Kim J Transl Med (2018) 16:8

https://doi.org/10.1186/s12967-018-1389-7 Journal of
Translational Medicine

REVIEW Open Access

Effects of surgery and anesthetic choice

on immunosuppression and cancer recurrence
Ryungsa Kim*

Abstract
Background: The relationship between surgery and anesthetic-induced immunosuppression and cancer recur-
rence remains unresolved. Surgery and anesthesia stimulate the hypothalamic–pituitary–adrenal (HPA) axis and
sympathetic nervous system (SNS) to cause immunosuppression through several tumor-derived soluble factors. The
potential impact of surgery and anesthesia on cancer recurrence was reviewed to provide guidance for cancer surgi-
cal treatment.
Methods: PubMed was searched up to December 31, 2016 using search terms such as, “anesthetic technique and
cancer recurrence,” “regional anesthesia and cancer recurrence,” “local anesthesia and cancer recurrence,” “anesthetic
technique and immunosuppression,” and “anesthetic technique and oncologic surgery.”
Results: Surgery-induced stress responses and surgical manipulation enhance tumor metastasis via release of
angiogenic factors and suppression of natural killer (NK) cells and cell-mediated immunity. Intravenous agents such as
ketamine and thiopental suppress NK cell activity, whereas propofol does not. Ketamine induces T-lymphocyte apop-
tosis but midazolam does not affect cytotoxic T-lymphocytes. Volatile anesthetics suppress NK cell activity, induce
T-lymphocyte apoptosis, and enhance angiogenesis through hypoxia inducible factor-1α (HIF-1α) activity. Opioids
suppress NK cell activity and increase regulatory T cells.
Conclusion: Local anesthetics such as lidocaine increase NK cell activity. Anesthetics such as propofol and locore-
gional anesthesia, which decrease surgery-induced neuroendocrine responses through HPA-axis and SNS suppres-
sion, may cause less immunosuppression and recurrence of certain types of cancer compared to volatile anesthetics
and opioids.
Keywords: Cancer surgery, Anesthetic agent, Anesthetic technique, Immunosuppression, Cancer recurrence

Introduction surgery-induced or anesthesia-induced activation of

Surgical resection is the most effective method to remove these two systems may facilitate metastasis through sev-
primary tumors and metastatic lymph nodes. How- eral tumor-derived soluble factors [6].
ever, some cancer cells may remain after surgery, and HPA-axis and SNS activation suppress cell-mediated
micro-metastases or tumor dislodged during surgical immunity (CMI) and release of catecholamines and
manipulation may spread via lymphovascular vessels [1]. prostaglandin ­E2 ­(PGE2). These factors, in turn, increase
During the perioperative period, surgery induced stress immunosuppressive cytokines, soluble factors (e.g.,
responses and anesthetic-induced immunosuppression interleukin 4 [IL-4], IL-10, transforming growth factor
may play a critical role in establishment and growth of beta [TGF-β], and vascular endothelial growth factor
metastatic lesions [2–5]. Because immune responses [VEGF]), and proinflammatory cytokines (e.g., IL-6 and
are regulated by the hypothalamic–pituitary–adre- IL-8), which promote tumor angiogenesis and metasta-
nal (HPA) axis and sympathetic nervous system (SNS), sis [7–11]. Furthermore, volatile anesthetics and opioids
suppress CMI and promote cancer cell proliferation and
*Correspondence: ryu@hbc‑center.com angiogenesis, whereas propofol inhibits tumor angio-
Breast Surgery, Hiroshima Mark Clinic, 1‑4‑3F, 2‑chome, Ohte‑machi, genesis and does not suppress CMI [12, 13]. Regional
Naka‑ku, Hiroshima, Japan

© The Author(s) 2018. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License
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and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/
publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Kim J Transl Med (2018) 16:8 Page 2 of 13

anesthesia (RA) preserves CMI and decreases surgery- induction, followed by muscle relaxants and endotracheal
induced neuroendocrine responses by attenuating affer- intubation, then volatile anesthetics (e.g., sevoflurane)
ent neural transmission activation of the HPA-axis and and opioids for maintenance and pain control. In con-
SNS response. Thus, reduction in opioid and volatile trast, RA uses a local anesthetic (e.g., lidocaine or bupi-
anesthetic use may reduce cancer recurrence [14]. vacaine) to block peripheral or spinal nerve transmission
Clinically, the key question of whether anesthetic to produce a paravertebral or epidural block. Local anes-
choice affects cancer outcome remains unresolved. Ret- thetics prevent surgical pain and reduce surgery-induced
rospective studies and meta-analyses suggest that par- neuroendocrine stress by suppressing afferent neural
ticular anesthetic techniques may reduce cancer related transmission to the central nervous system. Thus, HPA-
mortality and recurrence by decreasing immunosup- axis and SNS responses are avoided. Anesthetic choices
pression after surgical treatment for certain types of during cancer surgery positively or negatively affect
cancer [15]. Several prospective randomized controlled immune function during the perioperative period, and
trials (RCTs) to define the effect of anesthesia on can- this immune balance may play a key role in cancer spread
cer recurrence are currently underway [15]. The present and recurrence (Fig. 1b).
study relied on preclinical study review to determine Tumors release soluble factors into their microenvi-
the potential effects of surgery and anesthetic choice on ronments to block CMI surveillance and facilitate tumor
immunosuppression and cancer outcomes to help guide growth and metastasis [16]. Soluble factors affect residual
treatment choices by clinicians and cancer surgeons. cancer cells and pre-existing micro-metastases to promote
new metastases, which are the major cause of cancer-
Perioperative period and immune function related death if not eliminated by immune cells [17–19].
The perioperative period is divided into three phases: the In these situations, the perioperative period is pivotal in
preoperative period (a few preoperative hours), the intra- determining cancer outcomes following primary surgi-
operative period, and the postoperative period (several cal treatment. Surgery, anesthesia, analgesia, and specific
days after surgery) (Fig. 1a). During the intraoperative agents all influence immune function and tumor metas-
period, general anesthesia consists of administration of tasis [19]. Immunosuppression arises within a few hours
intravenous anesthetics (e.g., thiopental or propofol) for of surgery and lasts for several days, in proportion to the

