pro-angiogenic factors such as fibroblast cells, leading to vascular maturation and maintenance of homeostasis in
6
newly formed blood vessels [46]. paracrine manner [114]. For example, TGF-β1 activates intracellular
Although Ang-1 is widely expressed in vascular supporting cells, mediators, including Smad proteins, p38 MAPK, and ERK pathways
Ang-2 expression is restricted to sites of vascular remodeling [92]. When through TGF-β type I and type II receptors [115]. Some of the above
VEGF is present, Ang-2 induces endothelial cell proliferation and activated signals as the upstream target genes of HIF-1 will interfere
migration and stimulates the sprouting of new blood vessels [47], with HIF-1, thereby aggravating hypoxic expression in TME. Moreover,
whereas when endogenous VEGF activity is inhibited, it promotes hypoxia has been shown to cause upregulation of TGF-β signaling in a
endothelial cell death and vascular degeneration [93]. This suggests a variety of cancer cells [116] and affect angiogenesis in tumors in a va
paradoxical role of Ang-2 in tumor angiogenesis. Hypoxia has been riety of ways. For example, TGF-β induces endothelial cell proliferation
shown to increase Ang-2 expression in endothelial cells in vitro [94], and migration via activin receptor-like kinase 1 (ALK1) type I receptor
and overexpression of Ang-2 promotes tumor neovascularization and and endoprotein, thereby promoting angiogenesis [49], which is critical
neocapillary remodeling and formation [95] and impairs the stability of for tumor growth and metastasis. The pro-angiogenic activity of TGF-β
the newly formed vessels. In addition, Ang-2 competitively inhibits was also shown by promoting capillary formation [50] and increasing
Ang1-induced activation of endothelial cell specific tyrosine kinase the expression of VEGF [51]. Additionally, increased TGF-β expression
receptor-2 (Tie2) [96], thereby relaxing the interaction between endo has also been demonstrated to be associated with increased microvessel
thelial and perivascular supporting cells and extracellular matrix to density in some tumors [52]. TGF-β can also induce mesenchymal stem
abrogate vascular integrity [97,98]. cells to differentiate into endothelial cells [53]. Differentiated endo
thelial cells in turn can promote the recruitment of perivascular cells and
4.1.2.2. PDGF. The PDGF family consists of PDGF-A, PDGF-B, PDGF-C, myofibroblasts to support vascular integrity by secreting TGF-β [117].
PDGF-D peptide homodimers and PDGF-AB heterodimers [99]. PDGF
binds to the PDGF receptor (PDGFR), and tyrosine kinase receptors (α, β) 4.1.2.4. Fibroblast growth factor. FGFs are heparin-binding growth fac
expressed on other mesenchymal cells, such as fibroblasts, smooth tors that contain a family of 22 members and function as ligands for four
muscle cells, and pericytes. Moreover, PDGF-PDGFR signaling is mainly receptor tyrosine kinases, FGFR-1, − 2, − 3, and − 4 [118]. FGFs and
through autocrine and paracrine activation of similar or identical fibroblast growth factor receptor (FGFR) is ubiquitously expressed in
pathways as VEGF-induced [100] to play an important role in almost all cell types and have multiple functions, including regulation of
tumorigenesis. cell growth and angiogenic differentiation [92,119]. FGF-2 is a member
Malignant tumors, including ovarian cancer (OC), non-small cell of the FGF protein family, also known as basic FGF (bFGF), which is a
lung cancer (NSCLC), and hepatocellular carcinoma (HCC), are known key regulator of cell proliferation, survival, development, tumorigen
to have tumor angiogenesis associated with overstimulation of PDGF esis, and angiogenesis physiologically and pathologically [120]. Cells
signaling [101]. In tumor angiogenesis, aberrant PDGF signaling is exposed to hypoxia have been reported to secrete large amounts of
responsible for pericyte recruitment to blood vessels, the release of biologically active FGF2 [121,122]. In the initial stages of tumor
proangiogenic factors, stimulation [102] of endothelial cell migration, growth, FGF – 2 can be independent of the VEGF promote angiogenesis
proliferation, and tube formation, promotion of lymphangiogenesis, and [123,124]. It can also induce neovascularization and further tumor
ultimately lymphatic metastasis [48]. HIF-1α can induce endothelial growth by crosstalk with VEGFA [54]. In addition, studies have found
cells to secrete PDGF-B [103] to initiate vascular sprouting. PDGFB and that high levels of FGF-2 are usually present in patients with highly
PDGFR-β play a crucial role in the recruitment of positive pericytes to vascularized tumors and advanced cancer [125]. Mechanically, FGF-2
blood vessels. Zhang et al. found in the mouse experiment that PDGFB integrates the extracellular domains of FGFR and heparan sulfate pro
