Exercise-dependent regulation of the tumour microenvironment.

PERSPECTIVES OPINION

Exercise-dependent regulation of the tumour microenvironment Graeme J. Koelwyn, Daniela F. Quail, Xiang Zhang, Richard M. White and Lee W. Jones

Abstract | The integrity and composition of the tumour microenvironment (TME) is highly plastic, undergoing constant remodelling in response to instructive signals derived from alterations in the availability and nature of systemic host factors. This ‘systemic milieu’ is directly modulated by host exposure to modifiable lifestyle factors such as exercise. Host exposure to regular exercise markedly reduces the risk of the primary development of several cancers and might improve clinical outcomes following a diagnosis of a primary disease. However, the molecular mechanisms that underpin the apparent antitumour effects of exercise are poorly understood. In this Opinion article, we explore the putative effects of exercise in reprogramming the interaction between the host and the TME. Specifically, we speculate on the possible effects of exercise on reprogramming ‘distant’ tissue microenvironments (those not directly involved in the exercise response) by analysing how alterations in the systemic milieu might modulate key TME components to influence cancer hallmarks. The lower genetic limit of cancer risk for a given individual is substantially elevated with exposure to ‘genotoxic’ lifestyle behaviours such as smoking, excess caloric intake and low physical activity or energy expenditure1,2. This notion is perhaps most clearly illustrated by the profound deleterious consequences of smoking and exposure to ultraviolet light on the incidence of lung cancer and malignant melanoma, respectively 3–5. If such genotoxic lifestyle behaviours accelerate the pathogenesis of cancer, then it stands to reason that the opposite might also be true — exposure to ‘physiological’ lifestyle behaviours might prevent and/or delay carcinogenesis. Approximately two million years ago, selective pressures on early human species of the genus Homo led to the emergence of ‘striding bipedalism’, a unique adaptation that bestowed humans with the capacity for long-distance walking and endurance running, an obligatory requirement for effective scavenging, avoidance of predation and persistent hunting 2,6,7. Over the next one

million years, humans evolved a genome that was adapted not only for superior endurance capacity (cardiorespiratory fitness) but also for remarkable phenotypic plasticity in physiological response to both acute (single bout) and chronic (repeated) exposure to mobility-related stimuli and rest periods6,7. The contemporary era of modern history, particularly that of Western or Westernized societies, is predominantly characterized by a substantial mismatch between over-nutrition and low energy expenditure, which chronically perturbs cellular, tissue, organ and systemic homeostasis, leading to accelerated onset and an increased risk of many forms of cancer 8–13. The daily energy expenditure resulting from any bodily movement (such as physical activity) of those living in Western civilizations is markedly lower than that of our Homo ancestors14 and continues to decline at an alarming rate15,16. The recent radical shift from a predominantly ‘blue-collar’ workforce (vocations requiring manual labour) to ‘white-collar’ occupations

(office-based vocations) in the twentieth century has caused a marked decline in physical activity. Despite these recent global shifts, individuals who maintain a lifestyle with high mobility and physical activity appear to have a remarkably lower risk of non-communicable diseases, including cancer 9–11,17,18. Over the past 30 years, numerous observational studies have shown that exposure to chronic exercise strongly reduces the risk of the primary development of many cancers19. In addition, initial data published over the past decade suggest that exposure to exercise following the diagnosis of certain solid tumours might lower the progression of disease and reduce cancer-related mortality 20. However, the molecular mechanisms that underpin the potential antitumour effects of exercise are poorly understood21,22. In this Opinion article, we explore the putative effects of exercise on reprogramming the interaction between the host and the tumour microenvironment (TME). First, we provide an overview of the physiological adaptations to exercise in tissue-relevant biological processes (including metabolic, angiogenic and immune responses) in skeletal muscle. We then discuss how these changes, along with changes in other tissues that are primarily implicated in the exercise response (for example, bone, heart, adipose tissue, liver and endothelium), trigger a highly complex and integrated network of communicative signals between multiple organs and tissues that profoundly alter the systemic milieu. Finally, we speculate on the possible effects of exercise on the reprogramming of ‘distant’ tissue microenvironments (those not directly involved in the exercise response) that might harbour transformed or pre-malignant cells by analysing how alterations in this communicative signalling and systemic milieu might modulate key TME components to influence major cancer hallmarks.

Host adaptation to exercise Interrogation of exercise-dependent modulation of the host–TME relationship begins with the remarkable integrative response at the whole-organism level that is triggered by a single bout of acute exercise.

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PERSPECTIVES The central nervous system coordinates the initiation as well as the integration of the systemic exercise response. This is achieved through the coordination of the respiratory and cardiovascular systems to maintain organ perfusion pressure and increase the delivery of oxygen and nutrients to metabolically active skeletal muscle to facilitate ATP re‑synthesis23,24 (FIG. 1). Consequently, exercise requires an integrative response of multiple organ systems (for example, lungs, heart, vascular system, skeletal muscle, liver, pancreas, adrenal glands and adipose tissue) to transport both oxygen and substrates (for example, glucose and free fatty acids) to metabolically active skeletal muscle25. The degree to which this integrative organ response can transport and utilize oxygen determines the maximal rate of whole-organismal oxygen consumption (VO max, or maximal cardiorespiratory fitness)26. Repeated acute bouts of 2

exercise stimulate marked improvements in VO max, an obligatory adaptive response in early humans for effective scavenging and hunting 7. This remarkable adaptive capacity permits the continued re‑establishment of a new homeostatic ‘set point’, which increases wholeorganismal capacity — and presumably tissue and cellular capacity — to withstand subsequent physiological and pathological perturbations27. Here, we focus our discussion on physiological adaptations to exercise that occur in skeletal muscle, specifically the regulation of metabolism, angiogenesis and the immune response. It is important to stress, however, that given stark differences in adaptability and network signalling regulation, or dysregulation in malignant states, skeletal muscle and solid tumour responses to exercise-induced perturbation of the systemic milieu are likely highly distinct. Nevertheless, an overview 2

of how exercise triggers adaptation in these key processes in skeletal muscle provides a proof‑of‑concept platform to understand how exercise might regulate such processes in the TME.

Skeletal muscle metabolism Several excellent reviews23,28–30 have summarized the mechanistic basis of metabolic adaptation to exercise in skeletal muscle. In brief, exercise activates a diverse network of transcription factors, kinases and co-regulatory proteins that culminate in gene expression changes that increase mitochondrial biogenesis and stimulate metabolic reprogramming in skeletal muscle30 (FIG. 2a). Depletion of ATP and NADH levels elevates the ratios of AMP:ATP and NAD+:NADH, which activates numerous metabolic sensors, including NAD-dependent protein deacetylase sirtuin 1 (SIRT1) and kinases such as AMP-activated

Central nervous system

Central command

Lungs Heart Liver Pancreas Kidney Adipose tissue

↑ Respiration

↑ Glucose output

Alterations in mean arterial pressure, pO , pCO , ² ² pH and temperature

Chemoreceptor sensing and activation; baroreceptor resetting

↑ Free fatty acid mobilization

↑ Blood glucose

↑ Adrenaline ↑ Cortisol ↑ Glucagon

↑ Cardiac output

Skeletal muscle

Figure 1 | Integrated physiological response to acute exercise. The central nervous system orchestrates the initiation as well as the integra‑ tion of the exercise response through a feedforward ‘central command’ response involving coordination of the respiratory and cardiovascular systems (for example, increased respiration and cardiac output) to main‑ tain organ perfusion pressure and increase the delivery of oxygen and nutrients (for example, increased glucose output and free fatty acid mobilization) to metabolically active skeletal muscle for ATP re‑ synthesis. The exercise response (light blue boxes) therefore involves the integration of multiple organ systems, including the lungs, heart, liver,

Type III and IV muscle afferent feedback

vascular system, adipose tissue and skeletal muscle. Feedback from type III and type IV afferents in the skeletal muscle, as well as feedback Nature Reviews | Cancer from changes in baroreceptor resetting and chemoreceptor sensing and activation in response to changes in mean arterial pressure, partial pres‑ sure of O2 (pO2), partial pressure of CO2 (pCO2), pH and body temperature (grey boxes), further regulates the exercise response. Reductions in blood glucose levels during exercise promote the release of adrenaline and cortisol from the adrenal gland and glucagon from the pancreas, which collectively delay exercise-induced hypoglycaemia. Adapted with permission from REF. 28, Elsevier.

