Abstract
Cancer remains one of the major causes of death worldwide, and the global burden of the disease is rising continuously. Clinical retrospective data suggested that inhalational anesthetics might affect the prognosis of cancer patients, but the underlying molecular mechanism remained unknown. Hypoxia-inducible factor-1 (HIF-1) is a dimeric transcription factor and mediates various cellular responses to hypoxia, including metabolism, cell death and survival, angiogenesis, oxygen delivery, immune evasion, and genomic adaptation. HIF-1 system has been shown to be the driving force of solid tumor progression and substantially contributes to the malignancy of cancer. Inhalational anesthetics such as isoflurane have been demonstrated to confer cytoprotection in a HIF-1-dependent manner in various vital organs. In addition, a recent study has demonstrated the pivotal involvement of HIF-1 in the impact of inhalational anesthetics on cancer cells. This review provides critical insights into the new understanding of cancer sensing of inhalational anesthetics and examines the recent understanding of the underlying molecular mechanisms. However, this area of research is just beginning and warrants further studies preclinically and clinically prior to making any conclusions that inhalational anesthetics may affect cancer outcomes. In addition, it is important to note that there is not enough evidence to support any change in the current clinical practice.
Keywords
anesthetics, inhalation; disease progression; neoplasm metastasis; hypoxia-inducible factor 1;
1. Introduction
Cancer is the third leading cause of death worldwide, and the global burden of the disease continues to increase due to population aging and growth in economically developed countries, as well as adoption of cancer-associated lifestyles in economically developing countries.1 According to GLOBOCAN 2008, approximately 12.7 million cancer cases 7.6 million cancer deaths occurred globally. Solid tumors account for most of the cancer cases and cancer mortality.2 Cancer morbidity and mortality trends are predicted to keep rising in the next few decades, and it is predicted that by 2030 there will be about 26.4 million incidences and 17 million deaths per year.3 Surgery and/or chemo/radiotherapy are the main treatment options for cancer patients; however, complete cure of cancer is difficult to achieve and cancer recurs frequently. Inhalational anesthetics have been indicated or demonstrated to play a critical role in cancer malignancy and its progression. However, the detailed mechanisms of how anesthetics affect tumor progression are not fully understood. Here, we will present and review recent evidence from experimental and clinical studies pointing to a fundamental role of the effects of anesthetics on cancer.
Accumulating clinical evidence strongly supports the assumption that the choice of anesthesia and application technique can influence the long-term prognosis of cancer patients. Exadaktylos et al4 observed a substantial reduction in tumor recurrence and metastases when breast cancer surgery was performed with paravertebral anesthesia and analgesia. Christopherson et al5investigated long-term survival after resection of colon cancer with different anesthetic techniques. They found that epidural anesthesia was associated with improved survival among patients initially, but with poorer survival in the later stage. The study by Schlagenhauff et al6 demonstrated an increased risk of mortality for patients with melanoma anesthetized with general anesthesia for the primary excision of the tumor.
There have been limited studies to explain the molecular basis of how cancer cells sense inhalational anesthetic gas. However, an understanding of how cancer cells sense the oxygen level during hypoxia and the underlying molecular mechanisms can provide clues to the action of inhalational anesthetics on cancer cells. This review provides a perspective of the biology of the hypoxia-inducible factor (HIF) system and its activation by anesthetics, which may serve a vital link to cancer malignancy during the perioperative period.