deficiency resulted in the destruction of the integrity of tumor blood teoglycan (HSPG), induces autophosphorylation of the tyrosine kinase
vessels and the reduction of vascular perfusion rate, indicating that domain of FGFR cells and leads to the activation of complex signal
PDGFB could maintain the vascular integrity in the tumor microenvi transduction pathways [126,127]. FGF-2 produced by melanoma, for
ronment by promoting the recruitment of pericytes [104]. example, uses paracrine pathways to promote angiogenesis and fibrous
HIF-1→PDGF-B→PDGFRβ signaling plays a key role in lymphangio matrix formation through its mitogenic effects on endothelial cells and
genesis of moderately to poorly differentiated invasive breast cancer. fibroblasts [128,129]. FGF-2 induced tumor angiogenesis is known to be
HIF-1 can also promote lymphatic metastasis of breast cancer by directly mainly mediated by αvβ3 and α5β1 integrin [130]. During tumor
transactivating the gene encoding PDGF-B. This gene has a proliferative angiogenesis, these two integrins are highly up-regulated on angiogenic
and chemotactic effect on lymphatic endothelial cells, and the enhanced endothelial cells and promote tumor angiogenesis by regulating endo
expression of PDGF-B in tumors may not only affect pericyte recruitment thelial cell function [131]. Another study showed that FGF-2 upregu
but also lead to neovascularization and increased tumor cell growth lates PDGFR expression in endothelial cells, mainly through the
[105,106]. In addition, some studies have shown that PDGF may also FGF-2-induced signaling pathway that activates the promoter activity
activate HIF-1 [107], suggesting a potential bidirectional regulation of PDGFR-α and PDGFR-β in capillary endothelial cells [55] and pro
between the two; however, more studies are needed to prove this motes tumor angiogenesis through synergistic effects with PDGFR
conclusion. together. The above evidence fully demonstrates that FGF-2, as an
important class of pro-angiogenic factors, has complex and diverse ef
4.1.2.3. Transforming growth factor-β. Transforming growth factor-β fects on angiogenesis in tumors, therefore, targeting FGF-2 to inhibit
(TGF-β) is a dual function, both pathological and physiological functions tumor growth and angiogenesis is being widely investigated as a
of cytokines, and can be used as a tumor suppressor in cancer and start promising therapeutic strategy [127].
the factor. It is a key signal transduction pathway in cancer progression
[108] and plays an important role in the angiogenesis of tumor tissues
[109,110]. 4.2. Hypoxia-induced polarization of TAMs promotes angiogenesis
TGF-β ligands consist of TGF-β1, 2, and 3 and are secreted by a va
riety of cells, such as epithelial cells, fibroblasts, and immune cells Tumor-associated macrophages (TAMs) are mostly derived from
[111]. TGF-β secreted by most cultured cells is biologically inactive, bone marrow mononuclear cells and widely present in various tumors
unable to bind to the TGF-β receptor [112], and latent TGF-β can be [132]. TAMs as number one of the most abundant immune cells in the
activated by proteases (such as plasmin and cathepsin D), low pH, and TME [133], will usually be in in the region of the blood supply of oxygen
chaotropic agents (such as urea and heat) [113]. The activated TGF-β enrichment [133], and hypoxia can induce TAMs to promote tumor type
ligands can initiate downstream signaling pathways in an autocrine and M2 polarization [134]. M2-type TAMs can promote tumor angiogenesis,
inhibit T cell-mediated anti-tumor immune response, and lead to the
7
progression of tumors [56]. This means that TAMs and hypoxia can act between stromal cell-derived factor-1 (CXCL12) and; CXCR4, CXC che
synergistically to become a lethal combination. The pro-angiogenic ef mokine receptor 4 (CXCR4) [162–164] have been investigated as po
fect of TAMs involves the coordinated regulation of multiple cytokines, tential targets of CAFs-induced tumor pathological angiogenesis. CAFs
including bFGF, VEGF, interleukin-1(IL-1), interleukin-8(IL-8), TNF-α, can also affect tumor angiogenesis through EndMT. Endothelial cells are
and nitric oxide (NO) [135]. The coordinated expression of these mol believed to change their morphological and functional characteristics in
ecules promotes the proliferation of endothelial cells, matrix remodel TME through the process of EndMT, thereby acquiring CAFs charac
ing, and tumor angiogenesis. TAMs can also contribute to tumor teristics [165], and approximately 40 % of CAFs may be derived from
angiogenesis by releasing angiogenic molecules themselves and EndMT process [166]. Evidence supports the involvement of CAFs in
expressing a series of enzymes involved in angiogenesis regulation, tumor angiogenesis through transdifferentiation into endothelial cells.