Fig. 1 Perioperative period and immune balance. a The perioperative period includes the preoperative period, intraoperative period, and postop-
erative period. During these periods, several anesthetics agents and techniques may affect immune response and cancer recurrence after surgery.
b Immune balance during the perioperative period is achieved through control of positive effects from regional anesthesia, propofol, and local
anesthetics, with negative effects from volatile anesthetics, thiopental, and opioids. The immune balance needs to be shifted toward positive effects
to reduce immunosuppression, which promotes cancer metastasis
Kim J Transl Med (2018) 16:8 Page 3 of 13

extent of surgical trauma. Although the immune system Changes to NK cell activity depend on both the degree
normally protects against tumor development, surgery- of surgical treatment and the intensity of the surgi-
induced stress counteracts the anti-metastatic effects cal stress response [29], which activates the HPA-axis
of CMI to allow dissemination and metastasis of cancer and SNS to release catecholamines and prostaglan-
cells during and following surgery [12]. The perioperative dins [30]. Laparotomy increases lung tumor retention
period may be crucial to residual cancer cell spread, with (LTR), whereas combined β-adrenergic antagonism and
anesthetic-induced immunosuppression affecting cancer cyclooxygenase (COX) inhibition decrease LTR and
recurrence and long-term prognosis [13, 14]. restore NK cell function in experimental animal mod-
els [31]. Clinically, surgery decreases circulating NK
Effect of surgery on immune function and tumor and T cells through the programmed death-1 (PD-1)
metastasis and programmed death–ligand 1 (PD-L1) pathway, due
Although surgical resection is a major component of to increased caspase-3 activity in association with PD-1
cancer treatment, surgery itself suppresses immunity; expression on immune cells [32]. Surgical stress increases
thus, metastasis is promoted through growth facilita- Th2 cells and decreases Th1 cells, which decreases the
tion of pre-existing micro-metastases and dissemination Th1/Th2 ratio and eventually suppresses CMI [33].
of cancer cells during resection of the primary lesion During surgical stress, levels of immune stimulating
[20]. Detection of tumor cells in peritoneal blood and cytokines such as IL-2, IL-12, and interferon-γ (IFN-γ)
fluid after surgery has been associated with significantly are decreased, whereas anti-inflammatory cytokines such
shorter disease-free survival in patients with colorectal as IL-10 are increased [33]. The magnitude of immu-
cancer [1, 21]. Given that surgery modifies neural, endo- nosuppression is in proportion to the extent of surgical
crine, metabolic, inflammatory, and immunologic micro- treatment. The overall effect of surgery on immune func-
environments [22], surgery-induced stress responses may tion and tumor metastasis is summarized in Table 1.
activate angiogenesis and increase vascularization to pro-
mote tumor growth [2–5]. Effect of anesthetic agents on immune function
Additionally, surgical resection may promote tumor Intravenous and volatile anesthetics
growth and metastasis through increased matrix met- Intravenous anesthetics such as ketamine and thiopental
alloproteinase 9 (MMP-9) and VEGF expression, as in produce multiple effects on immune system components.
one model of breast cancer [23]. Plasma VEGF levels Unlike propofol, ketamine and thiopental suppress NK
are increased by surgery-induced stress during laparot- cell activity [34, 35]. Whereas ketamine induces human
omy and mastectomy [2], whereas TGF-β plasma levels lymphocyte apoptosis via the mitochondrial pathway
decrease in response to lung metastasis in animal models [36] and inhibits dendritic cell (DC) functional matura-
[24]. Acceleration of metastasis after surgical resection tion [37], whereas thiopental protects against T-lympho-
through proliferation of distant, dormant micro-metasta- cyte apoptosis through induction of heat shock proteins
ses has been observed in patients with breast cancer [25]. [38]. However, both of these intravenous anesthetics
Primary tumor resection may directly stimulate cancer suppress the immune system in other ways: ketamine
cell spread through metastatic lesion growth. Following decreases production of pro-inflammatory cytokines
surgical resection of a primary tumor, decreased endosta- such as IL-6 and tumor necrosis factor-α (TNF-α), and
tin and angiostatin levels allow new blood vessel growth, thiopental inhibits neutrophil function and suppresses
which promotes growth or metastatic lesions and uncon- activation of nuclear factor kappa B (NF-κB). This NF-κB
trolled proliferation [26]. Following primary colorectal suppression by thiopental is associated with inhibition
tumor resection, decreased angiostatin and endostatin of NF-κB-driven reporter gene activity, which includes
levels in urine and plasma are associated with increased T-lymphocyte activation as well as IL-2, IL-6, IL-8, and
metabolic activity in liver metastases [27]. Thus, it seems IFN-γ expression [39]. Thiopental also inhibits lipopoly-
that the primary tumor inhibits angiogenesis for distant saccharide-induced production of IL-1β, TNF-α, and IL-6
metastases, but that primary tumor resection allows for by monocytes [40]. Although intraperitoneal injection of
neovascularization and increased metabolic activity in midazolam impairs monocyte and neutrophil function, it
metastases [25]. If surgery-induced immunosuppression does not affect cytotoxic T-lymphocyte (CTL) activity in
occurs, surgery may fail to prolong survival in patients a mouse model [41].
with cancer. Surgery reduces levels of endogenous In contrast to other intravenous anesthetics, propo-
antiangiogenic factors such as endostatin and angiosta- fol increases CTL activity, decreases pro-inflammatory
tin while weakening the immune surveillance needed to cytokines, and inhibits COX-2 and ­ PGE2 functions
inhibit the growth of metastatic lesions [28]. [41–43]. Furthermore, propofol does not affect Th1/Th2,
 Kim J Transl Med (2018) 16:8