2. Sensing of cancer cells to hypoxia
Approximately 90% of solid tumor cells live in a microenvironment with relatively low oxygen supply.7 Recent findings have shown that tumor cells overcome hypoxia by triggering a series of cellular events in response to this hypoxic stress. Hypoxia is defined as an oxygen tension (pO2) below the normal range of cellular oxygen demand.8 There is no universal level of pO2that is considered as hypoxia, as pO2 varies across different organs in the body. For example, the normal pO2 level in the lung is around 150 mmHg, whereas in the retina, a pO2 around 5 mmHg could still be considered normal.9 However, hypoxic response would be triggered in most cancer tissues when venous pO2 drops below 40 mmHg and the hypoxic stress increases gradually as oxygen tension goes down to about 1.6–0.8 mmHg, close to anoxia.10, 11 The major cellular response to hypoxia is the expression of a transcription factor–protein complex, known as HIF-1. HIF-1 transcriptionally activates a range of genes involved in processes such as angiogenesis, erythropoiesis, energy metabolism, cell proliferation, apoptosis, survival, cell migration, and tissue remodeling.12
3. HIF system
Currently, three HIF-α isoforms have been discovered: HIF-1α, HIF-2α, and HIF-3α. HIF-1α and HIF-2α share greater than 70% homology in their DNA sequences. Both HIF-1α and HIF-2α function similarly through dimerization with HIF-1β, although studies have shown that each has its own transcriptional targets to regulate; by contrast, HIF-3α produces multiple splice variants that lack domains such as the transactivation domain.13, 14, 15
HIF-1 stabilization is the primary response in hypoxia, and it has profound effects on tumor progression. HIF-1 is a heterodimeric protein composed of a constitutional HIF-1β subunit and an oxygen-sensitive HIF-1α subunit. HIF-1 is a basic helix–loop–helix protein, part of the PER-ARNT-SIM (PAS) DNA-binding protein family.16 It orchestrates a series of downstream effects such as promoting angiogenesis.17 Abundant and intact intracellular HIF-1α can translocate into the nucleus and dimerize with HIF-1β. The oxygen-insensitive subunit HIF-1β is an aryl hydrocarbon receptor nuclear translocator (ARNT) and is essential for the dimerization and subsequent binding of HIF-1 to DNAs, leading to transcription of downstream genes as a consequence.18
HIF-1α is regulated at both transcriptional and translational levels. Two major factors involved in this regulation are factor inhibiting HIF and prolyl hydroxylase domain proteins (PHDs).19 Both proteins can function properly only in the presence of oxygen. Factor inhibiting HIF is a 2-oxoglutarate-dependent dioxygenase that catalyzes hydroxylation of asparagine 803 in the C-terminal transactivation domain of HIF-1α. The HIF complex, therefore, fails to assemble due to the loss of interaction between HIF-1α and the transcriptional coactivators CREB-binding protein.20 PHD-2 is the key enzyme regulating HIF-1α degradation in normoxia.21 PHDs require oxygen and 2-oxoglutarate as cosubstrates, as well as iron and ascorbic acid as cofactors to catalyze hydroxylation of the oxygen-dependent degradation domain of HIF-1α.22 HIF-1α hydroxylation and/or HIF-1α acetylation by arrest defective-1 protein has been shown to increase the binding affinity of HIF-1α for the von Hippel–Lindau protein. Von Hippel–Lindau protein is a component of the E3 ubiquitin ligase complex that induces ubiquitin-mediated proteosomal degradation of HIF-1α.23, 24
Because oxygen is critical for the function of both factor inhibiting HIF and PHD, HIF-1α is not hydroxylated or degraded in hypoxia. Studies have shown that other processes such as phosphorylation and nitrosylation can affect the stability and transcriptional activity of HIF-1α, which indicates other undiscovered regulatory pathways.13, 25, 26 In addition, the mitochondrial electron transport chain has been shown to regulate HIF-1 stabilization.27
4. Downstream effects of HIF-1 in tumor progression
Many of the hundreds of genes that are regulated by HIF code for proteins are crucial for tumor progression. They influence tumor progression under hypoxic conditions via promoting or modifying several cellular processes, including metabolism, cell death and survival, angiogenesis, immune evasion, and genetic instability.28
4.1. Metabolism
Depletion of oxygen causes cancer cells to switch to anaerobic metabolism, which greatly increases their genetic instability.29 HIF-1 regulates expression of a series of metabolic proteins, including glycolytic enzymes, glucose transporters (GLUT1 and GLUT3), hexokinase 1 and 2, phosphoglycerate kinase 1, and lactic dehydrogenase A.30 The function of most of them is to overcome hypoxic stress by improving glucose uptake. The exception is phosphoinositide-dependent kinase-1. phosphoinositide-dependent kinase-1 inhibits the conversion of pyruvate to acetyl coenzyme A, so that lactate is produced by lactic dehydrogenases.31 It also blocks excessive production of mitochondrial reactive oxygen species and promotes regeneration of NAD+ for anaerobic glycolysis.14, 26
Furthermore, hypoxia also attenuates biosynthesis of amino acids, proteins, lipids, and nucleotides by inhibiting mammalian target of rapamycin (mTOR).32 The conserved serine/threonine protein kinase mTOR phosphorylates a number of substrates related to protein translation, including eukaryotic initiation factor 4E-binding protein-1 and ribosomal p70 S6 kinase.33, 34 The mTOR pathway has been shown to be suppressed by hypoxia. Hypoxia increases the level of AMP and induces AMP-activated protein kinases. AMP-activated protein kinases phosphorylate several downstream substrates including tuberous sclerosis complex 2 (TSC2) and subsequently activates the TSC2–TSC1 complex, a negative regulator of mTOR.35 HIF-1 directly induces gene expression of REDD1/RTP801, which also activates the formation of the TSC complex.36, 37 HIF-1 has been shown to optimize the efficiency of respiration through cytochrome oxidase in mitochondria.38 However, hypoxia-mediated metabolic adaptations remain partially understood and need further investigation.