NATURE REVIEWS | CANCER

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PERSPECTIVES a Metabolism and angiogenesis Metabolism

Angiogenesis ↑ AMP:ATP ↑ NAD+:NADH ↑ SIRT1 ↑ AMPK ↑ ERK1/2, p38 MAPK, JNK

Nucleus PGC1α ERRs

PPARs

PGC1α

NRFs

ERRα

VEGF

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Mitochondrion TFAM

↑Angiogenesis ↑ Mitochondrial biogenesis ↑ Metabolic reprogramming (↑ OXPHOS)

↑ Transcription of mtDNA

b Immune response ↑ M2 macrophages

Inflammation

IGF1 Treg cell

↑ CCL2 ↑ TNF ↑ IL-1β Muscle damage

↑ M1 macrophages ↑ CD8+ T cells ↑ Monocytes ↑ Neutrophils

↑ IL-10 ↑ TGFβ • ECM remodelling • Angiogenesis • Myogenic cell differentiation and growth Return to homeostasis ↓ M2 macrophages

Time ↑Muscle turnover and adaption

Figure 2 | A simplified model of the adaptive response to exercise in skeletal muscle. Exercise induces adaptations in multiple cellular processes in skeletal muscle, including metabolism, angio genesis and immune regulation. a | Depletion of ATP and NADH levels elevates the AMP:ATP and NAD+:NADH ratios, activating a number of metabolic sensors, including NAD-dependent protein deacetylase sirtuin 1 (SIRT1) and kinases such as AMP-activated protein kinase (AMPK), ERK1/2, p38 MAPK and JUN N‑terminal kinase (JNK). These metabolic sensors activate peroxisome proliferator- activated receptor-γ coactivator 1α (PGC1α), which regulates the expression of mitochondrial pro‑ teins encoded in both the nuclear and mitochondrial genomes via interaction with multiple transcription factors, such as peroxisome proliferator-activated receptor-γ (PPARγ), oestrogen- related receptor-α (ERRα), ERRγ, nuclear respiratory factor 1 (NRF1) and NRF2. NRF1 also increases the expression of mitochondrial transcription factor A (TFAM). Cumulatively, this results in enhanced mitochondrial biogenesis and metabolic reprogramming to facilitate increased oxidative phosphorylation (OXPHOS) in skeletal muscle. Exercise-induced activation of PGC1α (which regu‑ lates vascular endothelial growth factor (VEGF) expression through co-activation of ERRα) and hypoxia-inducible factors (HIFs) also increase angiogenesis and capillarization. b | Moderate to vigorous bouts of exercise can induce structural damage to muscle fibres, triggering an intra muscular, inflammatory immune response that is characterized by increased neutrophil, monocyte, macrophage and CD8+ T cell accumulation, as well as increased levels of CC-chemokine ligand 2 (CCL2), interleukin-1β (IL-1β) and tumour necrosis factor (TNF), which induce macrophage activa‑ tion towards a pro-inflammatory (M1) phenotype and enhance myeloid cell recruitment. Inflammatory resolution after muscle damage is coordinated by anti-inflammatory factors such as macrophage- and regulatory T (Treg) cell-derived interleukin‑10 (IL‑10), as well as macrophage- derived transforming growth factor-β (TGFβ) and insulin-like growth factor 1 (IGF1). Macrophage-produced IGF1 can also act in an autocrine manner to activate macrophages towards an anti-inflammatory (M2) phenotype. Adapted with permission from REF. 30, Elsevier.

protein kinase (AMPK), ERK1/2, p38 MAPK and JUN N‑terminal kinase (JNK)28. These metabolic sensors activate transcriptional regulator peroxisome proliferator-activated receptor-γ coactivator 1α (PGC1α), which regulates the expression of mitochondrial proteins encoded in both the nuclear and mitochondrial genomes31 via interaction with other transcription factors, including peroxisome proliferator-activated receptor-γ (PPARγ), a crucial regulator of fatty acid metabolism32; and oestrogen-related receptor-α (ERRα) and ERRγ, which directly control aspects of mitochondrial energy metabolism, including mitochondrial biogenesis, oxidative phosphorylation, fatty acid oxidation and the tricarboxylic acid (TCA) cycle29,33. PGC1α also interacts with nuclear respiratory factor 1 (NRF1) and NRF2, which increase the expression of genes encoding mitochondrial respiratory chain proteins34. NRF1 increases the expression of mitochondrial transcription factor A (TFAM), which is shuttled to the mitochondria, where it regulates transcription of mitochondrial DNA28. Many metabolic sensors involved in the exercise response (for example, AMPK, p38 MAPK, JNK, ERK1/2, activating transcription factor 2 (ATF2) and NF-κB) are also redox sensitive27. For example, reactive oxygen species (ROS) and reactive nitrogen species directly regulate contraction-induced mitochondrial biogenesis35 and skeletal muscle metabolic reprogramming via AMPK and PGC1α36.

Skeletal muscle angiogenesis Exercise is a potent stimulator of angiogenesis in skeletal muscle37,38. Increased capillarization of muscle tissue provides a larger surface area for oxygen diffusion, an increased area for oxygen flux and an improved transit time for gas and nutrient exchange39. PGC1α is a major regulator of exercise-induced angiogenesis and directly induces the expression of vascular endothelial growth factor (VEGF) through co-activation of ERRα in a hypoxia-inducible factor 1 (HIF1)-independent manner 40 Nature Reviews | Cancer (FIG. 2a). Whether exercise causes a sufficient decrease in the partial pressure of oxygen in myocytes to activate HIF-dependent angiogenesis is controversial41. Nevertheless, exercise-induced metabolic perturbations, including generation of ROS42 or activation of alternative oxygen-sensing pathways (for example, prolyl hydroxylase domain (PHD) enzymes)43,44, likely provide an alternate mechanism for HIF activation and the subsequent regulation of angiogenesis45.



PERSPECTIVES Skeletal muscle immune response Skeletal muscle damage and regeneration are principal features of the physiological adaptation to exercise28,46. Acute bouts of moderate to vigorous exercise can induce structural damage in muscle fibres46,47, which triggers an initial intramuscular pro-inflammatory immune response characterized by neutrophilia48,49, CD8+ T cell accumulation50 and increased numbers of monocytes and macrophages, the latter of which are functionally shifted towards a pro-inflammatory M1 phenotype (classically activated)51,52 (FIG. 2b). This process is mediated by proinflammatory cytokines released from damaged muscle tissue, including tumour necrosis factor (TNF; encoded by TNFA), CC-chemokine ligand 2 (CCL2; MCP1) and interleukin‑1β (IL‑1β)49,53. Resolution of inflammation following exercise-induced muscle damage is less defined. In models of muscle damage and repair (for example, cardiotoxin, notexin, hindlimb unloading and/or reloading), inflammatory resolution is associated with a phenotypic shift of macrophage populations towards an antiinflammatory, reparative M2 phenotype (alternatively activated)54. Many factors mediate this transition from M1 to M2, including macrophage- and regulatory T (Treg) cell-induced interleukin‑10 (IL‑10)51,55, macrophage-induced insulin-like growth factor 1 (IGF1)56 and phagocytosis of cellular debris by M1 macrophages51. Exerciseinduced muscle damage is postulated to closely mimic this response; however, direct comparisons are likely imprudent given differences in the degree of damage that occurs between experimental techniques and exercise53. Of note, the use of the M1/M2 macrophage polarization paradigm is likely over-simplistic, as macrophages can adopt a broad range of multidimensional phenotypes in response to various stimuli57, including exercise51,58,59, as discussed in more detail below. Exercise and TME reprogramming Exercise is a potent whole-organismal environmental challenge that perturbs numerous physiological processes that are regulated by several integrated homeostatic control circuits that operate at the cellular, tissue and systemic levels60. A detailed overview of the design and regulation of homeostatic systems and disease susceptibility is provided by a recent excellent review 60. Emerging work demonstrates that homeostatic control circuits are maintained by inter-organ

signalling. Such signalling is achieved by the secretion of hormones, cytokines and growth factors into the host systemic milieu from various tissues and organs (for example, skeletal muscle, heart, bone and adipose tissue), which can subsequently regulate diverse processes in local or distant organs via paracrine and endocrine regulatory feedback loops61–63. Over time, we speculate that chronic exercise-induced perturbation of inter-organ signalling promotes physiological adaptation across homeostatic control circuits (establishment of a higher homeostatic ‘set point’); in concert, such adaptations stimulate reprogramming of the systemic milieu, potentially characterized by alterations in the availability (reservoir), mobilization, recruitment, retention and function of specific cell types and/or molecules. In turn, this reprogramming of the systemic milieu might consequently alter the nature and strength of instructive signals at the tissue and cellular levels in the environment of ‘distant’ organs that potentially harbour transformed cells or a pool of cells primed for malignant transformation21,64,65 (FIG. 3). Surprisingly, little is known about the mechanistic effects of exercise on tissues that are distant from those directly implicated in the exercise response23. Consequently, there is a paucity of data on how exercise modulates the function, biology and programming of cells that reside within ‘distant’ tissues, organs or cellular compartments. In this section, we speculate on how exercise might reprogram ‘distant’ tissues harbouring tumour cells (that is, the TME), focusing on three key processes that are known to be regulated by exercise in skeletal muscle and are critical components of the TME that influence cancer hallmarks — metabolism, angiogenesis and immune response66. The pleiotropic nature of exercise suggests it might plausibly influence the entire breadth of TME contributions to cancer hallmark capabilities66; however, this would be highly conjectural given the current lack of available data and, therefore, will not be discussed.

