Exercise under hypoxic condition as a potential therapeutic paradigm for digestive system cancers: A narrative review

Journal of Cancer Research and Clinical Oncology Exercise under hypoxic condition as a potential therapeutic paradigm for digestive system cancers: A narrative review --Manuscript Draft-- Manuscript Number: JOCR-D-21-03498 Full Title: Exercise under hypoxic condition as a potential therapeutic paradigm for digestive system cancers: A narrative review Article Type: Review – Clinical Oncology Keywords: SPOA-D-21-00857 Corresponding Author: Josefa León San Cecilio Hospital, ibs.GRANADA Granada, SPAIN Corresponding Author Secondary Information: Corresponding Author's Institution: San Cecilio Hospital, ibs.GRANADA Corresponding Author's Secondary Institution: First Author: Sergio Perez-Regalado, SPORT SCIENCE First Author Secondary Information: Order of Authors: Sergio Perez-Regalado, SPORT SCIENCE Josefa León belén feriche Order of Authors Secondary Information: Funding Information: Abstract: Cancer, like other chronic pathologies, is associated with the presence of hypoxic regions due to the uncontrolled cell growth. Under this pathological hypoxic condition, various molecular signalling pathways are activated to ensure cell survival, such as those that govern angiogenesis, erythropoiesis, among others. These molecular processes are very similar to the physiological response caused by exposure to altitude, the use of artificial hypoxia devices (systemic simulated hypoxia) or the delivery of vascular occlusion to the extremities (also called local hypoxia by the blood flow restriction technique). “Tumor hypoxia” has gained further clinical importance due to its crucial role in both tumor progression and resistance to treatment. However, the ability to manipulate this pathway through physical exercise and systemic hypoxiamediated signalling pathways could offer an important range of therapeutic opportunities that should be further investigated. This review is focused on the role of systemic hypoxia combined with exercise as a potential therapeutic proposal in digestive system neoplasms. We conclude that there is evidence that exercise performed under hypoxic conditions can improve digestive system cancers modulating prognosis and quality of life, which could be considered as a potential new intervention in digestive oncological population. Suggested Reviewers: Ginés Viscor Full professor, University of Barcelona: Universitat de Barcelona [email protected] expert in hypoxia physiology and practical application Prue Cornie Associate Professor, Australian Catholic University Saint Patricks Campus: Australian Catholic University [email protected] Expert in oncology and sport medicine Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation Opposed Reviewers: Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporation 1 Title page 1 2 Title: Exercise under hypoxic condition as a potential therapeutic paradigm for digestive system cancers: A 3 narrative review 4 5 Sergio Pérez Regalado (MSc). Department of Physical Education and Sport, Faculty of Sport Sciences, 6 University of Granada, Spain. ORCID: 0000-0001-9503-4286 7 8 Josefa León (PhD). Clinical Management Unit of Digestive System, San Cecilio Hospital, ibs.GRANADA, 9 Granada, Spain. ORCID: 0000-0002-0543-4823 10 11 Belén Feriche (PhD). Department of Physical Education and Sport, Faculty of Sport Sciences, University of 12 Granada, Spain. ORCID: 0000-0002-3933-6041 13 14 Corresponding author: Josefa León (PhD). Clinical Management Unit of Digestive System, San Cecilio 15 Hospital, ibs.GRANADA, Granada, Spain. ORCID: 0000-0002-0543-4823. [email protected] 16 17 18 19 20 21 22 23 24 25 26 27 28 29 Manuscript Click here to access/download;Manuscript;Final manuscript version.docx Click here to view linked References 2 Abstract 1 2 Cancer, like other chronic pathologies, is associated with the presence of hypoxic regions due to the 3 uncontrolled cell growth. Under this pathological hypoxic condition, various molecular signalling pathways are 4 activated to ensure cell survival, such as those that govern angiogenesis, erythropoiesis, among others. These 5 molecular processes are very similar to the physiological response caused by exposure to altitude, the use of 6 artificial hypoxia devices (systemic simulated hypoxia) or the delivery of vascular occlusion to the extremities 7 (also called local hypoxia by the blood flow restriction technique). “Tumor hypoxia” has gained further clinical 8 importance due to its crucial role in both tumor progression and resistance to treatment. However, the ability to 9 manipulate this pathway through physical exercise and systemic hypoxia-mediated signalling pathways could 10 offer an important range of therapeutic opportunities that should be further investigated. This review is focused 11 on the role of systemic hypoxia combined with exercise as a potential therapeutic proposal in digestive system 12 neoplasms. We conclude that there is evidence that exercise performed under hypoxic conditions can improve 13 digestive system cancers modulating prognosis and quality of life, which could be considered as a potential new 14 intervention in digestive oncological population. 15 16 Keywords: aerobic exercise, cell hypoxia, digestive system neoplasms, exercise, hypoxia, resistance training. 17 18 Key points: 19 - Systemic hypoxia exposure operates as the main regulator of haematological, angiogenic, metabolic 20 and neural adaptations. 21 - The physiological effect of systemic hypoxia exposure contributes to vascular remodelling that could 22 reduce the local hypoxia of the tumor microenvironment and decrease the leakages in the vascular wall 23 making the tumor more vulnerable to anti-tumor treatment and immune system action. 24 - Although further research focused on the main topic is needed, a wide spectrum of new possibilities 25 support the exercise performed under hypoxic conditions as a new potential therapeutic intervention 26 in digestive oncological population. 27 28 3 Introduction to digestive system neoplasms 1 2 Cancer is a disease in which genetic and/or epigenetic changes drive abnormal cell growth in a way that is 3 deleterious to the organism (1). Immunosuppression, a sedentary lifestyle, old age, chronic debilitating disease, 4 previous use of chemotherapy and abuse of some drugs (such as analgesics, antibiotics and corticosteroids) 5 increase cancer risk (2). 6 7 This disease is usually classified according to the characteristics of the tumor itself, as well as the location and 8 organ affected. Digestive system cancer encompasses seven variants of malignancies derived from the organs 9 that make up the digestive system (3, 4). According to global cancer statistics, only lung cancer is more 10 prevalent than colorectal cancer, a digestive cancer in the top five causes of cancer-associated mortality 11 worldwide (5). 12 13 Numerous treatments are used to treat gastrointestinal cancers, but many are invasive and/or cause side effects. 14 Regular exercise has been linked to a lower risk of digestive system cancer development (6, 7). Considering the 15 sequelae of cancer and its treatments, this practice is also emerging as a non-invasive colorectal cancer 16 modulator therapy. In fact, many reports support the beneficial effects of exercise in cancer patients. 17 Specifically, Devin et al. demonstrated that acute high intensity interval exercise transiently reduces cell growth 18 in patients with colorectal cancer (8). Another review concluded that regular exercise reduces body fat and 19 regulates insulin levels, modulating colorectal cancer progression (9). 20 21 Supporting this idea, new evidence is suggesting the positive effects of exposure to systemic hypoxia at rest or 22 during exercise on angiogenesis, mitochondrial biogenesis and promotion of skeletal muscle fiber type I 23 transition (7, 10). Unfortunately, there is insufficient data to determine how exercise performed under hypoxic 24 conditions could modulate the development of digestive system cancers. From this perspective, we discuss 25 recent reports about the modulation of digestive system cancer by exercise from a molecular point of view, 26 targeting future potential treatments linking exercise programmes with systemic hypoxia. 