including MMP-2, MMP-7, MMP-9, MMP-12, and cyclooxygenase-2 Cai et al. found that PDAC CAFs can differentiate into endothelial cells
(COX2) [136]. In addition, hypoxic TAMs strongly up-regulate the through PERK-eIF2α-ERK1/2 axis both in vitro and in vivo to promote
expression of mammalian target of rapamycin (mTOR) negative regu tumor angiogenesis process [167]. To meet the bioenergetic and
lator regulated in development and DNA damage responses 1 (REDD1), biosynthetic demands of proliferating tumor cells and their rapid
and REDD1-mediated mTOR inhibition can block glycolysis in TAMs adaptation to hypoxia, tumor cells switch to glycolytic metabolism
and reduce their excessive angiogenic response, thereby forming [168]. Lactate produced by glycolytic metabolism accumulates in tu
abnormal blood vessels [137]. Under the influence of hypoxic micro mors and contributes to the angiogenic phenotype largely by inhibiting
environment and tumor cells, TAMs are involved in all stages of PHD-2 and activating HIF1a and NF-kB [169]. Lactate has been shown
angiogenesis, from early sprouting of angiogenesis to late stabilization to stimulate NF-kB activation in endothelial cells and CAFS to drive
of new vessels. In multiple myeloma (MM), TAMs expressing multiple tumor angiogenesis [170].
endothelial markers cooperate with endothelial cells to form the endo CAFs can also produce and organize ECM to promote tumor angio
thelial lining of tumor blood vessels [138]. In glioblastoma (GBM), genesis. In addition to serving as a structural scaffold for tissue archi
TAMs have been shown to enhance the vascular mimicry of tumor cells tecture, the ECM can regulate tissue homeostasis and affect cell motility
through the mediation of COX2 and interleukin-6 (IL-6) [139]. In and viability [171]. The ECM acts as a reservoir of growth factors and
addition, paracrine interactions between TAMs and mature endothelial cytokines that can be released upon matrix remodeling and cleavage
cells also control the process of vessel sprouting, which is the first step in [172]. CAFs degrade and remodel the ECM [61] mainly by secreting
the formation of new tubular structures from preexisting vasculature fibronectin, collagen, and MMP. The resulting dense ECM structure also
[140]. GBM-derived C-reactive protein has been reported to promote leads to a change in effective oxygen utilization, which induces hypoxia
IL-1 and IL-2β production by cyclooxygenase-6 (COX6) + TAMs [141, and further promotes tumor angiogenesis [173,174].
142]. IL-1 is known to promote endothelial cell proliferation, enhance
endothelial expression of pro-angiogenic factors [143] (including IL-8, 4.4. Hypoxia accelerates EVs release to induce vascular lumen generation
VEGFA and HIF-1α), and stimulates tip and stem cell activity during
germination. Tip cells are newly formed endothelial cells that determine EVs are lipid bilayer membrane-delimited, nano- to micro-sized
the direction of blood vessel growth [144], and stem cells are endo particles that appear to be released by all cell types [175]. They all
thelial cells that form the lining of new blood vessels, which open a contain multiple types of proteins (such as Rab gtpase), lipids (such as
suitable lumen for the creation of blood flow [145]. Direct binding of ceramides), nucleic acids (i.e., messenger RNA (mRNA), microRNA,
pro-angiogenic neuropilin 1 (NRP1) expressed by TAMs to VEGFR2 circRNA and long non-coding RNA (lncRNA)), and metabolites [176].
present on tip cells contributes to vessel branching during sprouting. EVs are involved in angiogenesis in cancer progression by transporting
Paracrine stimulation of vascular cells by TAMs also contributes to many proangiogenic biomolecules, such as VEGF, MMP, and microRNA
endothelial-mesenchymal transition (EndMT), a process by which [62].