Table 1 Effect of surgery on immune function and tumor metastasis

Factor Experimental data Clinical data

Surgery-induced stress Increased vascularization [3] Modification of neural, endocrine, metabolic, inflammatory, and immuno-
Surgical manipulation Augmentation of angiogenesis [2] logic microenvironments [1]
Inadvertent dispersal of tumor cells [20] Detectable tumor cells in blood and peritoneal fluid after surgery associ-
ated with shorter disease-free survival in colorectal cancer [1]
Surgery causes neoplastic cells to be dislodged from primary tumor [1, 21]
Induction of angiogenesis and proliferation of distant, dormant micro-
metastases in breast cancer surgery [4]
Surgery-induced angiogenesis in breast cancer [5]
Acceleration of metastasis by surgical resection of primary breast cancer
[25]
NK cell activity Suppression of NK cell activity, dependent on extent of surgical trauma Decrease in circulating NK cell levels [32]
Cell-mediated immunity and intensity of stress response [29] Decrease in dendritic cells, CTLs, and T-helper cells [32, 33] Decrease in the
Stimulation of the hypothalamic-pituitary-adrenal (HPA) axis and the Th1/Th2 ratio [33]
Cytokines sympathetic nervous system Increase in pro-inflammatory cytokines (e.g., IFN-α, IL-6) [32]
Others Release of catecholamines and prostaglandins [30] Increased cortisol and catecholamines [32]
Laparotomy associated with a significant increase in LTR [31] Magnitude of immunosuppression is proportional to degree of surgical
Combination of beta-antagonism and COX inhibition reduces LTR and manipulation [33]
restores NK cell function [31]
MMPs Promotion effect on tumor growth and pulmonary metastasis of human Decrease in circulating anti-angiogenic factors angiostatin and endostatin
VEGF breast cells by surgical process [23] after surgical resection of primary colorectal carcinoma [27]
Increased plasma VEGF levels induced by surgical stress [2, 23] Regional anesthesia combined with propofol attenuates effect of breast
TGF-β Decreased plasma levels in lung cancer metastasis [24] surgery on MMPs compared to balanced general anesthesia with opioid
Endostatin and angiostatin Reduction of growth control factors endostatin and angiostatin [28] anesthesia [48]
Surgery induces a transient endostatin decrease in colorectal carcinoma
[26]
Decrease in circulating anti-angiogenic factors angiostatin and endostatin
after surgical resection of primary colorectal carcinoma coincides with
increased metabolic activity of liver metastases [27]
NK natural killer; CTL cytotoxic T-lymphocyte; IL interleukin; Th1 T-helper 1; Th2 T-helper 2; IFN interferon; LTR lung tumor retention; COX cyclooxygenase; VEGF vascular endothelial growth factor; TGF-β tumor growth
factor β; MMPs matrix metalloproteinases
Page 4 of 13
Kim J Transl Med (2018) 16:8 Page 5 of 13