Metabolism In non-transformed cells, nutrient uptake is strictly regulated in a non-cellautonomous manner by growth factor signalling or extracellular stimuli; for example, PI3K is activated by growth factors (for example, insulin and IGF1) in the tissue microenvironment67,68. This places a high degree of reliance on sufficient mitogenic growth factor availability to

sustain proliferation in transformed cells69. As such, in cancer cells, metabolic signalling pathways downstream of growth factor receptors can be constitutively activated, permitting an adequate uptake of nucleotides, proteins and lipids to support the bioenergetic and biosynthetic demands of hyperproliferation70,71. Metabolic reprogramming, most predominantly the switch to aerobic glycolysis, is considered a key intrinsic feature of cancer cells but one that remains subject to modulation from the TME70. Nutrient and growth factor signalling. Prolonged physical inactivity results in excess nutrient and growth factor availability in the systemic milieu and presumably in the TME72,73. Growth factors such as insulin and IGFs signal through their respective receptor tyrosine kinases, which activate the major signal transduction pathways (for example, the PI3K–AKT, MAPK and MYC pathways), stimulating the uptake of nutrients to support proliferation9,69. By contrast, chronic exercise reduces growth factor availability in the systemic milieu, subsequently improving and/or restoring whole-organismal metabolic homeostasis74. For example, chronic exercise substantially increases glucose uptake and clearance in skeletal muscle via insulinindependent mechanisms, leading to decreased basal levels of insulin, IGF1 and glucose in the circulation74. Randomized trials indicate that chronic exercise might confer similar favourable effects in patients with primary cancer 75,76. Although overly simplistic, exercise-induced restoration and/or maintenance of whole-organismal metabolic control might, in turn, alter homeostatic control signals that regulate nutrient and growth factor uptake and/or availability at the tissue level and ultimately cancer-cell level, causing downstream effects on metabolism and bioenergetics. Data to support this notion are emerging. In a chemically induced model of mammary carcinogenesis, physical activity (wheel running) caused a delay in tumorigenesis77, with concurrent reductions in circulating levels of insulin, IGF1 and leptin78. These reductions at the systemic level occurred in conjunction with alterations in intratumoural metabolic signalling, signified by increased activation of AMPK and reductions in levels of activated AKT and mTOR77. Similarly, in a TPA-induced SENCAR (sensitivity to carcinogenesis) mouse model of skin cancer, 10 weeks of forced treadmill running reduced the activation of PI3K, AKT and



PERSPECTIVES Repeated exercise bouts Sedentary

Acute exercise

Fit/trained

Physiological adaption Reset physiological ‘set point’

↑ Respiration ↑ Cardiac output ↑ Glucose output ↑ Free fatty acid release

Adipose tissue

Liver

Heart

Bone Muscle

Homeostatic control circuits Systemic milieu: ↑ Metabolic (insulin, glucose, IGF1) ↑ Sex steroid (oestrogen) ↑ Inflammation (IL-6, CRP) ↑ Autonomic dysfunction

↑ Tumour perfusion ↑ O2 delivery ↑ Catecholamines ↓ Hypoxia ↑ Shear stress

Systemic milieu

Systemic milieu: ↓ Metabolic (insulin, glucose, IGF1) ↓ Sex steroid (oestrogen) ↓ Inflammation (IL-6, CRP) ↓ Autonomic dysfunction Resolution of immune homeostasis Tumour (TME)

TME Metabolism ↓ PI3K signalling ↓ Lactate ↓ MCT1

Figure 3 | Exercise-dependent regulation of the tumour microenvironment. Prolonged exposure to physical inactivity is associated with elevated circulating concentrations of numerous growth factors and hormones — a pro-tumorigenic milieu (blue boxes). By contrast, host exposure to acute bouts of exercise stimulates inter-organ signalling achieved by the secretion of hormones, cytokines and growth factors into the host systemic milieu from various tissues and organs (for example, skeletal muscle, heart, bone, liver and adipose tissue), which can subsequently regulate multiple highly integrated homeostatic control circuits that operate at the cellular, tissue and whole-organismal levels (purple boxes). Over time, chronic exercise- induced perturbation of inter-organ signalling promotes physiological adaptation across homeostatic control circuits (establishment of a higher homeostatic ‘set point’) that, in concert, stimulates the reprogramming of the systemic milieu, potentially characterized by alterations in the

ERK1/2 in skin tissues79. In three distinct, claudin-low, triple-negative syngeneic breast cancer mouse models, forced treadmill running either inhibited, had no effect or accelerated tumour growth compared with the sham control80; metabolomic profiling of excised bulk tumours indicated differential alterations in tumour metabolic programming between models, although whether these differences were responsible for the differential tumour response to exercise was not determined. Interestingly, a series of observational studies suggest that the association between exercise and disease outcomes in patients

Immune regulation ↑ T cell content ↑ NK cell infiltration ↓ TAM accumulation

Angiogenesis ↓ Decreased hypoxia ↑ Vessel maturity ↑ Pericyte coverage

availability (reservoir), mobilization, recruitment, retention and function of Nature Reviews | Cancer specific cell types and/or molecules (green boxes), potentially altering their availability and composition in ‘distant’ tumour microenvironments (TMEs). Exercise-induced alterations in the systemic milieu influence key regulatory mechanisms in the TME, such as angiogenesis, immune regulation and metabolism, thus having a cumulative antitumorigenic effect (ochre box). In addition to activating the secretion of numerous factors from skeletal muscle, during acute exercise, blood flow is redirected to the metabolically active skeletal muscle that paradoxically occurs in conjunction with increased tumour blood perfusion and reduced tumour hypoxia. As such, this represents an alternative mechanism of exercise regulation of the TME (red box). CRP, C‑reactive protein; IGF1, insulin-like growth factor 1; IL‑6, interleukin 6; MCT1, monocarboxylate transporter 1; NK cell, natural killer cell; TAM, tumour-associated macrophage.

with colorectal cancer (CRC) might differ on the basis of intratumoural expression of factors involved in cellular metabolic regulation. For example, in tumours negative for the activation of WNT signalling (through the nuclear accumulation of β‑catenin, also known as CTNNB1), post-diagnosis exercise was associated with a marked reduction in cancer-specific mortality 81. The protective influence of exercise was not observed in patients with nuclear CTNNB1‑positive tumours. WNT signalling has a critical role in many biological functions in cancer, including metabolism82. In subsequent work, exercise

was associated with substantial reductions in CRC-specific mortality in patients with tumours with negative or low expression of insulin receptor substrate 1 (IRS1), whereas patients with tumours with high IRS1 expression did not appear to benefit from exercise83. IRS1 is a cytoplasmic substrate of the insulin receptor (INSR) and IGF1 receptor (IFG1R) signalling pathways84 and is aberrantly activated in numerous cancers85. Whether the antitumour effect of exercise is altered by the activation status of specific tumour metabolic signalling pathways has not been investigated in preclinical studies; however, there is indirect



PERSPECTIVES evidence from caloric restriction models to support this hypothesis. For instance, human xenograft tumours in mice with activating mutations in PIK3CA and/or PTEN loss are resistant to the anticancer effects of caloric restriction, despite systemic reductions in insulin and IGF1; however, restoration of PI3K signalling in cancer cells re‑sensitized xenografted tumours to the anticancer effects of caloric restriction86. Autophagy. Another process that might contribute to exercise-dependent regulation of tumour metabolism is autophagy, a process by which cellular components are degraded to maintain cell viability and homeostasis in response to stressful conditions87. When extracellular nutrients within the TME are depleted, cancer cells utilize autophagy to support growth and proliferation, suggesting that inhibition of autophagy might be a viable anticancer approach88,89. However, context is critical, as autophagy can be tumour suppressive (for example, via elimination of damaged organelles), as well as tumour promoting, in established cancers (for example, via intracellular recycling to provide essential substrates for metabolism)90. In the context of chronic exercise, a transgenic mouse model with normal autophagy under basal conditions but a deficiency in stress (exercise or starvation)-induced autophagy in skeletal muscle had decreased exercise endurance and altered glucose metabolism following acute and chronic exercise91. In addition to effects in skeletal muscle, exercise also induced autophagy in the liver, pancreas, adipose tissue and cerebral cortex in this transgenic mouse model91,92. Whether exercise-induced stress activates autophagy in tissues that harbour malignant cells (or cells primed for malignant transformation), or cancer cells themselves within those TMEs, and whether such effects inhibit or potentiate tumorigenesis, is not known. Lactate. The metabolic status or programming of cancer cells also alters the metabolic composition of the extracellular milieu, influencing the fate of other genetically stable cells in the TME66. One important manner in which cancer cells might exert this effect is via the accumulation of lactate as a result of the high utilization of extracellular glucose and glutamine69. Increased levels of lactate in the TME cause a number of pro-tumorigenic alterations, including promotion of an immunosuppressive environment via immune cell recruitment

and/or reprogramming, tumour cell invasion and angiogenesis69. In a mouse model of breast cancer (using the human MC4‑L2 cell line), 7 weeks of forced treadmill exercise inhibited tumour growth and reduced lactate concentrations (in bulk tumour lysates) with concomitant reductions in monocarboxylate transporter 1 (MCT1)93. Although not investigated, it could be speculated that reductions in lactate concentrations are the consequence of either exercise-induced reductions in nutrient (glucose) availability, which stimulates cancer cells to shift from glycolysis as the predominant form of ATP production to alternative processes that generate lower levels of lactate by‑product (for example, oxidative phosphorylation), or enhanced tumour vascularization following acute or chronic exercise exposure, which enhances the clearance of extracellular lactate69.