endothelial cells lose their specific vascular phenotype [146,147]. Other The increase of reactive oxygen species under hypoxic conditions can
studies have shown that adrenomedullin (ADM) and semaphoring 4D induce oxidative stress, which in turn promotes the release of EVs. For
(Sema4D) secreted by TAMs can not only induce tumor angiogenesis but example, Jurkat T cells secrete approximately 15-fold more EVs under
also promote the maturation of new blood vessels [57]. oxidative stress conditions, while Raji cells secrete approximately 32-
fold more EVs [177]. This study well supports the fact that tumor cells
4.3. Hypoxia induces and maintains the malignant phenotype of cancer- express several EVs under hypoxic induction, which is also regarded as
associated fibroblasts (CAFs) to promote angiogenesis an important characteristic of solid tumors [63]. Although the secretion,
composition, and function of hypoxic EVs have a significant impact, the
CAFs are a representative component of stromal cells in the tumor detailed function and mechanism of hypoxic EVs in the tumor micro
microenvironment of most solid tumors and are activated after tissue environment are not very clear [62,178]. In the present study, the tu
injury [148]. Malignant tumors are called “wounds that never heal,” mors under hypoxic conditions can stimulate tumor cells to secrete
which leads to the continuous recruitment, activation, and trans various substances, such as proteins and nucleic acids, into the extra
formation of fibroblasts into CAFs in the TME [61]. Among them, related cellular space. These substances modulate cellular functions and inter
studies in Skin Cutaneous Melanoma (SKCM) [149], ovarian cancer cellular communication, thereby changing the local tumor
(OV) [150], and pancreatic ductal adenocarcinoma (PDAC) [151] have microenvironment [65]. Thus, it induces the formation of vascular
shown that hypoxia plays an important role in the transformation of lumen, promotes angiogenesis, and eventually promotes the malignant
normal fibroblasts into CAFs. Hypoxia also promotes the transformation proliferation and invasive phenotype of tumor cells [179].
of normal fibroblasts into CAFs by accelerating TGF-β1 signaling [152]. Under hypoxic conditions, cancer cells secrete EVs that can modulate
Another view suggests that hypoxia is involved in the process of the characteristics of endothelial cells and promote angiogenesis.
exosome-mediated CAFs differentiation [153]. Conversely, the endocytic action of endothelial cells under hypoxia se
CAFs promote tumor progression by supporting tumor cell survival, cretes EVs, which promotes endothelial cell proliferation and angio
proliferation, and invasion, promoting angiogenesis, promoting in genesis [64]. These EVs are taken up by normal endothelial cells and
flammatory responses, remodeling the extracellular matrix (ECM), and then help the tumor form a new vascular network by transferring exo
mediating immune suppression [154–157]. CAFs can mediate tumor somal angiogenic proteins [180]. Studies show that EVs of tetraspanin
angiogenesis by secreting TGF-β, FGF, VEGF, PIGF, MMP, and other (TSPN, a family of membrane proteins with four membrane spans)
vascular growth factors [59,60,158] in the form of autocrine and promote tumor growth by inducing angiogenesis [181]. Soluble E-cad
paracrine [159,160]. In addition, WNT pathway [161] and crosstalk herin carried by EVs heterodimerizes with vascular endothelial cadherin
8
on endothelial cells to activate β-catenin and NF-κB signaling to promote 5. Therapeutic approaches targeting tumor hypoxic
angiogenesis [65]. The experiments of Xu et al. demonstrated that C-C microenvironment-induced angiogenesis
motif chemokine ligand 19 (CCL19) could inhibit HIF-1α/VEGF-A
related signaling pathway by transferring exosomal miR-206, thereby Since Dr. Folkman’s introduction of the doctrine of anti-angiogenesis
inhibiting the proliferation of human umbilical vein endothelial cells in the treatment of cancer in 1971, inhibition of angiogenesis has
(HUVECs) and angiogenesis of colorectal cancer (CRC) in vivo [182]. evolved into an important therapeutic strategy for a variety of solid
Other views suggest that EVs can also affect the permeability of tumors. Anti-angiogenic drugs block the production of new blood vessels
blood vessels to promote tumor angiogenesis, migration, invasion, and that support tumor growth, inhibiting or slowing tumor growth by
other malignant phenotypes. Previous studies have found that miR-210 reducing the blood supply needed by the tumor. Angiogenesis inhibitors
is significantly expressed in EVs and malignant cells of PDAC, and high intervene in the various steps of blood vessel growth in a variety of ways.