IL-2/IL-4, or CD4/CD8 T cell ratios, so surgery-induced concentrations enhanced NK cell activity against can-
immunosuppression is mitigated [44]. cer cells in vitro via the release of lytic granules [64]. The
Volatile anesthetics also affect immune response. overall effect of anesthetic agents on immune function is
For example, halothane decreases NK cell activity and summarized in Table 2.
increases expression of hypoxia-inducible factor 1α
(HIF-1α) [45, 46], and sevoflurane induces T-lymphocyte Effect of anesthetic agents on tumor development
apoptosis and upregulates HIF-1α expression [46, 47]. Intravenous and volatile anesthetics
Sevoflurane has also been shown to increase levels of Treatment with intravenous anesthetics such as keta-
pro-tumorigenic cytokines and MMPs in breast cancer mine and thiopental stimulate lung and liver metasta-
surgery [48]. One study comparing desflurane to sevo- ses in animal models [65], with one study showing that
flurane showed that sevoflurane decreases lymphocytes ketamine and thiopental increase LTR or lung metas-
and NK cells while increasing leukocytes and neutro- tasis via NK cell suppression in a rat model [66]. Simi-
phils during abdominal surgery [49]. Similarly, isoflurane larly, the volatile anesthetic halothane can stimulate
attenuates NK cell activity, induces T-lymphocyte and lung and liver metastases [65]. In contrast, sevoflurane
B-lymphocyte apoptosis, and decreases the Th1/Th2 suppresses hypoxia-inducible growth and metastasis of
ratio [44–46, 50]. Desflurane does not induce T-lympho- lung cancer cells by inhibiting HIF-1α, which is involved
cyte apoptosis [47]. in the p38 mitogen-activated protein kinase (MAPK)
signaling pathway [67]. Another study has shown that
Opioids and COX‑2 inhibitors sevoflurane increases proliferation, migration, and
Opioids usually inhibit T-lymphocyte proliferation [51]. invasion of estrogen receptor (ER)-positive breast can-
Morphine suppresses NK cell activity and T cell differen- cer cells, as well as proliferation and migration of ER-
tiation, promotes lymphocyte apoptosis, and decreases negative cells [68]. Furthermore, serum from patients
toll-like receptor 4 (TLR4) expression on macrophages who received sevoflurane and an opioid for breast can-
[51–54]. Likewise, fentanyl and sufentanil decrease cer surgery did not inhibit proliferation of ER-negative
NK cell activity but increase regulatory T cells [55, 56]. breast cancer cells, but serum from those receiving
Sufentanil also inhibits leukocyte migration [57]. Alfen- propofol and paravertebral anesthesia did inhibit prolif-
tanil decreases NK cell activity [52], and remifentanil has eration [69].
demonstrated suppression of NK cell activity and lym- Exposure to sevoflurane but not total intravenous anes-
phocyte proliferation in a rat model [58]. A comparison thesia (TIVA) by propofol results in increased prosurvival
of sufentanil and remifentanil using target-controlled proteins such as cytoplasmic HIF-2α and nuclear p38
infusion during laparoscopic colorectal cancer resec- MAPK in head and neck squamous cell carcinoma [70].
tion showed that cortisol and IL-6 increased more in the Isoflurane is associated with increased HIF-1α levels and
remifentanil group and that the proportion of T cell sub- increased prostate cancer cell proliferation and migration
sets decreased more in the sufentanil group [59]. [71]. In contrast, isoflurane-induced HIF-1α activation
COX-2 induction, which is frequently observed in is prevented by propofol, which is associated with par-
cancer, plays a role in immune evasion and resistance tial reduction of malignant activities by cancer cells [71].
to the immune response. COX-2 inhibitors increase NK Additionally, tumor growth in inoculated in mice is sup-
cytotoxicity and β-adrenergic antagonism while reduc- pressed by propofol, which may have immune-mediated
ing postoperative LTR [31]. Additionally, combined antitumor effects [41]. Isoflurane increases the malignant
β-adrenergic antagonism and COX-2 inhibition have potential of ovarian cancer cells through the upregula-
been shown to eliminate LTR and decrease metastasis in tion of insulin-like growth factor (IGF)-1 and its receptor
animal models [60]. A selective COX-2 inhibitor can sup- IGF-1R, as well as VEGF, angiopoietin-1, MMP-2, and
press ­PGE2 release and promote CTL immune responses MMP-9 [72]. Furthermore, isoflurane exposure leads to
that cause ovarian tumor regression [61]. Furthermore, a apoptotic resistance in human colon cancer cells through
murine model has shown that celecoxib, a COX-2 inhibi- a caveolin-1-dependent mechanism [73]. Nitrous oxide
tor that reduces ­ PGE2 levels, reduces and suppresses ­(N2O) impairs DNA, purine, and thymidylate synthe-
myeloid-derived suppressor cells (MDSCs); this in turn sis, which can itself cause of oncogenesis [74]. A tumor-
decreases reactive oxygen species and nitric oxide (NO) bearing mouse model has shown that ­N2O suppresses
levels and reverses T cell tolerance [62]. Preoperative chemotaxis, which may be the most potent stimulator of
treatment with nonsteroidal anti-inflammatory drugs postsurgical lung and liver metastasis development [18,
(NSAIDs) increases infiltration of activated immune 65]. However, it is unlikely that ­N2O increases the risk
cells into colorectal cancer tissue [63]. Of interest, a of cancer recurrence compared to that of nitrogen after
recent study showed that lidocaine at typical clinical colorectal surgery [75].
Table 2 Effect of anesthetic agent on immune function
Agent Experimental data NK cell T-lymphocyte Others Clinical data
numbers (activity)