4.2. Cell death and survival
Depletion of oxygen can enhance the production of the proapoptotic protein Bcl-2/adenovirus E1B 19 kDa interacting protein 3 (BNip3) more than 100-fold via action of HIF-1.39 BNip3 accumulation is shown to be enhanced by acidosis caused by opening of the mitochondrial permeability transition pore during hypoxia.18, 19, 40
Paradoxically, hypoxia also contributes to tumor immortalization through HIF-1-induced mitogen-activated protein kinase signaling that increases telomerase activity.41 It is believed that these hypoxia-induced responses confer cellular protection to cancer cells to survive through hypoxic stress.42The exact role of hypoxia in tumor cell death and survival still remains to be elucidated.
4.3. Angiogenesis
Angiogenesis is defined as the growth of new blood vessels in areas where nutrients and/or oxygen is insufficient. Angiogenesis is essential for a tumor to grow beyond a certain size, as tumor cells located far away from the blood supply will become deoxygenated.43 Hypoxia exerts its effects on tumor angiogenesis mainly through genes activated by HIF both directly and indirectly. Among these genes, HIF-dependent transcription of the vascular endothelial growth factor (VEGF) genes is the most crucial.44 VEGFs have been shown to promote tumor angiogenesis via various mechanisms. Interestingly, VEGF has also been found to have an autocrine effect on tumor survival, migration, invasion, immune suppression, and metastasis.45
There are several VEGF family members and corresponding receptors. VEGF-A is the proangiogenic isoform that interacts with two receptor tyrosine kinases: VEGF receptors 1 and 2 (VEGFR-1 and VEGFR-2). The VEGF isoforms VEGF-C and VEGF-D engage in lymphangiogenesis by interacting with VEGFR-3.46, 47 In general, VEGFs enhance endothelial cell proliferation and vessel formation, as well as control integrin expression and enzyme activity in the extracelluar matrix during angiogenesis.48 Studies have found enhanced levels of serine proteases, urokinase-type plasminogen activator, and tissue-type plasminogen activator upon VEGF stimulation.49 Serine functions to degrade the extracelluar matrix. Overexpression of urokinase-type plasminogen activator and its receptor promotes survival signaling in various cancers.46, 50
VEGF-A has been found to have multiple isoforms as a result of alternative splicing.51 The predominant isoform is VEGF165, which is usually found to be overexpressed in solid tumors.52 VEGF-A is responsible for guiding sprouting neovessels to the area where oxygen is insufficient. VEGF-A is expressed in most cells, and its expression is regulated by interstitial oxygen concentration. Abundant VEGFR-2s were found to be expressed on the filopodia of endothelial cells situated at the tip of sprouting neovessels, and their migration was influenced by VEGF-A distribution gradients.53, 54
VEGF-A expression is regulated mainly through transcription, mRNA stabilization, and translation.41 During hypoxia, HIF-1 is first bound to the vegf promoter and activates transcription of the vegf gene. Activator protein-1 is another transcription factor required for the upregulation of vegf gene transcription.55 VEGF-A mRNA is stabilized through the stress-activated kinase p38, and its translation is regulated via internal ribosome entry site sequences present in 5′ noncoding regions of VEGF-A.55, 56, 57 Recently, Jafarifar et al58 revealed a new mechanism of hypoxia-induced VEGF-A activation through reversing the microRNA-mediated gene silencing by binding of heterogeneous nuclear ribonucleoprotein-L to the VEGF-A 3′-UTR CA-rich element 5. Hypoxia is believed to induce the translocation of the heterogeneous nuclear ribonucleoprotein-L to the cytoplasm.