miR-210 significantly promotes tumor angiogenesis, cell invasion, and (Fig. 5).
proliferation in PDAC cells. Further experiments showed that miR-210 Some are monoclonal antibodies against specific angiogenic growth
negatively regulated the expression of Ephrin A3 (EFNA3) and was factors and/or their receptors, the most prestigious of which are bev
involved in PI3K/AKT/VEGFA or Wnt/В-catenin/RHOA pathways, acizumab and ramuciruma; There is also a subset of angiogenesis in
thereby promoting tumor angiogenesis and cell permeability [66]. In hibitors that are small molecule tyrosine kinase inhibitors of multiple
addition, Xu et al. demonstrated that exosomal miR-23a, which is spe pro-angiogenic growth factor receptors, which exert anti-angiogenic
cifically expressed and secreted by hypoxic tumor cells, is a strong effects by binding to VEGF and/or its receptor, as well as to other re
pro-angiogenic factor produced by triggering HIF-1α and reducing ceptors on the surface of the endothelial cell or other proteins in the
endothelial tight junctions, which can inhibit the tight junction protein downstream signaling pathway, and block their activity; a representa
zonula occludens-1 (ZO-1), thereby increasing vascular permeability tive of this class of fusion proteins is aflibercept. Beyond that, Over the
and cancer trans-endothelial migration [153]. past 20 years, the Flight Data Analysis (FDA) has approved a variety of
The above studies fully demonstrate that hypoxic tumor-derived EVs anti-angiogenic drugs (AADs) for clinical use (Table 1), and two
can promote tumor angiogenesis by regulating endothelial cell func different phase III trials have shown that, compared with placebo,
tions, such as promoting endothelial cell proliferation, increasing Ramucirumab, which targets the VEGF2 receptor, and everolimus,
vascular permeability, and regulating signal transduction. which targets mTOR, have both modestly improved survival [183,184].
This suggests that anti-angiogenic therapy may bring some survival
benefits to patients.
As an important means of anti-tumor therapy, anti-angiogenic ther
apy can not only cut off the tumor blood supply system but also promote
Fig. 5. Targets of action of antiangiogenic agents and natural products. Created with www.figdraw.com.
9
the progress of "tumor vascular normalization," that is, correct the vessels do not depend on VEGF for survival. Thus, targeting VEGF did
abnormal vascular network, restore part of the tumor oxygenation and not completely inhibit tumor angiogenesis [192]. This has resulted in
perfusion, and destroy the tumor TME [185]. The vascular normaliza limited clinical benefit from most antiangiogenic drugs. On the other
tion hypothesis was first proposed by Jain, which is thought to have hand, antiangiogenic drugs can normalize blood vessels only at low
important implications in anti-tumor therapy [186]. doses [193], in contrast, when they are used at high doses for long pe
On one hand, vascular normalization can improve the integrity of riods, they cause blood vessels to overbuild, which can cause the tumor
vascular structure and reduce the leakage and metastasis of tumor cells, to change to a hypoxia-tolerant phenotype, thereby enhancing tumor
and reduce interstitial fluid pressure (IFP) to improve the delivery effi revascularization and invasiveness. This will have a very serious adverse
ciency of chemotherapy drugs [187]. Conversely, the restoration of impact on the prognosis of patients [194]. Finally, despite considerable
tumor partial oxygenation and perfusion can alleviate the immunosup effort in the exploration of angiogenesis-specific biomarkers in basic and
pression caused by hypoxic TME and enhance the efficacy of chemo clinical practice, few specific biomarkers have been approved for the
therapy. However, the maintenance of vascular normalization induced clinical use of angiogenic drugs [195]. Indeed, the development of
by antiangiogenic drugs has a time limit, commonly referred to as the biomarkers will be a great challenge due to many factors such as the
"normalization window" [188]. Therefore, the exploration of the complexity of tumor angiogenesis, the unpredictability of tumor het
normalization window is an area worthy of further study. Currently, erogeneity, and the limitations of preclinical and clinical trials.