Intravenous
Kim J Transl Med (2018) 16:8

Ketamine Decrease [34, 35, 66] Apoptosis [36] Attenuation of proinflammatory cytokine Inhibition of the lipopolysaccharide-induced
Thiopental Decrease [66] Protection of apoptosis [38] (IL-6, TNF-α) production [35] Inhibition of production of IL-1β, TNF-α, and IL-6 by
functional maturation of DC [37] monocytes [40]
Midazolam No effect on CTL [41] Suppression of neutrophil functions [35] No change in Th1/Th2 ratio [44]
Propofol No suppression [66] Increased activity on CTL [41] Inhibition of NF-κB activation [39]
Impairment of monocyte and neutrophil
function [42]
Decrease in secretion of proinflammatory
cytokines [42]
Inhibition of COX-2 and ­PGE2
43
Volatile anesthetics
Halothane Decrease [45, 66] Upregulation of HIF-1α [46] Increased levels of pro-tumorigenic cytokines
Sevoflurane Decrease [49] Apoptosis [47] /Decrease [49] Upregulation of HIF-1α [46] and matrix metalloproteinases
B-lymphocyte apoptosis [50] (MMPs) in breast cancer surgery [48]
Isoflurane Attenuation [45] Apoptosis [47] Decrease in Th1/Th2 ratio [44]
Nitrous oxide Depression of neutrophil chemotaxis [18] No difference in cancer recurrence compared
Inhibition of formation of hematopoietic with oxygen [75]
cells for tumor surveillance [52]
Impairment of DNA, purine, and thymi-
dylate synthesis [74]
Opioids
Morphine Suppression [52] Suppressive effect on Th-cell differentia- Inhibition of NF-κB binding [52] Decrease in T-lymphocyte proliferation [51]
Fentanyl Decrease [34, 55] tion [53] Decrease of TLR4 on MΦ [54] Increase in IL-6; decrease in T cell subsets [59]
Increase in Tregs [56] Promotion of apoptosis in lymphocytes and Increase in IL-6; decrease in T cell subsets
Sufentanil Decrease [55] Increase in Tregs [56] macrophages [77] (less than sufentanil) [59]
Alfentanil Decrease [52] Decease in proliferation [58] Inhibitory effect on leucocyte migration
Remifentanil Decrease [58] [57]
Others
COX-2 inhibitor Attenuation of NK cytotoxicity Promotes CTL immune response [61] Reduced postoperative LTR [31] NSAIDs increase tumor infiltration by acti-
β-adrenergic antagonist reduction using combined Reduced number of and suppressive func- Combination with β-adrenergic antagonist vated immune cells [63]
β-adrenergic antagonism [31] tion of MDSC [62] eliminates LTR [31] and decreases metas-
tasis in animal models [60]
Local anesthetics
Lidocaine Increase [64]

NK natural killer; IL-6 interleukin 6;TNF-α tumor necrosis factor-α; DC dendritic cell; CTL cytotoxic T-lymphocyte; COX-2 cyclooxygenase 2; PGE2 prostaglandin E­ 2; HIF-1α hypoxia inducible factor-1α; MMPs matrix
metalloproteinases; TLR4 toll-like receptor 4; MΦ macrophage; NF-κB nuclear factor kappa B; LTR lung tumor retention; Tregs CD4(+) CD25(+) Foxp3(+) regulatory T cells; MDSC myeloid-derived suppressor cells
Page 6 of 13
Kim J Transl Med (2018) 16:8 Page 7 of 13