Angiogenesis Solid tumours have ‘abnormal’ blood vessels, leading to impaired oxygen delivery and low oxygen tension (hypoxia). Hypoxia activates HIF1, which regulates a highly conserved cellular response mechanism that involves a wide variety of critical cellular processes that are hijacked by tumours, including invasion, metabolism and angiogenesis94. Unlike physiological angiogenesis, HIF1‑induced angiogenesis in solid tumours paradoxically causes pathological angiogenesis, characterized by abnormal blood vessel formation and impaired perfusion and oxygenation of the tumour, thus creating a self-perpetrating, vicious cycle of hypoxia and a more aggressive tumour phenotype95. Given the aforementioned regulatory effects of exercise on physiological angiogenesis in skeletal muscle, investigation of whether such effects translate to solid tumours has received attention. In a syngeneic mouse model of breast cancer (4T1 cell line), voluntary wheel running (that is, in‑cage wheels permitting ad libitum running 24 hours per day) increased the density and maturity of the tumour vasculature, as assessed by the presence of CD31+ vessels and desmin-positive pericyte coverage of capillaries, respectively, which occurred in concert with reduced intratumoural hypoxia and inhibition of tumour growth relative to sedentary mice96. Several additional studies have corroborated this finding in syngeneic mouse models and xenograft models of breast and prostate cancer 97,98. Several mechanisms might underpin these effects. First, exercise increases

vascular maturity in solid tumours through enhanced association between desminpositive, chondroitin sulfate proteoglycan (NG2)-positive pericytes and CD31+ endothelial cells; however, this phenotype occurred in concert with reduced expression of Pdgfrb (which encodes platelet-derived growth factor receptor-β (PDGFRβ)) in bulk tumour samples96, suggesting that alternative mechanisms might be responsible. Second, exercise increases shear stress on the vascular wall, leading to upregulation of angiogenic factors (for example, VEGF‑A, osteopontin and macrophage inflammatory protein 1α (MIP1α)) within endothelial cells, which in turn induce transcriptional activation of nuclear factor of activated T cells (NFAT) via nuclear localization of NFAT cytoplasmic 1 (NFATc1) and subsequent expression of thrombospondin 1 within endothelial cells, thus stimulating angiogenesis99. Finally, exercise increases the bioavailability of nitric oxide, a critical mediator of tumour angiogenesis and metastasis, vascular maturity and lymphatic vessel function100,101. An acute bout of exercise might also influence solid tumour physiology directly via redistribution of cardiac output. Specifically, in response to local vasodilatory signals, blood flow to active skeletal muscles markedly increases (hyperaemia) to meet the increase in metabolic demand28. Consequently, blood flow is redistributed away from the majority of visceral organs and inactive muscles via vasoconstriction in these vascular beds28. This raises the intriguing question of how this response could alter tumour blood flow. In a mouse model of prostate cancer, tumour blood perfusion increased by ~200% during exercise compared with basal conditions, resulting in a ~50% reduction in tumour hypoxia, postulated to result from diminished tumour-specific α‑adrenergic receptor-mediated vasoconstriction with a concurrent loss of myogenic tone at higher intraluminal pressures98. These data demonstrate that in addition to the modulation of host factors in the systemic milieu (‘indirect’ mechanisms), exercise also modulates the TME via ‘direct’ mechanisms (FIG. 3). These initial studies raise many further questions. First, given its stimulating effects on angiogenesis and blood flow in primary tumours, exercise could also impact metastatic seeding and/or colonization in secondary sites. To facilitate seeding efficiency, the primary tumour communicates with distant tissues by



PERSPECTIVES releasing a broad array of factors to establish a pre-metastatic niche102. Primary tumour hypoxia increases the expression of the canonical HIF target gene LOX (which encodes lysyl oxidase)103,104, as well as inflammatory mediators such as CCL2 or granulocyte colony-stimulating factor (G‑CSF)105,106. Collectively, these factors promote the recruitment of pro-tumorigenic, immunosuppressive myeloid cells to secondary sites to establish a pre-metastatic niche107. Hence, exercise-induced attenuation of primary tumour hypoxia could reduce communication between the primary tumour and distant metastatic sites. Second, primary tumours stimulate the release and mobilization of bone marrow-derived cells (BMDCs), which are critical regulators of primary tumour angiogenesis, promote pre-metastatic niche formation and contribute to the repopulation of tumour cells to collectively facilitate invasion and metastasis102,108. Clinical data in individuals with109 and without cancer 110 demonstrate that chronic exercise increases the number of circulating BMDCs, suggesting that — at least in theory — exercise could facilitate the acquisition of an invasive tumour phenotype or augment metastatic seeding and/or colonization. By contrast, the torturous and poorly perfused nature of the TME vasculature creates a substantial physical barrier for the infiltration of cytotoxic immune cells66 and the delivery (and efficacy) of systemic therapeutic agents111. In addition, certain cell types, such as cytotoxic T cells, avoid hypoxic regions of the TME112. In a mouse syngeneic pulmonary fibrosarcoma model (MC205 cell line), levels of tumour hypoxia via hyperoxic conditioning (with 60% oxygen) reduced adenosinergic immunosuppression via increased production of pro-inflammatory cytokines (for example, IL‑2, IL‑12 and CXC-chemokine ligand 10 (CXCL10)), enhanced the infiltration and function of CD8+ cytotoxic T cells and natural killer (NK) cells, reduced the immunosuppressive function of forkhead box P3 (FOXP3)+ Treg cells and improved long-term survival112. Depletion of T cells or NK cells completely reversed this phenotype, revealing a critical relationship between oxygen tension and immunity in cancer. Exercise-mediated normalization of the TME vasculature might therefore improve immune infiltration. Indeed, the concept that exercise-induced alteration of the TME can improve therapeutic efficacy is supported by at least two preclinical studies showing that the combination of exercise

and chemotherapy leads to superior tumour control compared with chemotherapy alone in mouse models of breast96 and pancreatic cancer 99. Reconciliation of the potential pro-tumorigenic and antitumorigenic effects of exercise-induced tumour vascular normalization, and the context that determines these effects, are crucial areas of investigation in exercise-oncology.

Immune response Cancer cells must circumvent host immunity to survive and propagate113. Acute and chronic exercise alters the quantity and function of immune cell types that comprise the innate and adaptive immune system in both the circulation53 and within certain tissue compartments (for example, adipose tissue, bone marrow and lung)58,114. In this section, we discuss the available evidence for exercise-dependent modulation of innate and adaptive immune cell types in healthly states and in cancer. Innate immunity. In healthy physiological states, acute exercise increases the number of circulating innate immune subtypes (for example, monocytes, neutrophils and NK cells) as a consequence of haemodynamic shear stress and catecholamine-induced β2‑adrenergic receptor (β2AR) signalling 115. However, chronic exercise lowers the number of circulating pro-inflammatory (CD14+CD16+) monocytes116 and reduces the myeloid inflammatory response, as measured by reduced lipopolysaccharide (LPS)-induced production of proinflammatory cytokines (for example, TNF) in monocytes116,117 and a diminished neutrophil oxidative burst118,119. The antiinflammatory effects of chronic exercise in myeloid cells are in contrast to those observed in NK cells. For example, in elderly individuals (65 ± 0.8 years), chronic exercise exposure increased the cytolytic activity of unstimulated NK cells in peripheral blood mononuclear cells against K562 cells in vitro120. Exercise might also modulate innate immune cell activity in specific tissues. In healthy mice exposed to chronic exercise, mRNA expression analysis in adipose tissue indicated a shift in macrophage phenotype from a pro-inflammatory M1 state to an anti-inflammatory M2 state, as indicated by decreased expression of Tnfa and Adgre1 (commonly known as F4/80) and increased expression of Icam1 (which encodes intercellular cell-adhesion molecule 1 (ICAM1)), Cd11c (also known as Itgax) and Cd163 (REF. 121). Conversely, multiple preclinical mouse studies demonstrate that

chronic exercise increases the LPS-induced release of pro-inflammatory factors such as interferon‑γ (IFNγ), TNF and IL‑1β from peritoneal macrophages in vitro, suggesting a shift to an M1 phenotype122,123. Exercise might regulate innate immunity in cancer either through reprogramming or altered abundance of myeloid cells in the TME. In various mouse models of cancer, exercise promotes a pro-inflammatory M1 phenotype in peritoneal macrophages, which are generally considered to be antitumorigenic124. For instance, in a chemically induced mouse model of breast cancer, exercise delayed tumour development and promoted M1 activation of isolated peritoneal macrophages (indicated by increased LPS-induced release of IFNγ, TNF and IL‑12), whereas peritoneal macrophages from mice not exposed to exercise exhibited a pronounced pro-tumorigenic M2 phenotype (evidenced by increased LPS-induced release of IL‑10 and TGFβ)125. Similarly, exercise inhibited the metastatic outgrowth of syngeneic B16 melanoma tumours in mice, and isolated peritoneal macrophages displayed increased cytotoxicity against B16 cells in vitro126. It is also important to emphasize that macrophages, including tumour-associated macrophages (TAMs), have a spectrum of activation states that represent a much broader range of functional phenotypes than the over-simplistic M1/M2 linear paradigm57,127. For example, in tumours, further sub-classifications of TAM populations (for example, M2a to M2c) have been discovered, and these different TAM populations might have differential effects on tumour growth128. Areas of future investigation include how exercise shifts TAM phenotypes (basic evidence generally suggests a shift to an M1 state with exercise but also to an M2 state depending on tissue context), whether this differs as a function of the emerging TAM M2 subgroup classifications and whether such a shift results in either pro-tumorigenic or antitumorigenic effects. In terms of myeloid abundance, exercise might limit the accumulation of macrophages and neutrophils in the TME. For example, 6 weeks of forced swimming exercise delayed the growth of syngeneic Ehrlich tumours in mice, which occurred in conjunction with marked decreases in intratumoural macrophage and neutrophil accumulation129. Similarly, 2 weeks of treadmill running in mice decreased macrophage and neutrophil content in syngeneic EL4 lymphoma tumours130. Finally, in the ApcMin/+ mouse model of