Angiopoietin (Ang)-2 secretion during hypoxia has been shown to be the rate-limiting step in vessel remodeling in angiogenesis.59 Ang-2 is a receptor ligand that naturally antagonizes binding of Ang-1 to the angiopoietin receptor Tie-2 in endothelial cells. Normally, Ang-1 binding triggers tyrosine kinase signaling. Blood capillaries are maintained in a mature and dormant state through pericyte recruitment.60, 61
There are more proangiogenic proteins with specific roles in regulating angiogenesis, from early sprouting to vessel stabilization. Some are controlled directly by HIF-1, e.g., metalloproteinases 2 and 9, plasminogen-activator inhibitor-1, and platelet-derived growth factor-B,62 whereas other proteins such as fibroblast growth factor, placental growth factor, Ang-1 lack HIF-responsive elements (HREs) sites for HIF-1 binding and, therefore, may be regulated through indirect HIF signaling pathways.63 Some antiangiogenic factors such as thrombospondin can be downregulated through HIF-1.64
In addition, oxygen transport to tumor cells is another important factor that contributes to cancer survival. HIF-1 controls the expression of genes whose products are necessary for oxygen delivery, such as transferrin, transferring receptor, ceruloplasmin, and hepcidin.65, 66 HIF-1 can also induce erythropoietin expression, which increases red blood cell production in hematopoietic tissues in the bone marrow. HIF-1 increases oxygen delivery to invading tumors in a systematic way.13, 67 Additionally, arteriogenesis is another mechanism utilized by cells to increase oxygen supplies; the monocyte-chemoattractant-protein-1 involved in the process has also been found to be induced by HIF-1 in hypoxia.68
4.4. Immune evasion
Hypoxia affects host immune cells and stromal niche that facilitates the evasion of cancer from immune surveillance; however, the exact mechanism is poorly understood.69 It has been shown that monocytes are recruited to tumors in the same way as endothelial cells via graded VEGF distribution. These monocytes then differentiate into tumor-associated macrophages, secreting mitogenic factors, proangiogenic cytokines, and immunosuppressive agents.70, 71 Antitumor functions of macrophages and T-cells are inhibited in hypoxic conditions.71, 72 Wei et al73 showed that hypoxia enhanced the ability of gliomas to induce immunosuppressive cells such as Tregulatory cells and M2 macrophages, and demonstrated the essential involvement of signal transducer and activator of transcription 3 pathways in hypoxia-mediated immunosuppression. Together with HIF-1-mediated anti-inflammatory effects, the immunosuppressive effects induced by hypoxic tumor tissues are further enhanced.74, 75
4.5. Genomic instability
Hypoxia has long been known to enhance tumor genomic instability through increased chromosomal rearrangement, gene amplification, and induction of intrachromosomal fragile sites.76 Loss of DNA mismatch repair (MMR) gene functions has been observed in human colon carcinoma cells under hypoxic conditions, and it contributes to drug resistance of the surviving cancer population.77 It has now been found that HIF-1 can function to repress MMRgenes, including MSH2 and MSH6.78 Hypoxia also downregulates the expression of BRCA1 and RAD51, which mediate homologous recombination in mammalian cells, resulting in more common hypoxia-associated polyploidy phenotype.29, 79 Furthermore, some other DNA damage and DNA repair checkpoint proteins are induced in hypoxia, such as ataxia-telangiectasia mutated, ataxia and telangiectasia and RAD3 related, Chk1, Chk2, BRCA1, and p53.79, 80, 81, 82, 83
5. Inhalational anesthetics and HIF-1
Similar to sensing oxygen level, it has been found that mammalian cells can sense the inhalational anesthetic gas, which may change their genetic phenotype.84 Similarly, cancer cells exposed to volatile anesthetics may have altered biological response to external stress, which promotes subsequent adaptation in favor of survival and migration. Volatile anesthetics have been found to be capable of altering or modulating gene expression in human cancer in a unique and time-dependent manner.85 Several genetic changes responded to anesthetic exposure would well predict cancer patients' survival, demonstrated by microarray gene expression profiling.85 Recently, accumulating evidence has shown that inhalational anesthetics affect the expression of HIF-1 in different tissues, including malignant solid tumor.