Opioids and other agents opioid antagonist, inhibits LLC invasion and anchorage-
Commonly used opioid analgesics may affect tumor independent growth, whereas continuous MNTX infu-
development through their modulation of cell prolifera- sion decreases primary LLC tumor growth and lung
tion and cell death [76–78]. It has been suggested that metastasis [85]. Further, MNTX inhibits opioid-induced
opioids suppress the immune response because vari- proliferation and migration of pulmonary microvascu-
ous immune competent cells express opioid receptors lar endothelial cells through its effects on VEGF recep-
and induce apoptosis during opioid alkaloid treatment. tor phosphorylation and transactivation and inhibition
Tumor growth promotion is mediated through AKT of Rho A activation [87]. Clinically, MNTX treatment
and extracellular signal–regulated kinase (ERK) signal- is associated with increased overall survival in patients
ing cascades, whereas death-promoting effects are medi- with advanced cancer; this finding supports the hypoth-
ated through NF-κB inhibition, increased Fas expression, esis that MOR is involved in tumor progression and
p53 stabilization, activation of p38, and c-Jun-N-terminal that MNTX may target MOR [88]. Because morphine
kinase (JNK) [79]. It is likely that opioid-induced cell pro- reciprocally transactivates MOR and VEGF receptors,
liferation and cell death depend on opioid concentration MOR-knockout mice do not grow significant lung can-
or exposure duration. Tumor growth promotion occurs cer tumors; MNTX treatment markedly decreases tumor
with low concentrations or single doses of opioids, growth in experimental mouse models [89].
whereas growth inhibition occurs with chronic opioid Morphine at clinical blood concentrations stimu-
use or relatively high drug concentrations [80]. lates proliferation and angiogenesis of microvascular
Breast cancer cells treated with low morphine concen- endothelial cells by activating MAPK/ERK phosphoryla-
trations induce naloxone (NX)-sensitive, concentration- tion using Gi/Go-coupled G protein receptors and NO.
dependent increases in GTPase activity, with morphine Effects include apoptotic inhibition of apoptosis through
signals being transmitted by opioid receptors via a G pro- AKT activation and promotion of cell cycle progression
tein [81]. In contrast, the anti-proliferative effects of mor- through increased cyclin D1 [76]. Morphine at clini-
phine are not eliminated by NX. Morphine-induced p53 cally useful doses promotes tumor neovascularization
phosphorylation and stabilization in breast cancer cells and progression in a xenograft model of a human breast
expressing wild type p53 causes increased production of tumor [76]. Similarly, clinical doses of morphine pro-
p53-dependent proteins, including p21, Bax, and Fas [81]. mote angiogenesis and tumor progression in ER-negative
These findings suggest that morphine may reduce growth breast cancer cells in vitro and in vivo [90]. Morphine is
of certain cancer cells through p53 activation. Addition- also able to stimulate in vitro vascular endothelial cell
ally, morphine has been shown to inhibit expression and proliferation, which is mediated by the MAPK pathway
secretion of MMP-2 and MMP-9 in breast cancer cells in [91]. It is likely that MOR has an important role in angio-
a time-dependent and concentration-dependent manner. genesis and oncogenic signaling.
This MMP activity is not reversible with NX, indicating Preoperative and postoperative morphine administra-
that attenuation of MMP secretion by morphine is not tion for analgesia decreases the tumor promotion surgical
mediated by opioid receptors, but is controlled by the effects in a rat model [92]. Preoperative and postopera-
NO system [82]. tive morphine treatment in rats significantly reduces sur-
Based on preclinical and clinical studies, differences gery-induced corticosterone increases [93]. This finding
in recurrence rates for certain cancers may be due to suggests that preoperative morphine may play a key role
immune suppression and direct effects of volatile anes- in protecting against surgery-induced metastasis. Intra-
thesia and opioids on cancer growth. Overexpression of operative opioid use has been associated with increased
the μ-opioid receptor (MOR), which promotes tumor overall survival in patients with stage I but not stage II or
growth and metastasis, is observed in several human III NSCLC [94].
cancers [83]. AKT and mTOR activation, cell prolifera- Fentanyl has demonstrated antitumor-like effects in
tion, and extravasation are all related to MOR overex- colorectal cancer cells in vitro. Its use is associated with
pression in a nude mouse model of non-small cell lung decreased cell clone formation, and inhibition of cell
cancer (NSCLC) [84]. In addition, a potential direct effect migration and invasion through inhibition of negative
of opiates has been observed in animal models that show regulation of E26 transformation–specific sequence-1
MOR regulating tumorigenicity in Lewis lung carcinoma on serine/threonine kinase protein kinase B-raf (BRAF)-
(LLC) [85]. Similarly, a study has shown the potential activated lncRNA [95]. Another study has shown that
direct effect of opioids on MOR through growth factor- fentanyl inhibits tumor growth and cell invasion in colo-
signaling proliferation, migration, and epithelial–mesen- rectal cancer by downregulating miR-182 and MMP-9
chymal transition during lung cancer progression [86]. expression using β-catenin [96]. A recent study showed
Treatment with methylnaltrexone (MNTX), a peripheral that sufentanil does not affect the apoptosis rate or cell
Kim J Transl Med (2018) 16:8 Page 8 of 13