PERSPECTIVES intestinal cancer, forced treadmill exercise reduced large polyp burden and reduced the intestinal mRNA expression of Adgre1 (F4/80), a canonical macrophage marker 131. Finally, the quantity and function of NK cells in cancer might be responsive to exercise. In postmenopausal women with early-stage breast cancer, 15 weeks of moderate-intensity aerobic exercise training enhanced the ex vivo cytotoxic capacity of NK cells in peripheral blood mononuclear cells132. Similarly, in the syngeneic B16 melanoma mouse model, voluntary wheel running enhanced cytotoxic NK cell recruitment, which infiltrated primary tumours, via release of adrenaline and IL‑6 (REF. 133). Blockade of either β‑adrenergic or IL‑6 signalling prevented NK cell infiltration and abrogated the antitumorigenic effect of exercise. These data indicate that exercise might alter a potential novel link between factors secreted by skeletal muscle (such as IL‑6) and the tumour infiltration and cytotoxicity of NK cells. Adaptive immunity. The number of circulating adaptive immune cells rapidly decreases following a bout of acute exercise, likely reflecting the preferential movement of these cell types from the circulation into peripheral tissues53. In humans, lymphocytes that enter and exit the circulation following exercise express high levels of adhesion molecules and markers of lymphocyte activation, such as ICAM1 (also known as CD54), integrin β2 (also known as CD18) and CD53 (REF. 134). Moreover, although evidence is limited, lymphocyte translocation seems to occur towards both lymphoid (for example, bone marrow) and non-lymphoid (for example, lungs) organs, at least in animal models114. Acute exercise therefore appears to prime effector cells (such as T cells) to transmigrate into peripheral tissues135. Chronic exercise also alters the function of circulating lymphocytes beyond the activation or expression of adhesion molecules. In elderly individuals, chronic exercise was associated with increased telomere length and reduced commitment to apoptosis in T cells compared with individuals not reporting regular exercise exposure136. In related work, 6 months of chronic exercise increased the whole-blood lymphocyte proliferative response to mitogen stimulation in vitro compared with a non-exercise control group120. Conversely, a considerable body of literature indicates that exposure to chronic high-intensity exercise without sufficient periods of rest and recovery (overtraining)

Box 1 | Exercise-dependent modulation of bone metastases Osteoblast and osteoclast behaviour Exercise promotes the differentiation of mesenchymal stem cells (MSCs) into osteoblasts to stimulate enhanced bone formation155–157. Concurrently, exercise lowers receptor activator of nuclear factor‑κB (NF‑κB) ligand (RANKL) expression and increases expression of osteoprotegerin (OPG) in bone cells, which inhibits osteoclast differentiation and activity158. Restoration of the osteoblast:osteoclast balance could promote dormancy of disseminated tumour cells (DTCs). Alternatively, exercise-induced osteogenesis could stimulate a greater bone niche area for population by DTCs, potentially augmenting metastatic outgrowth159. HSC biology Exercise increases haematopoietic stem cell (HSC) content in bone marrow155,160 and transmigration into the circulation155,160. Exercise therefore may also promote the release of DTCs into the circulation, exposing their vulnerability to immune surveillance or cytotoxic therapy161,162. Exercise also improves the global function of the bone marrow microenvironment, as evidenced by increased survival and enhanced haematopoietic regeneration following bone marrow transplantation163. As DTCs and HSCs compete for localization in the bone marrow niche164, enhanced HSC viability might outcompete colocalized DTCs. MSC biology Exercise induces MSC proliferation in response to mechanical loading of bone (an exercise mimetic)165, and MSCs isolated from mice following acute exercise produce greater levels of granulocyte colony-stimulating factor (G‑CSF), SKP1–cullin 1–F‑box protein (SCF) and interleukin‑3 (IL‑3) compared with controls166. These factors can induce the secretion of matrix metalloproteinase 9 (MMP9) from bone marrow cells, which cleaves CXC-chemokine ligand 12 (CXCL12; also known as SDF1) to release HSCs into the circulation167. Bone marrow adiposity Bone marrow adiposity enhances adipocyte–macrophage interactions as well as local inflammation and dysregulates bone remodelling, leading to activation of pathways that might drive metastatic outgrowth168,169. Exercise reduces adipocyte content in murine bone marrow155,156 and could drive MSC differentiation towards osteoblast as opposed to adipocyte formation156.

impairs adaptive immune responses and immune surveillance, leading to increased susceptibility to opportunistic infections such as upper respiratory tract illnesses53,115. In mice, 6 weeks of high-intensity exercise, but not moderate-intensity treadmill endurance exercise, increased the proportion of CD4+CD25+ Treg cells and upregulated Foxp3 (which encodes FOXP3) expression in the spleen, indicating that higher-intensity training might elicit a Treg cell-mediated dampening of the adaptive immune response compared with moderate intensity training 137. Little is known regarding the effects of exercise on adaptive immunity in cancer. In one of the few available studies, 12 weeks of moderate- to high-intensity exercise in patients with solid tumours reduced circulating concentrations of select cytokines (for example, hepatocyte growth factor (HGF), IL‑4, MIP1β (also known as CCL4), VEGF and TNF) in conjunction with a trend towards an increased number of activated CD4+ helper T cells and CD8+ cytotoxic T cells138. In related preclinical work, voluntary wheel running increased levels of CD3+ T cells in mice bearing subcutaneous syngeneic B16F10 melanoma tumours133; however, this increase was not observed in lung metastatic lesions

in the same model. Given the current paucity of data, areas of future investigation should include how exercise regulates lymphocyte transmigration to peripheral tissues (particularly tissues that harbour cells primed for malignant transformation or malignant cells) and the induction of spontaneous tumour antigen-specific T cell responses, as well as how training intensity and/or volume modulates these responses. As described, evidence supporting the effects and mechanisms of exercise in the regulation of immune function in healthy states and in those with cancer is limited. Accordingly, the following TME-specific concerns are germane. First, tumour cells deplete their respective TME of glucose and produce high levels of lactate, which selectively weakens antitumorigenic cytotoxic and effector T lymphocytes. Under normal physiological conditions, this is an important process for self-tolerance. For example, recent studies demonstrated that FOXP3 expression in Treg cells provides a metabolic advantage within the low-glucose, high-lactate TME, resulting in the accumulation of immunosuppressive Treg cells139. This raises the interesting question of whether exercise-induced reduction in nutrient and/or growth factor



PERSPECTIVES Box 2 | Components of exercise prescription Physiological characterization The objective assessment of cardiorespiratory fitness is a prerequisite for the optimal design of endurance-based exercise prescriptions. For endurance training, the preferred assessment tool is a cardiopulmonary exercise test (CPET), which provides information on pre-intervention peak rate of whole-organismal oxygen consumption (VO2peak) and submaximal and maximal cardiopulmonary responses to exercise, enabling personalization of the prescription and cardiovascular screening prior to exercise participation 170. Principles of training Individualization. The customized application of exercise training towards the physiological status of the subject. Using CPET, workloads that correspond with a specific percentage of VO2peak are identified, and the corresponding heart rate, blood pressure and rating of perceived exertion are directly measured at each percentage workload. Adoption of this approach ensures subjects are training at, or close to, the prescribed intensity during subsequent exercise sessions171. Specificity. Adaptations in metabolic and physiological functions, based on the type and mode of exercise stimulus. In other words, the notion that a selected aerobic exercise stress can be targeted to the primary underlying system or pathway known or postulated to underpin the primary end point of interest171–174. Progressive overload. A gradual increase in intensity and duration to ensure continual perturbation of homeostasis to stimulate physiological adaptation (establishment of a new homeostatic set point)27. Prescriptions that fail to alter exercise stress insufficiently perturb homeostasis, resulting in a plateau in adaptation175. Identifying the optimal stimulus-to-rest threshold for adaptation within each individual is also crucial to avoid maladaptive (overtraining) responses176. Rest and recovery. Periods of reduced training load or complete rest are critical for necessary biological re-synthesis of required constituents of affected physiological systems during chronic exercise stress177,178. The above data were adapted from a prior commentary147.