27 28 4 Cancer metabolism and tumor microenvironment 1 2 Cancer cells adapt their metabolism to obtain the energy necessary to support their growth (11). In the 1920s, 3 Otto Warburg first described increased glucose metabolism in cancer cells, even in the presence of oxygen, 4 with marked lactate production, which was interpreted as mitochondrial dysfunction (1, 12). Actually, it is now 5 known that mutations in genes responsible for mitochondrial metabolism are crucial for tumour cell survival 6 and proliferation in an environment with limited resources (13). Mutations in genes of the mitochondrial 7 tricarboxylic acid cycle (TCA), such as succinate dehydrogenase (SDH), fumarate hydratase (FH), and 8 isocitrate dehydrogenase 1 (IDH1) and 2 (IDH2) have been well studied (Fig. 1) (1). 9 10 SDH, complex II (CII) of the electron transport chain (ETC), is composed of four encoded subunits and 11 contributes to electron transfer (14). SDH is also part of the TCA, catalysing the oxidation of succinate into 12 fumarate (15). Genetic defects in SDH lead to mitochondrial complex II activity inhibition and succinate 13 accumulation, which blunt prolyl hydroxylase (PHD) activity and reactive oxygen species (ROS) generation. 14 Similar effects are found in the mutation of FH genes (16). Fumarate is an oncometabolite and its accumulation 15 suppresses α-KG-dependent dioxygenases, inducing hypoxia-inducible transcription factor-1α (HIF-1α) 16 stabilisation. Also, depletion of FH increases the dissociation, nuclear translocation and activity of nuclear 17 factor (erythroid-derived 2)-like 2 (Nrf2) and increases the transcription of antioxidant and oncogenic genes, 18 promoting tumor survival (14, 17, 18). Finally, FH mutation contributes to epithelial to mesenchymal transition 19 (EMT), mainly by suppressing miR-200 and E-cadherin expression, and also promoting Twist1 and vimentin 20 expression (14). Next, IDHs catalyse the oxidative decarboxylation of isocitrate to produce 2-oxoglutarate (α21 KG). Conversely, mutant IDHs metabolise α-KG into 2-hydroxyglutarate (2-HG). The tumorigenic activity of 22 2-HG has been linked to a suppressive effect of PHDs, αKG-dependent histone and DNA demethylases, 23 enhancing HIF-1α activity (19, 20). 24 25 [Insert Figure 1] 26 27 5 HIF are a group of DNA-binding proteins that induce transcription of numerous genes involved in angiogenesis, 1 glycolysis, metabolic adaptation, erythropoiesis and cell survival. They are heterodimeric transcription factors 2 composed of α and β subunits. HIF-1α is directly regulate by oxygen levels (gradual increase from 20 to 5% O2 3 and a pronounced increase below 5% O2) as well as a master controller of the transcriptional response to 4 systemic hypoxia (21, 22). Three distinct genes are known to encode the HIF-α subunit in mammals: HIF-1α 5 and HIF-2α, which function as transcriptional regulators and have unique and overlapping target genes, and 6 HIF-3α, whose role is less well understood. Acute adaptation to hypoxia is governed by HIF-1α (< 24 h), 7 promoting initial angiogenesis. In normoxia, HIF-α degrades rapidly, while in hypoxia it stabilises, translocates 8 to the nucleus, and dimerises with HIF-β subunits (present independently of partial pressure of oxygen (PaO2)) 9 to form HIF-1. HIF-1α binds to hypoxia-sensitive elements of HIF-1 target genes and stimulates protein 10 synthesis by regulating the transcription of genes involved in the control of erythropoiesis, angiogenesis, 11 vasodilation, energy metabolism, apoptosis and synthesis of catecholamines (23). When exposure to systemic 12 hypoxia becomes chronic (> 24 h), HIF-1α levels progressively decrease and HIF-2α and HIF-3α begin to be 13 expressed in the human endothelium, favouring further development of the vascular network (24). 14 Overexpression of HIF-1α in the tumor microenvironment (TME) contributes to cancer progression and 15 promotes tumor cell adaption, even in the presence of oxygen. Then, HIF-1α plays a critical step in cancer 16 survival and growth by modulating the activity of several metabolic enzymes of glycolysis, supporting the 17 reprogramming of glucose metabolism in cancer cells (21, 25). 