cycle distribution of colon and pancreatic cancer cells at kinesin motor proteins, reduce formation and function
clinical concentrations in vitro [97]. of tubulin micro-tentacles; thus, these drugs may have a
Although benefits of using RA to avoid opioids have novel ability to decrease metastatic spread in breast can-
been suggested by clinical trials, it is unclear whether cer cells [107]. Lidocaine use at clinical concentrations
benefits result from withholding opioids or adding RA. results in DNA demethylation from ER-positive and ER-
Morphine administration may be beneficial for pain negative breast cancer cells in vitro [108]. Although infil-
control, but MOR is involved in tumor progression for trative anesthetics have the same membrane-stabilizing
certain cancer cell types. Opioids may play a crucial activity as lidocaine, they effectively inhibit the invasive
role in cancer metastasis and recurrence, but this effect ability of human cancer cells at the 5 mM to 20 mM con-
varies by cancer cell type [98]. Prostaglandin E ­ 2, a solu- centrations used in surgery [109]. Lidocaine additionally
ble, tumor-derived angiogenic factor, is associated with blocks human cancer cell invasion through modulation
VEGF-independent angiogenesis. ­ PGE2 production in of intracellular ­Ca2+ concentrations and inhibition of
preclinical breast and colon cancer models is controlled ectodomain shedding of heparin-binding epidermal
by COX-2 expression, and COX-2 inhibition enhances growth factor from cell surfaces [109]. Furthermore,
VEGF blockade to inhibit angiogenesis, tumor growth, lidocaine, ropivacaine, and bupivacaine all reduce MSC
and metastasis to increase overall survival [99]. Previous proliferation at 100 μM concentrations by causing cell
case control studies show that selective COX-2 inhibitors cycle delay or arrest at the G
­ 0/1-S phase; this feature is the
reduce breast and colorectal cancer risk [100, 101], with reason why local anesthetics are used perioperatively for
the NSAID analgesic ketorolac being associated with a treatment of patients with cancer [96]. In contrast, ropiv-
five-fold reduction in cancer relapse in the first few years acaine and bupivacaine do cause apoptosis and cell cycle
after breast surgery [102]. Because transient and sys- distribution at clinical concentrations for colon and pan-
temic inflammation following surgery may be involved in creatic cancer cells in vitro; their only antitumor growth
metastatic tumor seeding and angiogenesis, periopera- activity occurs at high concentrations [97]. Based on
tive antiinflammatory agents may be used to block those these findings, it is unlikely that the observed protective
effects. effects of RA on CMI result from direct effects on can-
cer cells. The overall effect of anesthetic agents on tumor
Local anesthetics development is summarized in Table 3.
Although local anesthetics suppress proliferation of
several cancer cell types, their mechanism is unknown. Potential for cancer recurrence caused by surgery
Local anesthetics block voltage-gated sodium channels and anesthetic‑induced immunosuppression
(VGSC), which are transmembrane proteins composed In general, cancer is considered as a systemic disease with
of one pore-forming α-unit and one or more auxiliary circulating tumor cells and micro-metastases present at
β-units. Cancer cells express an array of ion channels that initial diagnosis. Surgery and anesthetic-induced immu-
their terminally differentiated counterparts do not [103]. nosuppression activate HPA-axis and SNS responses,
VGSCs are highly expressed and active in breast, colon, which in turn increase neuroendocrine mediators. These
and lung cancers, and local anesthetics that cause chan- mediators promote metastasis to regional lymph nodes
nel blockade may inhibit tumor growth. In fact, lidocaine, and distant sites from residual or circulating tumor cells,
ropivacaine, and bupivacaine, which inhibit proliferation and stimulate growth of preexisting, dormant micro-
and differentiation, are cytotoxic to mesenchymal stem metastases through immunosuppression (Fig. 2). During
cells (MSCs) in vitro, and have key functions for tumor this process, cancer cells must escape immunoediting by
growth and metastatic formation in cancer cells [104]. NK cells and CTLs to establish themselves at distant sites
Locally administered lidocaine directly inhibits epi- and proceed to angiogenesis.
dermal growth factor receptor (EGFR), which is a poten- Tumor dormancy, often described as “cancer with-
tial target for anticancer drugs. Clinical concentrations out disease,” is the poorly understood phenomenon
of lidocaine have been shown to inhibit serum-induced by which quiescent cancer cells exist but do not pro-
and EGF-induced proliferation in human tongue cancer duce clinical disease [110]. Distant recurrence appear-
cells in association with tyrosine kinase activity of EGFR ing months or years after surgical resection have been
[105]. One study that assessed the direct effect of local described as dormant metastases, which are clinically
anesthetics showed that clinically useful concentrations undetectable, pre-existing disease foci that then become
of lidocaine and bupivacaine induce apoptosis in breast clinically detectable. Two potential explanations for
cancer cells in vitro and in vivo, suggesting a poten- tumor dormancy are 1) lack of angiogenic activity; and
tial benefit of local anesthetics for breast cancer sur- 2) immunologic equilibrium between tumor and host
gery [106]. Lidocaine and tetracaine, which both inhibit immunity, which prevents further tumor growth in the
Table 3 Effect of anesthetic agents on tumor development
Agent Experimental data Clinical data

Intravenous
Ketamine Stimulator of lung and liver metastasis [65] Increase in lung tumor retention or lung metastasis
Thiopental [66]
Increase in lung tumor retention or lung metastasis [66]
Propofol Inhibition of HIF-1α activation [71]
Prevention of isoflurane-induced HIF-1α activation [71] Antitumor effect [18]
Kim J Transl Med (2018) 16:8