availability can reprogramme and/or reduce Treg cell accumulation in the TME and/or restore the balance of antitumorigenic cytotoxic and effector T cells. Second, as hypoxia maintains Treg cell abundance in the TME140, the normalization of the TME vasculature through acute or chronic exercise could favourably modulate the ratios of T cell subsets to promote an antitumorigenic TME milieu. Third, in addition to Treg cells, macrophages are also highly sensitive to changes in lactate concentrations within the TME;

First publication showing that exercise training improves QOL in post-surgical breast cancer patients181

First preclinical study showing that exercise inhibits tumour growth179

1944

macrophages generally avoid lactate-rich regions of the TME and preferentially localize to highly perfused, oxygen-rich areas such as the perivascular niche and invasive edge141. Indeed, macrophages exposed to lactate within the TME are activated towards a pro-tumorigenic anti-inflammatory M2 state characterized by upregulated expression of the canonical alternative activation markers Arg1 and Mrc1 (REFS 142,143). Thus, vascular normalization through exercise might improve oxygenation, reduce macrophage exposure to lactate, decrease

1989

First RCT in women with early-stage breast cancer receiving adjuvant chemotherapy180

2001

First study to show that exposure to exercise following a breast cancer diagnosis is associated with a reduced risk of recurrence and cancerassociated mortality183

2003

First exercise guidelines for cancer patients from the American Cancer Society182

2005

the frequency of M2 activation (or enhance M1 activation) in the TME and/or alter macrophage localization within the TME. In summary, although many important avenues of inquiry remain uninvestigated, the emerging evidence reviewed here indicates that exercise can reprogram the TME to alter reciprocal communications between cancer cells and cell types in their vicinity to alter certain hallmark capabilities. In addition, we recognize that an uninvestigated question is whether exercise-dependent modulation of the systemic milieu confers uniform reprogramming of the TME in all distant tissues and organs or if such effects are tissue and/or context specific. Nevertheless, bone, which is the most common site of distant relapse and metastases in a broad array of solid malignancies144, is also a tissue that is highly regulated by exercise. Therefore, it might represent an exemplar of how exercise might modulate the TME in distant tissues (BOX 1).

Exercise-oncology trials Although observational data have linked exposure to exercise with reductions in the primary development and progression of certain cancers19,20, these data are only the first of several steps in a translational pathway to investigate exercise as a candidate anticancer treatment145. To this end, important next steps are preclinical studies using clinically representative cancer models (for example, patient-derived xenografts, syngeneic allografts and genetically engineered mouse models) to investigate the anticancer activity, dose–exposure relationships and underlying mechanisms of action145. To facilitate clinical translation, such work could be integrated with human studies that leverage tumour sample collection during routine clinical procedures from patients who are divergent

First study to show that the relationship between exercise and cancer outcomes might differ as a function of a tumour's molecular profile184

2007

First study to compare the effects of different exercise training modalities in patients with early breast cancer150

2009

First study to show that exercise-induced inhibition of tumour progression is mediated by the immune system, namely, NK cells 133

2015

2016

First study to show that exercise improves the efficacy of chemotherapy96

Figure 4 | Timeline of exercise in cancer research. NK cells, natural killer cells; QOL, quality of life; RCT, randomized controlled trial. Nature Reviews | Cancer 628 | OCTOBER 2017 | VOLUME 17


PERSPECTIVES in exercise exposure or cardiorespiratory fitness or with existing cohort studies with a detailed exercise exposure history, corresponding tumour and matched normal tissues and clinical outcome data. Definitive testing of exercise as an antitumour therapy will require randomized controlled trials (RCTs) with established disease end points. To date, RCTs that have focused on symptom control have indicated that structured exercise training is both feasible and well-tolerated in patients with an array of cancers146 — directly challenging the notion that patients with cancer are unable to participate in, benefit from or tolerate exercise. Nevertheless, it is important to stress that response to an exercise prescription is considerably heterogeneous between individual patients. Such heterogeneity has substantial ramifications for the appropriate prescription of exercise regimens to patients with cancer,

Glossary Caloric restriction Reduction in calorie consumption.

Cardiorespiratory fitness The integrative capacity of the pulmonary and cardiovascular systems, the vasculature, blood and skeletal muscle to deliver and/or utilize oxygen from the environment to the skeletal muscle mitochondria.

Chronic exercise Structured, repeated and purposeful physical activity with the objective of improving health or cardiorespiratory fitness.

Exercise prescription A specific regimen with details regarding the frequency, duration, modality, intensity and length of exercise training.

Homeostasis The need to maintain a stable internal environment in the face of pathological and physiological perturbations.

Homeostatic control circuits Specialized homeostatic systems that operate at the cellular, tissue and systemic levels to regulate physiological processes within predefined ranges (‘set points’).

Pathological angiogenesis Dysfunctional or non-productive angiogenesis that results in pathological phenotypes.

Physical activity Any bodily movement produced by skeletal muscles that requires energy expenditure above resting levels.

Physiological angiogenesis Functional or productive angiogenesis that results in physiological phenotypes.

Pre-metastatic niche Secondary organ microenvironments (for example, lung, liver, brain or bone) that undergo molecular and possibly architectural alterations to augment engraftment and survival of subsequent tumour cell arrival.

given the potential of anticancer therapies to alter the exercise–adaptation response relationship25,147–150, thus underscoring the critical importance of developing exercise prescriptions that are adherent to the principles of training (BOX 2) to optimize tolerability, safety and efficacy 147. A critical prerequisite to the design of definitive RCTs will be early-phase ‘signal-seeking’ clinical trials to evaluate whether exercise modulates specific tumour pathways and/or targets by using noninvasive monitoring of blood-borne materials (for example, circulating tumour DNA and circulating tumour cells) combined with a more invasive evaluation of tumour-derived materials from surgical resection or research-directed biopsies. These early studies could provide insights into dose– response relationships, effects on the TME, mechanisms of action and response predictors, as well as inform the ‘go, no‑go’ decision on whether to advance exercise towards definitive testing (in a particular indication)145. The design of such studies will be greatly facilitated by identification of the biologically effective dose (a product of the frequency, intensity and duration) and schedule (length and progression and/or sequencing of treatment dose) of an exercise regimen. Two large, international phase III trials are already underway to evaluate the efficacy of exercise on disease end points in stage II–III colon cancer (Co.21)151 and metastatic prostate cancer (ClinicalTrials.gov identifier: NCT02730338).

Concluding remarks The therapeutic potential for exercise to influence the development and progression of cancer (for a historical timeline of exercise in cancer research, see FIG. 4) lies in its unique and unparalleled capacity for physiological adaptation across multiple organ systems to restore and/or enhance homeostatic set points at the tissue, cellular and systemic levels. This adaptation is achieved through integrative coordination between multiple systems and the considerable biological redundancy between these systems152. The concept of biological redundancy is of critical importance in cancer 153, as the TME provides a plethora of redundant signals that simultaneously or sequentially activate numerous biological processes to support and promote malignant phenotypes66. Hence, there is a strong rationale for therapeutic strategies, such as exercise, that have the capacity to alter numerous systemic signal inputs and lead to physiological adaptation of the TME, simultaneously inhibiting or

reversing multiple dysregulated cancer hallmarks60. Clearly, understanding how a complex, whole-organismal intervention such as exercise alters the highly integrated, redundant and dynamic host–TME interaction presents a daunting challenge that will require collaboration between several disparate disciplines spanning clinical oncology, molecular oncology, systems medicine and exercise physiology 154. Intriguingly, on the basis of current evidence, exercise might confer either pro-tumorigenic or antitumorigenic effects, depending on the context. However, when the known effects are considered in their entirety, we contend that exercise will confer an overall tumour-suppressive effect in the vast majority of oncology scenarios — providing it is appropriately prescribed and dosed — and therefore might hold promise as a candidate strategy to regulate the host–TME interaction. Graeme J. Koelwyn is at the NYU Langone Medical Center, Marc and Ruti Bell Vascular Biology and Disease Program, Leon H. Charney Division of Cardiology, Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA. Daniela F. Quail is at the Goodman Cancer Research Centre, McGill University; and at the Department of Physiology, McGill University, 1160 Pine Avenue West, Montreal, Quebec H3A 1A3, Canada. Xiang Zhang is at the Lester and Sue Smith Breast Center, Baylor College of Medicine; and at the Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030, USA. Richard M. White is at the Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA. Lee W. Jones is at the Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, New York 10065, USA; and at the Weil Cornell Medical Center, 1275 York Avenue, New York, New York 10065, USA. Correspondence to L.W.J. [email protected] doi:10.1038/nrc.2017.78 Published online 25 Sep 2017 Rozhok, A. I. & DeGregori, J. The evolution of lifespan and age-dependent cancer risk. Trends Cancer 2, 552–560 (2016). 2. Wu, S., Powers, S., Zhu, W. & Hannun, Y. A. Substantial contribution of extrinsic risk factors to cancer development. Nature 529, 43–47 (2016). 3. Govindan, R. et al. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 150, 1121–1134 (2012). 4. Jhappan, C., Noonan, F. P. & Merlino, G. Ultraviolet radiation and cutaneous malignant melanoma. Oncogene 22, 3099–3112 (2003). 5. [No authors listed.] TOBACCO and carcinoma of the lung. N. Engl. J. Med. 250, 125 (1954). 6. Richmond, B. G. & Jungers, W. L. Orrorin tugenensis femoral morphology and the evolution of hominin bipedalism. Science 319, 1662–1665 (2008). 7. Bramble, D. M. & Lieberman, D. E. Endurance running and the evolution of Homo. Nature 432, 345–352 (2004). 1.