5.1. Isoflurane
Studies have shown that isoflurane is an effective inducer of HIF-1α. Li et al86have demonstrated that isoflurane applied under normoxic conditions increased HIF-1α protein in the human hepatoma Hep3B cells in a time- and concentration-dependent manner. Expression of HIF-1 responsive genes heme oxygenase 1 (HO-1), inducible nitric oxide synthase (iNOS), and VEGF mRNA were also enhanced by isoflurane exposure. Induction of VEGF mRNA by isoflurane was attenuated when HIF-1α is inactivated. In addition, Li et al's86 study also demonstrated that isoflurane-mediated upregulation of HIF-1α depends on HIF-1α translation pathway rather than affecting HIF-1α protein degradation. Consistent with this study, isoflurane has been demonstrated to induce HIF-1 downstream effectors such as iNOS,87 HO-1,88 and VEGF,89 which could render the cell more tolerant or resistant to injury or stress.
It was found that pre- or post-treatment with isoflurane confers protection to the myocardium against ischemia–reperfusion injury, and this cardioprotection is mediated through an increased expression of HIF-1 and activation of downstream pathway.90 It was demonstrated that isoflurane treatment enhanced the expression of HIF-1α in a sustained manner in the rat heart, and nuclear translocation of HIF-1α was evident in both healthy and injured hearts, which indicated enhanced HIF-1α activation.91 Further studies showed that the upregulation of HIF-1α by isoflurane involved the upstream pathway, especially PI3K/Akt/mTOR. A study by Raphael et al92 showed that isoflurane pretreatment was cardioprotective in the rabbit model of regional myocardial ischemia–reperfusion injury, and this cardioprotective effect of isoflurane was mediated by the activation of HIF-1. Administration of the mTOR inhibitor rapamycin abolished the cardioprotective effect of isoflurane, with simultaneous inhibition of HIF-1α protein expression and activities; this indicated that isoflurane exerts its effects through HIF-1α upstream mTOR. These observations were further supported by other studies confirming that isoflurane upregulates HIF-1α in vitro and in vivo, and activation of HIF-1 responsive genes such as iNOS.89, 92, 93
In addition to cardioprotection, it was also found that isoflurane pretreatment enhanced HIF-1α and its downstream iNOS gene expression in neurons, which was responsible for protection against oxygen glucose deprivation-induced injury.94 HIF-1α upstream PI3K/AKT pathway95 has been found to be associated with isoflurane-mediated neuroprotection.96 Isoflurane exposure has been shown to protect against cerebral ischemia, and it is associated with enhanced HIF-1α and iNOS expression. Silencing of HIF-1α attenuated the protective effects of isoflurane, which provided convincing evidence for the pivotal involvement of HIF-1α in the protection against ischemic brain injury.97
A recent study showed similar effects of isoflurane in kidney; isoflurane pretreatment protected the rodent kidney against ischemia–reperfusion injury, and this effect is HIF-1α dependent because knockdown of HIF-1α through siRNA abolished the protection.98 It was also demonstrated that isoflurane treatment induced a sustained increase of HIF-1α and its downstream effector erythropoietin (EPO), which exerts antiapoptotic effects on renal tubular cells, renal dysfunction and renal failure after ischemia–reperfusion injury were effectively prevented.
5.2. Sevoflurane
Sevoflurane was also shown to be cytoprotective, and this effect is mediated by HIF-1α. A study by Zitta et al99 demonstrated that when sevoflurane was applied to human neuroblast cell line IMR-32 cells in hypoxic conditions, cytoprotective effects were observed during treatment prior to hypoxia during the hypoxic period. This cytoprotection was associated with changes in both erk1/2 phosphorylation and HIF-1α protein levels. Ye et al100 demonstrated that sevoflurane post-treatment effectively protects the brain from ischemic-reperfusion injury after focal cerebral ischemia, through attenuation of neuronal caspase-3 activation. Real-time polymerase chain reaction and Western blotting showed that sevoflurane exposure significantly increased mRNA and protein expression of HIF-1α and its target gene HO-1. Ye et al's100study further showed that the PI3K/Akt pathway may play a crucial role in sevoflurane-induced neuroprotection, supported by the evidence that the selective PI3K inhibitor wortmannin abolished the neuroprotective effect of sevoflurane and reduced expression of HIF-1α, HO-1, and p-Akt after sevoflurane exposure.