anti-angiogenesis therapy has been used as the first-line therapy for Due to the limited clinical benefit of anti-angiogenesis therapy alone,
many cancer clinical strategy, can be in a more gentle, more secure way many scholars have favored the development of new anti-angiogenic
to prevent tumor growth [189], the treatment also can be used as a therapeutic regimens, such as co-medication and combination of
sensitization agent with other treatments in order to improve the cura drugs, inhibitors of alternative targets and emerging natural product
tive effect [190]. Over the past 20 years, the Flight Data Analysis (FDA) drugs.
has approved a variety of anti-angiogenic drugs (AADs) for clinical use Compared with monotherapy, combination therapy with antitumor
(Table 2), and two different phase III trials have shown that, compared agents improves therapeutic efficacy in a characteristically synergistic
with placebo, Ramucirumab, which targets the VEGF2 receptor, and or additive manner by targeting important signaling pathways. Diver
everolimus, which targets mTOR, have both modestly improved survival sified approaches to anticancer therapy provide more options for clinical
[183,184]. This suggests that anti-angiogenic therapy may bring some treatment and make powerful combinations possible. Studies have
survival benefits to patients. shown that the use of antiangiogenic drugs can improve the efficient
However, obstacles persist in the treatment of antiangiogenic agents, infiltration of immune cells into tumors, indicating that the combination
such as limited therapeutic efficacy, widespread drug resistance and of antiangiogenic drugs and immune checkpoint inhibitors (ICI) has
uncertain biomonitoring markers. On one hand, although most anti potential anti-tumor effects [196,197]. For example, in a phase III
angiogenic agents target the VEGF signaling system [191], mature blood clinical trial (NCT03434379), the combination of bevacizumab with the
PD-1 inhibitor atezolizumab significantly improved OS and PFS rates in
patients with unresectable HCC compared to sorafenib [198]. According
Table 2 to most clinical trials, the combination of antiangiogenesis and immu
Anti-angiogenic targeted drugs approved by the FDA. notherapy has positive implications for anticancer therapy, especially in
Drugs Trade Disease Targets patients with advanced malignancies who are insensitive, unwilling, or
name refractory to chemotherapy [199].
Sorafenib Nexavar HCC、RCC、DTC CRAF、BRAF、V600EBRAF、 In addition, drugs targeting the downstream factors of hypoxic
c-Kit、FLT-3、VEGFR-2、 environment, including HIF inhibitors and mTOR inhibitors, are also
VEGFR-3、PDGFR-β
being developed and used in combination in clinical trials [200]. The
Sunitinib Sutent GIST、mRCC、 VEGFRs、PDGFRb、KIT、
NET FLT-3 （CD135）、CSF1R、 highly specific HIF2α small molecule inhibitor belzutifan showed pre
RET liminary antitumor activity in patients with VHL mutant RCC in a phase
Pazopanib Votrient RCC、STC VEGFRs、FGFRs、PDGFR、 1 trial conducted in recent years [201], and the drug was also approved
KIT by the FDA for the treatment of mutant VHL patients in 2021 [202].
Vandetanib Caprelsa TC、MTC VEGFRs、EGFRs、RETs、
Notably, mTOR resulted in inhibition of the HIF1α-VEGF-mediated
TIE2
Cabozantinib Cometriq mMTC、RCC、 VEGFRs、RET、MET、TIE2、 angiogenic pathway [203], suggesting that the clinical benefit could be
HCC FLT-3 enhanced by combining mTOR inhibitors with anti-VEGF therapy. The
Regorafenib Stivarga mCRC、GIST、 VEGFRs、PDGFRs、FGFRs、 mTOR inhibitor afinitor improves progression-free survival in patients
HCC KITs、TIE2、Raf
with metastatic RCC after treatment with the first-line VEGFR-targeted
Axitinib Inlyta RCC VEGFR1–3、PDGFRβ、c-Kit
Lenvatinib Lenvima DTC、mHCC、 VEGFR1、VEGFR2、 TKI lenvatinib [203]. The development of such alternative target in
RCC VEGFR3FGFR1–3、KIT、 hibitors provides new directions for anti-angiogenic clinical therapy.