PERSPECTIVES Booth, F. W., Chakravarthy, M. V. & Spangenburg, E. E. Exercise and gene expression: physiological regulation of the human genome through physical activity. J. Physiol. 543, 399–411 (2002). 9. Hopkins, B. D., Goncalves, M. D. & Cantley, L. C. Obesity and cancer mechanisms: cancer metabolism. J. Clin. Oncol. 34, 4277–4283 (2016). 10. Lee, I. M. et al. Effect of physical inactivity on major non-communicable diseases worldwide: an analysis of burden of disease and life expectancy. Lancet 380, 219–229 (2012). 11. Kohl, H. W. III et al. The pandemic of physical inactivity: global action for public health. Lancet 380, 294–305 (2012). 12. Bauman, A. et al. Tackling obesity: challenges ahead. Lancet 386, 741–742 (2015). 13. Calle, E. E., Rodriguez, C., Walker-Thurmond, K. & Thun, M. J. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. S. adults. N. Engl. J. Med. 348, 1625–1638 (2003). 14. Pontzer, H. et al. Hunter-gatherer energetics and human obesity. PLoS ONE 7, e40503 (2012). 15. Hallal, P. C. et al. Global physical activity levels: surveillance progress, pitfalls, and prospects. Lancet 380, 247–257 (2012). 16. World Health Organization. Global health risks: mortality and burden of disease attributable to selected major risks (WHO, 2009). 17. Myers, J. et al. Exercise capacity and mortality among men referred for exercise testing. N. Engl. J. Med. 346, 793–801 (2002). 18. Gulati, M. et al. The prognostic value of a nomogram for exercise capacity in women. N. Engl. J. Med. 353, 468–475 (2005). 19. Moore, S. C. et al. Association of leisure-time physical activity with risk of 26 types of cancer in 1.44 million adults. JAMA Intern. Med. 176, 816–825 (2016). 20. Friedenreich, C. M., Neilson, H. K., Farris, M. S. & Courneya, K. S. Physical activity and cancer outcomes: a precision medicine approach. Clin. Cancer Res. 22, 4766–4775 (2016). 21. Betof, A. S., Dewhirst, M. W. & Jones, L. W. Effects and potential mechanisms of exercise training on cancer progression: a translational perspective. Brain Behav. Immun. 30, S75–S87 (2013). 22. Ashcraft, K. A., Peace, R. M., Betof, A. S., Dewhirst, M. W. & Jones, L. W. Efficacy and mechanisms of aerobic exercise on cancer initiation, progression, and metastasis: a critical systematic review of in vivo preclinical data. Cancer Res. 76, 4032–4050 (2016). 23. Neufer, P. D. et al. Understanding the cellular and molecular mechanisms of physical activity-induced health benefits. Cell Metab. 22, 4–11 (2015). 24. Jones, N. L. & Killian, K. J. Exercise limitation in health and disease. N. Engl. J. Med. 343, 632–641 (2000). 25. Jones, L. W., Eves, N. D., Haykowsky, M., Freedland, S. J. & Mackey, J. R. Exercise intolerance in cancer and the role of exercise therapy to reverse dysfunction. Lancet Oncol. 10, 598–605 (2009). 26. Levine, B. D. VO2,max: what do we know, and what do we still need to know? J. Physiol. 586, 25–34 (2008). 27. Peake, J. M. et al. Modulating exercise-induced hormesis: does less equal more? J. Appl. Physiol. 119, 172–189 (2015). 28. Hawley, J. A., Hargreaves, M., Joyner, M. J. & Zierath, J. R. Integrative biology of exercise. Cell 159, 738–749 (2014). 29. Fan, W. & Evans, R. M. Exercise Mimetics: Impact on Health and Performance. Cell. Metabolism 25, 242–247 (2017). 30. Egan, B., Hawley, J. A. & Zierath, J. R. SnapShot: exercise metabolism. Cell Metab. 24, 342–342.e1 (2016). 31. Lin, J., Handschin, C. & Spiegelman, B. M. Metabolic control through the PGC‑1 family of transcription coactivators. Cell. Metabolism 1, 361–370 (2005). 32. Fan, W. & Evans, R. PPARs and ERRs: molecular mediators of mitochondrial metabolism. Curr. Opin. Cell Biol. 33, 49–54 (2015). 33. Dufour, C. R. et al. Genome-wide orchestration of cardiac functions by the orphan nuclear receptors ERRalpha and gamma. Cell. Metabolism 5, 345–356 (2007). 34. Kelly, D. P. & Scarpulla, R. C. Transcriptional regulatory circuits controlling mitochondrial biogenesis and function. Genes Dev. 18, 357–368 (2004). 35. Silveira, L. R., Pilegaard, H., Kusuhara, K., Curi, R. & Hellsten, Y. The contraction induced increase in gene expression of peroxisome proliferator-activated 8.

receptor (PPAR)-γ coactivator 1α (PGC‑1α), mitochondrial uncoupling protein 3 (UCP3) and hexokinase II (HKII) in primary rat skeletal muscle cells is dependent on reactive oxygen species. Biochim. Biophys. Acta 1763, 969–976 (2006). 36. Irrcher, I., Ljubicic, V. & Hood, D. A. Interactions between ROS and AMP kinase activity in the regulation of PGC‑1α transcription in skeletal muscle cells. Am. J. Physiol. Cell Physiol. 296, C116–C123 (2009). 37. Yan, Z., Okutsu, M., Akhtar, Y. N. & Lira, V. A. Regulation of exercise-induced fiber type transformation, mitochondrial biogenesis, and angiogenesis in skeletal muscle. J. Appl. Physiol. 110, 264–274 (2011). 38. Prior, B. M., Yang, H. T. & Terjung, R. L. What makes vessels grow with exercise training? J. Appl. Physiol. 97, 1119–1128 (2004). 39. Gustafsson, T. & Kraus, W. E. Exercise-induced angiogenesis-related growth and transcription factors in skeletal muscle, and their modification in muscle pathology. Front. Biosci. 6, D75–D89 (2001). 40. Arany, Z. et al. HIF-independent regulation of VEGF and angiogenesis by the transcriptional coactivator PGC‑1α. Nature 451, 1008–1012 (2008). 41. Lindholm, M. E. & Rundqvist, H. Skeletal muscle hypoxia-inducible factor‑1 and exercise. Exp. Physiol. 101, 28–32 (2016). 42. Semenza, G. L. Regulation of metabolism by hypoxiainducible factor 1. Cold Spring Harb. Symp. Quant. Biol. 76, 347–353 (2011). 43. Fraisl, P., Aragones, J. & Carmeliet, P. Inhibition of oxygen sensors as a therapeutic strategy for ischaemic and inflammatory disease. Nat. Rev. Drug Discov. 8, 139–152 (2009). 44. Wong, B. W., Kuchnio, A., Bruning, U. & Carmeliet, P. Emerging novel functions of the oxygen-sensing prolyl hydroxylase domain enzymes. Trends Biochem. Sci. 38, 3–11 (2013). 45. Semenza, G. L. Oxygen sensing, homeostasis, and disease. N. Engl. J. Med. 365, 537–547 (2011). 46. Chazaud, B. Inflammation during skeletal muscle regeneration and tissue remodeling: application to exercise-induced muscle damage management. Immunol. Cell Biol. 94, 140–145 (2016). 47. Lieber, R. L., Thornell, L. E. & Friden, J. Muscle cytoskeletal disruption occurs within the first 15 min of cyclic eccentric contraction. J. Appl. Physiol. 80, 278–284 (1996). 48. Nunes-Silva, A. et al. Treadmill exercise induces neutrophil recruitment into muscle tissue in a reactive oxygen species-dependent manner. An intravital microscopy study. PLoS ONE 9, e96464 (2014). 49. Fielding, R. A. et al. Acute phase response in exercise. III. Neutrophil and IL‑1ß accumulation in skeletal muscle. Am. J. Physiol. 265, R166–R172 (1993). 50. Marklund, P. et al. Extensive inflammatory cell infiltration in human skeletal muscle in response to an ultraendurance exercise bout in experienced athletes. J. Appl. Physiol. 114, 66–72 (1985). 51. Tidball, J. G. Regulation of muscle growth and regeneration by the immune system. Nat. Rev. Immunol. 17, 165–178 (2017). 52. Neubauer, O. et al. Time course-dependent changes in the transcriptome of human skeletal muscle during recovery from endurance exercise: from inflammation to adaptive remodeling. J. Appl. Physiol. 116, 274–287 (2014). 53. Peake, J. M., Neubauer, O., Walsh, N. P. & Simpson, R. J. Recovery of the immune system after exercise. J. Appl. Physiol. 122, 1077–1087 (1985). 54. Arnold, L. et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J. Exp. Med. 204, 1057–1069 (2007). 55. Deng, B., Wehling-Henricks, M., Villalta, S. A., Wang, Y. & Tidball, J. G. IL‑10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. J. Immunol. 189, 3669–3680 (2012). 56. Tonkin, J. et al. Monocyte/macrophage-derived IGF‑1 orchestrates murine skeletal muscle regeneration and modulates autocrine polarization. Mol. Ther. 23, 1189–1200 (2015). 57. Ginhoux, F., Schultze, J. L., Murray, P. J., Ochando, J. & Biswas, S. K. New insights into the multidimensional concept of macrophage ontogeny, activation and function. Nat. Immunol. 17, 34–40 (2016). 58. Goh, J., Goh, K. P. & Abbasi, A. Exercise and adipose tissue macrophages: new frontiers in obesity research? Front. Endocrinol. (Lausanne) 7, 65 (2016).