18 19 In terms of neoplasm development, continuous tissue growth that exceeds the available resources implies the 20 activation of angiogenic mechanisms that provide nutrients, oxygen and waste removal (26). The intrinsic local 21 hypoxia of a tumor triggers a response through HIF-induced pro-angiogenic factors, including vascular 22 endothelial growth factor (VEGF), which is the master regulator of the angiogenesis process and is also involved 23 in endothelial proliferation (27, 28). This unbalanced proangiogenic response is characterised by an 24 uncontrolled and faster growth rate than seen in a normal endothelial cell, creating a chaotic and abnormal 25 network of blood vessels. (29). Tumor vessels are disorganised and leaky due to structural failures, which allow 26 the extravasation of intravascular fluid and proteins into the interstitial fluid, increasing the internal pressure 27 (30). As a result, the blood supply is not homogeneous throughout the tumor and local hypoxic regions develop. 28 6 Conversely, the collapses generated in this TME act as a shield against the immune response and drug 1 administration (31, 32). 2 3 Particularly in hypoxic cancer cells (Fig. 1), HIF-1α upregulates glucose transporter-1 (GLUT1), promoting 4 glucose uptake into tumor cells, and hexokinase-2 (HK2), an enzyme that generate glucose 6-phosphate (G-65 P) by glucose phosphorylation (21). Furthermore, HIF-1α also contributes to the maintenance of cellular 6 homeostasis by mediating pyruvate dehydrogenase kinase 1 (PDK1) expression. PDK1 reduces the conversion 7 of pyruvate into acetyl-coenzyme A through pyruvate dehydrogenase (PDH) inhibition (33). Additionally, the 8 HIF-1α-inducible enzyme lactate dehydrogenase A (LDHA) metabolises the accumulated pyruvate to produce 9 lactic acid, and monocarboxylate transporter 4 (MCT4) removes the lactate from cancer cells (34, 35). 10 Nevertheless, this ejected lactate is taken up by normoxic cancer cells through MCT1 (36). These normoxic 11 tumor regions convert lactate into pyruvate through lactate dehydrogenase B (LDHB) as an energy source for 12 the TCA cycle, reducing glucose consumption and promoting its diffusion distance (37, 38). As a result, a 13 feedback loop is established, through which the hypoxic tumor regions can evade the immune system and anti14 tumors treatment, and also achieve a continuous supply of nutrients coming from the normoxic tumour regions. 15 16 However, hypoxic cancer cells, due to their elevated lactate production, show an increase in hydrogen ion (H+) 17 concentration leading to an acidic intracellular pH (pHi). This is a crucial point in the progression of the tumor, 18 increasing the expression of HIF-1α-dependent genes in order to restore pHi levels (39). This is achieved 19 through activation of CA9 carbonic anhydrase IX (CAIX) by HIF-1α, which promotes bicarbonate and H+ 20 formation from released CO2, and activation of sodium-hydrogen exchanger 1, which exchanges intracellular 21 H+ for extracellular sodium ions (39, 40). As a consequence, lactate and protons accumulate and acidify the 22 extracellular space, acting as another obstacle to the effectiveness of radioand chemotherapy (41). 23 24 There is growing evidence on cancer cell survival under hypoxic intracellular conditions. On one hand, many 25 authors defend an adaptation process, showing less exposure to ROS through a HIF-1α-dependent mechanism 26 known as autophagy (42). Poor oxygen supply results in HIF-1α stabilisation, mediating a signalling pathway 27 response involving Bcl-2/adenovirus E1B 19-kDa interacting protein 3 (BNIP3) and BNIP3-like protein 28 7 (BNIP3L) activation. BNIP3 and BNIP3L increase beclin1 release, which in turn leads to a switch to autophagy 1 (43). On the other hand, cells may become adapted according to their resource availability due to adenosine 2 monophosphate-activated protein kinase (AMPK) activity. AMPK is an energy sensor that triggers autophagy, 3 promoting UNC-51-like kinase 1 (ULK1) activity and suppressing the mTOR pathway (43, 44). This process 4 allows the removal of defective mitochondria without releasing cytochrome C, which would induce cell 5 apoptosis (42). Lastly, toxic damaged proteins and organelles are processed and re-utilised for macromolecule 6 biosynthesis (40, 45). 7 8 The influence of the chaotic vascular physiology on the hypoxic tumour microenvironment development 9 10 Tumor growth and development depends on the availability of nutrients and oxygen. A resource-poor 11 environment implies the activation of mechanisms, such as angiogenesis, that allow the tumor to survive. Unlike 12 healthy tissue, tumor angiogenesis is characterised by an overabundance of pro-angiogenic factors, including 13 VEGF, basic fibroblast growth factor (bFGF), transforming growth factor β (TGFβ) and tumor necrosis factor 14 alpha (TNF-α), resulting in a disorganised, leaky and immature network of blood vessels (46, 47). Despite the 15 chaotic vasculature, this provides a hypoxic and acidified ecosystem that allows the tumor to evade the immune 16 response and antitumor treatment (48). 