PDGFRα and RET Indeed, targeting and modulating TME to normalize tumor micro
Bevacizumab Avastin mCRC、NSCLC、 VEGF-A vessels by natural compounds has emerged as a promising strategy for
HCC、GBM、CC、
anti-angiogenic and anti-tumor therapy [204]. Natural products have
OEC、FTC、
PPC、mRCC fewer toxic side effects and are better tolerated, which are important
Ramuciruma Cyramza GAC、NSCLC、 VEGFR-2 advantages for the development of new drugs. Several clinical trials
CRC、HCC have investigated the use of natural products to inhibit angiogenesis in
Aflibercept Zaltrap mCRC VEGF-A、VEGF-B、PIGF
cancer and other diseases, such as curcumin, dandelion polysaccharide,
Afinitor Afinitor BC、PC、GAC、 mTOR
RCC、SEGA
colchicine, cantharidin, astragaloside IV, and others [205]. The number
of natural products of antiangiogenic substances is enormous, and the
HCC, hepatocellular carcinoma; RCC, renal cell carcinoma; MTC, medullary study of the complex mechanisms of these compounds is only beginning.
thyroid carcinoma; TC, thyroid carcinoma; DTC, differentiated thyroid cancer;
The study of the role of natural compounds with different structures in
GIST, gastrointestinal stromal tumors; NET, neuroendocrine tumor; STC, soft
inhibiting tumor angiogenesis is helpful for the discovery and develop
tissue cancer; CRC, colorectal cancer; NSCLC, non-small cell lung cancer; GBM,
glioblastoma; PPC, primary peritoneal carcinoma; GAC, gastric adenocarci ment of anticancer drugs [206](Table 3).
noma; FTC, fallopian tube cancer; CC, cervical cancer; OEC, ovarian epithelial
carcinoma; BC, Breast cancer; PC, pancreatic cancer; SEGA, subependymal giant
cell astrocytoma; m, metastability. (Quoted from www.cancer.gov)
10
Table 3
Antiangiogenic natural products.
Categories Representative Experimental model Antiangiogenic mechanisms References
drugs
Polyphenols Curcumin A549 and PC-9 cells, Nude mice xenograft 1.Blocking c-Met expression and PI3K/Akt/mTOR pathway2.Blocking IGF2 [207–209]
tumor model, T24 and UMUC2 cells, and IGF2-mediated PI3K/AKT/mTOR signaling pathway3.Cyclic nucleotide
HUVEC cells phosphodiesterase inhibition
Polysaccharides Dandelion HUVECs, CAM, Mice xenografted with Inhibition of PI3K/AKT/HIF-1α/VEGF pathway [210]
Polysaccharide Hepa1–6 and H22 cancer cells
Alkaloid Narciclasine HUVECs Downregulation of VEGFR2 expression by RhoA-independent activation of [211]
the Rho-kinase ROCK
Terpenoids Cantharidin Subcutaneous and orthotopic pancreatic Inhibition of ERK, JNK, PKC and NF-κB pathways [212]
xenograft models with PANC-1 cells
Saponins Astragaloside IV C57BL/6 mice with LLC cells The M2 polarization of macrophages was partially blocked by AMPK [213]
signaling pathway
6. Conclusions and Prospects the work reported in this paper.
Angiogenesis is one of the key conditions for cancer cell prolifera Data availability
tion, invasion, and metastasis. Anti-angiogenesis as an important strat
egy for anti-tumor therapy has gone through a long journey from its No data was used for the research described in the article.
concept to the realization of its clinical benefits. Pathological tumor
angiogenesis and various oncogenic factors promote and maintain the Acknowledgments
hypoxic characterization of TME, and cancer cells adapt to hypoxia by
altering their metabolism through key genes such as HIF. Under hypoxic Thanks to the editors and reviewers for their hard work and impor
conditions, most of the downstream targets are dependent on HIF. Under tant comments. Thanks to figdraw.com for the drawing material. Thanks
the induction of hypoxic factors, macrophages, fibroblasts, and their to Editage (www.editage.cn) for English language editing
secreted cytokines in the tumor microenvironment will shape a pro-
tumor angiogenic niche, maintain the survival of tumors, and aggra
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Biomedicine & Pharmacotherapy 176 (2024) 116783

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

Survival strategies: How tumor hypoxia microenvironment

1. Introduction “antiangiogenic therapy”, and restricted our search to articles published

Fig. 3. Different modalities of tumor angiogenesis. Created with www.figdraw.com.

Pro-angiogenic VEGF-dependent VEGF 1. Promote capillary bud formation. [40–44]

6. Conclusions and Prospects the work reported in this paper.

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