5.3. Desflurane
It has been proposed that, similar to other volatile anesthetics, desflurane can induce HIF-1 and its downstream HO-1 and iNOS; it also possesses similar antioxidative, anti-inflammatory, and antiapoptotic properties to other volatile anesthetics.101 So far, there is no sufficient evidence showing the association between desflurane exposure and the HIF-1 system, which might warrant further investigation.
5.4. Halothane
Itoh et al102 have shown that halothane reversibly suppresses HIF-1α protein accumulation and transcriptional activity within a range of clinically relevant doses in the human hepatoma Hep3B cell line. In addition, halothane blocked HIF-1 downstream expression of enolase 1 (ENO1) or VEGF gene. This indicated that halothane may behave differently from isoflurane discussed previously. However, this property was not sufficiently investigated in other cell types or organs, and the relationship between halothane exposure and HIF-1 need to be elucidated further.
5.5. Nitrous oxide
The effect of nitrous oxide on HIF-1 expression remained largely unknown. A recent study by Tanaka et al103 showed that nitrous oxide suppressed hypoxia-induced upregulation of EPO mRNA in mouse brains. However, the potential impact of nitrous oxide directly on HIF-1 itself in other tissues or organs was not explored so far.
5.6. Xenon
Xenon has been shown to be a potent organoprotectant associated with HIF-1. In the kidney, xenon treatment was found to enhance the expression of HIF-1α, VEGF, HO-1, and Bcl-2, both in vivo and in vitro.104, 105, 106, 107 In a mouse model of renal warm ischemia–reperfusion injury, xenon provided morphologic and functional renoprotection; hydrodynamic injection of HIF-1α small interfering RNA demonstrated that this protection is HIF-1α dependent.105 Further studies showed that this upregulation is caused by enhanced HIF-1α production through PI3K–AKT–mTOR pathway, rather than by decreased molecular degradation.104, 105, 107 Exposure to xenon enhanced the expression of insulin growth factor-1 and its receptor in human proximal tubular (HK-2) cells, which, in turn, increased cell proliferation. This is direct evidence showing that xenon exposure is associated with the HIF-1 upstream pathway and subsequent cell proliferation. In a rat model of renal graft ischemia–reperfusion injury, xenon exposure of donors prior to graft retrieval or of recipients after engraftment suppressed renal cell death and cell inflammation and prolonged graft survival after renal transplantation.104, 106, 108 It has also been demonstrated that xenon conferred renoprotection on ex vivo renal grafts when supplemented with a preserving solution and is likely to stabilize cellular structure during ischemic insult.109
6. HIF-1 as the potential link between inhalational anesthetics and cancer
As a critical association exists between inhalational anesthetics and HIF-1-mediated cytoprotection, it may be reasonably postulated that inhalational anesthetics can be one of the contributors to tumor progression during and after oncological surgery. The recent work of Benzonana et al110 demonstrated that isoflurane induced upregulation of HIF-1α in renal carcinoma cells and enhanced its malignant potential such as cell proliferation and cell migration in vitro. Isoflurane exposure increased the expression of HIF-1α in a steady and constant manner, which is different from the immediate and transient increase of HIF-1α induced by hypoxia. This suggested that the HIF-1α upregulation is induced through enhanced HIF-1α protein synthesis rather than by inhibition of its degradation, as occurred during hypoxia. This was further supported by the constant level of PHD enzymes after isoflurane exposure and abolishment of HIF-1 upregulation cells through PI3K inhibitor LY294002, which indicated that the upstream PI3K/Akt/mTOR pathway was responsible for such an observation. Exposure of renal carcinoma cells to isoflurane induced and promoted the cytoskeletal rearrangement with both F-actin and α-Tubulin being involved, together with elevated migration activities. Although the above work may provide a solid base in the area of research, it is too early to make any conclusion regarding the potential impact of inhalational anesthetics on cancer reoccurrence after surgery due to the following reasons: (1) the nature of the work is in vitro cell culture, which is very different from real clinical situations; (2) multiple factors (e.g., cancer stage and patient's condition including immune function, surgical seeding effect, etc.) contribute to cancer outcome after surgery; and (3) although combined anesthesia, including opioid and sedatives, is often used clinically, how it affects cancer cell biology remains unknown.