17 18 In this context, several mechanisms upregulate the expression of VEGF, which is a key mediator of 19 angiogenesis, through the activation of various signalling pathways involved in initiating angiogenesis and the 20 creation of new blood vessels (49). A recent review shows a relationship between the upregulation of VEGF 21 and its receptors and colorectal cancer development in humans (50). Overexpression of VEGF also promotes 22 vascular permeability and upregulates the expression of angiopoietin-2 (ANG2) in colorectal cancer (51). Thus, 23 ANG2 inhibits ANG1, destabilising the interaction between endothelial cells (EC) and vascular pericytes (52). 24 Additionally, ANG2 increases interleukin-10 (IL-10) release by interaction with TIE2-expresing monocytes 25 (TEM) (53). Both IL-10 and VEGF contribute to the inhibition of T cell function, modulating the CD4+/CD8+ 26 ratio and the maturation process of dendritic cells (DCs) (47, 54). In fact, 8 weeks of moderate resistance 27 training (3  12 rep, 60% repetition maximum (RM)) in normoxia augmented blood VEGF and ANGP-1 28 14 reduction in arterial stiffness and vascular remodelling (115). In patients with obesity, an improvement in fitness 1 condition and lower mechanical work and joint stress was associated with prolonged exposure to natural 2 hypoxia (8 weeks; 90 min at 60% of the heart rate at maximum aerobic capacity, 3 days/week; FiO2 = 15%) 3 (116). Hypoxia-induced appetite reduction has been shown to occur due to hormonal regulation and an increase 4 in energy expenditure (117, 118). Another crucial area of study for disease treatment is the therapeutic use of 5 stem cells and how they work due to their ability to differentiate into any cell of an organism and have the 6 ability of self-renewal (119). Although the exact mechanism of HIF1-α and HIF-2α in stem cell survival (both 7 under normal and pathological conditions) is not known, HIF-1α appears to be the main regulator of normal 8 and neoplastic stem cells in all types of hypoxia (120). The upregulation of HIF-1α favors the treatment of 9 ischemic pathologies (121), while its reduction in tumor-specific regions could lead to the inhibition of tumor 10 growth (122, 123). In this context, miRNAs could provide therapeutic possibilities by modulating the HIF 11 switch, aiming to improve physiological and pathophysiological conditions (124). 12 13 In cancer, exercise performed in normoxia is considered to be a potential inhibitor of cancer progression that 14 regulates vascular maturity and improves intratumoral perfusion. It is also known to reduce the local hypoxia 15 of tumor structures and enhance the antitumor immune response, thereby improving the efficacy of treatment 16 and the quality of life of patients in a wide range of cancer types (64). Physiological adaptations associated with 17 physical exercise are potentially larger when accompanied by exposure to systemic hypoxia (125). Furthermore, 18 some pharmacological strategies have emerged targeting the HIF1-α signalling pathway (126). A recent review 19 summarises HIF-1α inhibitors in microenvironmental regions of tumor hypoxia as a potential anti-tumor 20 treatment, promoting apoptosis and reducing proliferation and angiogenesis (127). HIF-1α intratumoral 21 overexpression is associated with a poor prognosis in various solid cancers, including gastric and colon cancer 22 (128). Results from Ioannou et al. also supported the key role of HIF-1α in tumor angiogenesis and progression 23 in colorectal cancer patients (129). Despite this evidence of the negative intratumoral role of HIF1-α in cancer 24 progression, some studies show numerous physiological benefits when patients are exposed to systemic hypoxia 25 (130). Along with the modulatory effect of HIF on angiogenesis and apoptosis, even physical exercise combined 26 with simulated environmental intermittent hypoxia exposure at rest is also associated with mobilisation of NK 27 cells and pro-antioxidant balance improvements in cancer patients (131). 