Volatile anesthetics
Halothane Stimulator of lung and liver metastasis [65] Serum from sevoflurane/opioid anesthesia-analgesia for breast cancer surgery
Sevoflurane Suppression of hypoxia-induced growth and metastasis of lung cancer cells [35] Increased attenuates the inhibition of breast cancer cell proliferation [69]
proliferation, migration, and invasion of breast cancer cells [77] Increased expression of pro-oncogenic protein markers in head and neck squamous
cell carcinoma cells [70]
Isoflurane Upregulation of HIF-1α in prostate cancer cell line [71]
Increase in malignant potential of ovarian cancer cells [72]
Resistance against apoptosis via a Cav-1-dependent mechanism in cancer cells [73]
Nitrous oxide Suppression of neutrophil chemotaxis, potentially facilitating the spread of cancer [18] No effect on colorectal carcinoma recurrence [87]
Potent stimulator of lung and liver metastasis [65]
Opioids
Morphine Promotion of tumor growth (single-dose or low dose) [81] Increase in MOR expression in patients with non-small cell lung cancer [86] and
Fentanyl Involvement of MOR in tumor development [85–87] metastatic lung cancer [84]
Promotion of tumor growth and metastasis by MOR overexpression [85] Proangiogenic and A possible adjuvant therapy of MNTX for patients with advanced cancer [88]
Sufentanil proliferative effects in breast cancer xenografts [76, 90] Intraoperative opioid use is associated with decreased OS in stage I but not stage
Increase in endothelial cell proliferation expressed with mu3 opioid receptor [91] Stimulation of II-III NSCLC patients [94]
Rho A and Src activation downstream of the VEGFR [88]
Direct effect of morphine on breast cancer cell migration via NET1 [68]
Reduction in growth of certain tumors in part through activation of p53 [82] Attenuation of
MMP secretion under the control of nitric oxide system [83]
Beneficial effects on surgery-induced increases in metastasis by pre-surgical administration of
morphine [93]
Protective effect against metastasis development [34]
Antitumor-like effects on colorectal cancer cells [95, 96]
No change in apoptosis rate or cell cycle distribution at clinical concentrations [97]
Others
COX-2 inhibitor Antitumor and antiangiogenic properties [99] Reduced risk of breast and colorectal cancer [100, 101]
  β-adrenergic antagonist Reduction of ketamine-induced lung metastasis [81] Use of COX-2 inhibitor was associated with one-fifth reduction in breast cancer
recurrence [102]
Local anesthetics
Lidocaine Antitumor effect of lidocaine via the inhibition of EGF/EGFR pathway in human tongue cancer
Lidocaine/tetracaine cells [105]
Apoptotic cell death by lidocaine and bupivacaine in breast cancer cells [106]
Ropivacaine/bupivacaine Demethylation of DNA in breast cancer cell lines [108]
Inhibition of cancer cell invasion [109]
Reduced proliferation of mesenchymal stem cells [104]
Decreased metastatic progression in breast tumor cells [107] Reduced proliferation of MSCs [104]
No change in apoptosis rate or cell cycle distribution at clinical concentrations [97]

HIF-1α hypoxia inducible factor-1α; MOR Mu-opioid receptor; VEGFR vascular endothelial growth factor receptor; MNTX methylnaltrexone; MMP matrix metalloproteinase; NSCLC non-small cell lung cancer; COX-2
Page 9 of 13

cyclooxygenase-2; EGF epidermal growth factor; EGFR epidermal growth factor receptor; MSCs mesenchymal stem cells
Kim J Transl Med (2018) 16:8 Page 10 of 13

Fig. 2 Hypothesis to explain cancer metastasis and recurrence caused by surgery- and anesthetic-induced immunosuppression in the periopera-
tive period. Surgery, anesthesia, and analgesia stimulate the HPA-axis and SNS during the perioperative period. Activated neuroendocrine mediators
lead to increases in several immunosuppressive soluble factors that promote tumor progression and metastasis, resulting in increase of cancer
recurrence. Combined regional anesthesia with propofol decreases anesthesia-induced immunosuppression and avoids volatile anesthetics and
opioids, which may increase the risk of cancer recurrence

microenvironment. Because neuroendocrine mediators mitogen-activated protein kinase; ER: estrogen receptor; TIVA: total intrave-
nous anesthesia; IGF: insulin-like growth factor; ERK: extracellular signal–regu-
regulate tumor progression biology and act as endog- lated kinase; N2O: nitrous oxide; NX: naloxone; MOR: μ-opioid receptor; NSCLC:
enous angiogenesis modulators of reactivation from dor- non-small cell lung cancer; LLC: Lewis lung carcinoma; MNTX: methylnaltrex-
mancy, HPA-axis and SNS neuroendocrine dynamics one; VGSC: voltage-gated sodium channels; MSCs: mesenchymal stem cells;
EGFR: epidermal growth factor receptors.
may be responsible for loss of tumor dormancy [6]. Thus,
surgery-induced and anesthetic-induced immunosup-
pression may promote cancer recurrence through HPA- Acknowledgements
Not applicable.
axis and SNS activation during the perioperative period
in patients with cancer. Competing interests
The author declares no competing interests.
Conclusion Availability of data and materials
Currently available preclinical studies suggest that anes- Not applicable.
thetic-induced immunosuppression may promote cancer
Consent for publication
recurrence in patients with certain types of cancer. Vola- Not applicable.
tile anesthetic agents and morphine or synthetic opioids
produce diverse effects on cancer cells that depend on Ethics approval and consent to participate
Not applicable.
dose, duration, and timing of use. Nevertheless, locore-
gional anesthesia and propofol-based anesthesia seem Funding
to reduce surgical stress, perioperative immunosuppres- There was no funding support for this manuscript.
sion, and angiogenesis compared to general anesthesia
with volatile anesthetics and opioids. Although a causal Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub-
link between anesthetics, immune function, survival, and lished maps and institutional affiliations.
residual disease remains to be elucidated, several ongoing
prospective RCTs should provide more definitive infor- Received: 16 August 2017 Accepted: 15 January 2018
mation about the effects of anesthesia on cancer recur-
rence after surgery.

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