7. Clinical implication
7.1. Selection of anesthetics during cancer surgery
The use of regional anesthesia has been associated with lower recurrence rates and better survival rates in breast cancer,4 prostate cancer,111 melanoma,6 and colon cancer.5 Deegan et al112 demonstrated that patients who received combined propofol/paravertebral anesthesia–analgesia (propofol/paravertebral) exhibited reduced levels of protumorigenic cytokines and matrix metalloproteinases (MMPs), and elevated levels of antitumorigenic cytokines, compared with patients receiving sevoflurane anesthesia with opioid analgesia (sevoflurane/opioid). Sevoflurane was associated with increased levels of MMP-3 and MMP-9 in breast cancer patients. By contrast, patients in the propofol/paravertebral group showed a significant reduction in elevated MMP-3 and MMP-9 levels. Deegan et al's112 study suggested that anesthetics may have opposing effects; biological responses of cancer patients to these anesthetics may be diverse, leading to different survival prognoses. Given the wide choice of anesthetic agents and techniques currently available, further relevant studies both in vitro and in vivo would provide molecular rational for the selection of anesthetics in clinical settings for the ultimate benefit of cancer patients undergoing surgery.
7.2. HIF-1 inhibitor as an adjuvant to anesthetics
Therapeutic approaches that interfere with tumor response to hypoxia have been shown to be promising in treating cancer. Several drugs that act through the inhibition of HIF-1 and its downstream effectors have been developed and have shown beneficial effects for the prognosis of cancer patients.
Many genes regulated by HIF-1 are potential therapeutic targets to combat against tumor growth. Current drugs/agents, as well as those under development, suppress tumor growth or kill cancer cells mainly through their antiangiogenic effects, by means of inhibiting various stages of hypoxia-induced responses, such as inhibition of HIF-1 and VEGF. Therefore, an adjuvant therapy that can potentially block the effects of anesthetics may be considered prior to or during cancer surgery.
7.2.1. Direct inhibition of HIF-1
Therapies directly targeting HIF-1 could be an attractive idea to suppress cancer during peri- and postoperational period.113 Xu et al42 showed that silencing of HIF-1α short-hairpin RNA interference through significantly reduced renal cancer cell growth, migration and invasion, and tumor growth in animals was significantly inhibited in HIF-1α short-hairpin RNA-transfected renal cell carcinoma. Gene therapies blocking interactions between HIF-1α and CREB-binding protein have also been investigated, and have been demonstrated to halt tumor growth in a mouse xenograft model.114
7.2.2. Inhibition of HIF-1 downstream effectors
Angiogenesis is the most important and relevant hypoxia-mediated response leading to tumor growth and survival. VEGF is the key protein in controlling angiogenesis. Over 20 VEGF-targeted agents are currently under clinical trial115; several of them have been approved for clinical use, mostly antibodies that neutralize VEGF or VEGFRs, soluble VEGFRs, receptor hybrids, or tyrosine kinase inhibitors with selectivity for VEGFRs. Bevacizumab (Nexavar) and sorafenib (Pfizer) are well-known examples of this class of drug116, 117and should be considered as adjuvant therapies prior to exposure to volatile anesthetics during cancer surgery.
8. Conclusion
Inhalational anesthetics have been shown to be potentially associated with tumor progression in terms of cancer growth, metastasis, and invasion. HIF-1 upregulation has been intensively investigated in organoprotective effects of inhalational anesthetics during vital organ injury. However, inhalational anesthetics could potentially protect the cancer against external stress or insults, as it does in the heart, brain, and kidney. Understanding of all genes or proteins involved in HIF-1 regulation manipulated by inhalational anesthetics would contribute greatly to the development of new anesthetic regimens for the care of perioperative cancer patients, which would ultimately be beneficial for the overall prognosis of cancer patients. The area of research is just beginning and warrants further studies preclinically and clinically prior to making any conclusion that volatile anesthetics may affect cancer outcomes. In addition, it is important to note that there is not enough evidence to support any change in the current clinical practice.