28 15 1 Conclusion 2 3 In this review, we focus on the role of systemic hypoxia combined with exercise as a potential therapeutic 4 proposal in digestive cancer. We aim to highlight the crucial role that systemic hypoxia plays in athletic 5 performance, where it operates as the main regulator of haematological, angiogenic, metabolic and neural 6 adaptations. On one hand, numerous studies support the effectiveness of exercise programmes in the modulation 7 of tumor development and growth in many types of cancer. Furthermore, the literature shows that systemic 8 hypoxia exposure alone contributes to counteract the negative symptoms in cancer, in a wide range of 9 conditions, although this effect seems to be intensified when hypoxia is combined with an exercise programme. 10 This is partly explained by the vascular remodelling that reduces the local hypoxia of the TME and decreases 11 leakages in the vascular wall. This action makes the tumor more vulnerable to anti-tumor treatment and immune 12 system action. Therefore, the effect is determined by the balance of the HIF expression response induced by the 13 systemic hypoxia and the intratumoral HIF-1α/HIF-2α ratio. On the other hand, systemic hypoxia also affects 14 specific cytokines that play crucial roles in tumor growth, such as IL-6 in liver cancer and SPARC in colorectal 15 cancer. Considering the beneficial physiological effects of systemic hypoxia exposure documented in this 16 review, a wide spectrum of new possibilities arises for modulating prognosis and quality of life in digestive 17 oncological population. Nevertheless, further research focused on exercise programmes under systemic hypoxic 18 conditions in digestive cancer models is needed to determine how to utilise the potential effects of exercise in 19 hypoxia on patient prognosis, opening an unexplored non-pharmacological research area. 20 21 Declarations 22 Funding (none) 23 Conflicts of interest/Competing interests (none) 24 Availability of data and material (supplementary material) 25 Code availability ('Not applicable') 26 Ethics approval ('Not applicable') 27 Consent to participate ('Not applicable') 28 16 Consent for publication (all authors give their consent for publication) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 17 Bibliography 1 2 1. Wallace DC. 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GLUT1, glucose transporter-1; HK2, 5 hexokinase-2; PDK1, pyruvate dehydrogenase kinase 1; MCT4, monocarboxylate transporter 4; ROS, reactive 6 oxygen species; LDHA, lactate dehydrogenase A; Nrf2, (erythroid-derived 2)-like 2; Keap1, Kelch-like ECH7 associated protein 1; 2-HG, 2-hydroxyglutarate; PHD, prolyl hydroxylase; SDH, succinate dehydrogenase; 8 FH, fumarate hydratase; IDH2, isocitrate dehydrogenase 1; PDH, pyruvate dehydrogenase; HIF-1α, hypoxia9 inducible transcription factor; CI-V, electron transport chain complex I-V. Red lines, inhibition; black arrows, 10 healthy cellular process. 11 12 Figure 2. In response to exercise, several myokines are released into the bloodstream (A). On the one hand, 13 the joint action of IL-6, epinephrine and SPARC promotes an anti-tumour response (B). On the other hand, 14 shear stress-dependent signalling pathways trigger an angiogenic response leading to vascular remodelling 15 and reduces the local hypoxia of the tumor microenvironment (C). This increases tumour vulnerability and the 16 effectiveness of the anti-tumour treatment and immune system action. SPARC, secreted protein, acidic and 17 rich in cysteine; IL-6, interleukine-6. 18 19 Figure 3. The rapid depletion of nutrients and oxygen levels results in a favourable atmosphere for triggering 20 several signalling pathways necessary for tumour survival. Acute microenvironment hypoxia caused by rapid 21 tumour growth promotes the induction of both HIF-1α and HIF-2α. On the one hand, HIF-1α reduces hypoxia 22 levels through activation of angiogenesis and/or the reperfusion process or even cell death. Alternatively, 23 chronic hypoxia can increase HIF-2α levels, promoting tumour adaptation, proliferation and progression. 24 HIF-1α, hypoxia-inducible transcription factor-1α; HIF-2α, hypoxia-inducible transcription factor-2α. 25 26 27 28