59. Furrer, R., Eisele, P. S., Schmidt, A., Beer, M. & Handschin, C. Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC‑1α‑controlled BNP. Sci. Rep. 7, 40789 (2017). 60. Kotas, M. E. & Medzhitov, R. Homeostasis, inflammation, and disease susceptibility. Cell 160, 816–827 (2015). 61. Karsenty, G. & Olson, E. N. Bone and muscle endocrine functions: unexpected paradigms of interorgan communication. Cell 164, 1248–1256 (2016). 62. Karsenty, G. & Ferron, M. The contribution of bone to whole-organism physiology. Nature 481, 314–320 (2012). 63. Safdar, A., Saleem, A. & Tarnopolsky, M. A. The potential of endurance exercise-derived exosomes to treat metabolic diseases. Nat. Rev. Endocrinol. 12, 504–517 (2016). 64. Goodwin, P. J., Meyerhardt, J. A. & Hursting, S. D. Host factors and cancer outcome. J. Clin. Oncol. 28, 4019–4021 (2010). 65. McTiernan, A. Mechanisms linking physical activity with cancer. Nat. Rev. Cancer 8, 205–211 (2008). 66. Hanahan, D. & Coussens, L. M. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012). 67. Aaronson, S. A. Growth factors and cancer. Science 254, 1146–1153 (1991). 68. Rathmell, J. C., Vander Heiden, M. G., Harris, M. H., Frauwirth, K. A. & Thompson, C. B. In the absence of extrinsic signals, nutrient utilization by lymphocytes is insufficient to maintain either cell size or viability. Mol. Cell 6, 683–692 (2000). 69. Pavlova, N. N. & Thompson, C. B. The emerging hallmarks of cancer metabolism. Cell Metab. 23, 27–47 (2016). 70. Cairns, R. A., Harris, I. S. & Mak, T. W. Regulation of cancer cell metabolism. Nat. Rev. Cancer 11, 85–95 (2011). 71. Koppenol, W. H., Bounds, P. L. & Dang, C. V. Otto Warburg’s contributions to current concepts of cancer metabolism. Nat. Rev. Cancer 11, 325–337 (2011). 72. Raitakari, O. T., Porkka, K. V., Rasanen, L. & Viikari, J. S. Relations of life-style with lipids, blood pressure and insulin in adolescents and young adults. The cardiovascular risk young finns study. Atherosclerosis 111, 237–246 (1994). 73. Barnard, R. J. Effects of life-style modification on serum lipids. Arch. Intern. Med. 151, 1389–1394 (1991). 74. Stanford, K. I. & Goodyear, L. J. Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle. Adv. Physiol. Educ. 38, 308–314 (2014). 75. Irwin, M. L. et al. Randomized controlled trial of aerobic exercise on insulin and insulin-like growth factors in breast cancer survivors: the Yale Exercise and Survivorship study. Cancer Epidemiol. 18, 306–313 (2009). 76. Fairey, A. S. et al. Effects of exercise training on fasting insulin, insulin resistance, insulin-like growth factors, and insulin-like growth factor binding proteins in postmenopausal breast cancer survivors: a randomized controlled trial. Cancer Epidemiol. 12, 721–727 (2003). 77. Zhu, Z. et al. Effect of nonmotorized wheel running on mammary carcinogenesis: circulating biomarkers, cellular processes, and molecular mechanisms in rats. Cancer Epidemiol. 17, 1920–1929 (2008). 78. Thompson, H. J., Wolfe, P., McTiernan, A., Jiang, W. & Zhu, Z. Wheel running-induced changes in plasma biomarkers and carcinogenic response in the 1‑methyl‑1‑nitrosourea-induced rat model for breast cancer. Cancer Prevention Res. 3, 1484–1492 (2010). 79. Xie, L. et al. Effects of dietary calorie restriction or exercise on the PI3K and Ras signaling pathways in the skin of mice. J. Biol. Chem. 282, 28025–28035 (2007). 80. Glass, O. et al. Differential response to exercise in claudin-low breast cancer. Oncotarget (in the press). 81. Morikawa, T. et al. Association of CTNNB1 (ß-catenin) alterations, body mass index, and physical activity with survival in patients with colorectal cancer. JAMA 305, 1685–1694 (2011). 82. Klaus, A. & Birchmeier, W. Wnt signalling and its impact on development and cancer. Nat. Rev. Cancer 8, 387–398 (2008). 83. Hanyuda, A. et al. Survival benefit of exercise differs by tumor IRS1 expression status in colorectal cancer. Ann. Surg. Oncol. 23, 908–917 (2016).



PERSPECTIVES 84. Slattery, M. L. et al. Associations among IRS1, IRS2, IGF1, and IGFBP3 genetic polymorphisms and colorectal cancer. Cancer Epidemiol. 13, 1206–1214 (2004). 85. Pollak, M. Insulin and insulin-like growth factor signalling in neoplasia. Nat. Rev. Cancer 8, 915–928 (2008). 86. Kalaany, N. Y. & Sabatini, D. M. Tumours with PI3K activation are resistant to dietary restriction. Nature 458, 725–731 (2009). 87. Jiang, X., Overholtzer, M. & Thompson, C. B. Autophagy in cellular metabolism and cancer. J. Clin. Invest. 125, 47–54 (2015). 88. Amaravadi, R. & Debnath, J. Mouse models address key concerns regarding autophagy inhibition in cancer therapy. Cancer Discov. 4, 873–875 (2014). 89. Yang, A. et al. Autophagy is critical for pancreatic tumor growth and progression in tumors with p53 alterations. Cancer Discov. 4, 905–913 (2014). 90. White, E. Deconvoluting the context-dependent role for autophagy in cancer. Nat. Rev. Cancer 12, 401–410 (2012). 91. He, C. et al. Exercise-induced BCL2‑regulated autophagy is required for muscle glucose homeostasis. Nature 481, 511–515 (2012). 92. He, C., Sumpter, R. Jr & Levine, B. Exercise induces autophagy in peripheral tissues and in the brain. Autophagy 8, 1548–1551 (2012). 93. Aveseh, M., Nikooie, R. & Aminaie, M. Exercise‑induced changes in tumour LDH‑B and MCT1 expression are modulated by oestrogen-related receptor alpha in breast cancer-bearing BALB/c mice. J. Physiol. 593, 2635–2648 (2015). 94. Semenza, G. L. Targeting HIF‑1 for cancer therapy. Nat. Rev. Cancer 3, 721–732 (2003). 95. Carmeliet, P. & Jain, R. K. Angiogenesis in cancer and other diseases. Nature 407, 249–257 (2000). 96. Betof, A. S. et al. Modulation of murine breast tumor vascularity, hypoxia and chemotherapeutic response by exercise. J. Natl Cancer Inst. 107, djv040 (2015). 97. Jones, L. W. et al. Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer. J. Appl. Physiol. 108, 343–348 (2010). 98. McCullough, D. J., Stabley, J. N., Siemann, D. W. & Behnke, B. J. Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise. J. Natl Cancer Inst. 106, dju036 (2014). 99. Schadler, K. L. et al. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget 7, 65429–65440 (2016). 100. Kashiwagi, S. et al. Perivascular nitric oxide gradients normalize tumor vasculature. Nat. Med. 14, 255–257 (2008). 101. Fukumura, D., Kashiwagi, S. & Jain, R. K. The role of nitric oxide in tumour progression. Nat. Rev. Cancer 6, 521–534 (2006). 102. Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nat. Rev. Cancer 9, 285–293 (2009). 103. Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009). 104. Cox, T. R. et al. The hypoxic cancer secretome induces pre-metastatic bone lesions through lysyl oxidase. Nature 522, 106–110 (2015). 105. Sceneay, J. et al. Primary tumor hypoxia recruits CD11b+/Ly6Cmed/Ly6G+ immune suppressor cells and compromises NK cell cytotoxicity in the premetastatic niche. Cancer Res. 72, 3906–3911 (2012). 106. Chafe, S. C. et al. Carbonic anhydrase IX promotes myeloid-derived suppressor cell mobilization and establishment of a metastatic niche by stimulating G‑CSF production. Cancer Res. 75, 996–1008 (2015). 107. Quail, D. F. & Joyce, J. A. Microenvironmental regulation of tumor progression and metastasis. Nat. Med. 19, 1423–1437 (2013). 108. Gao, D. et al. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319, 195–198 (2008). 109. Jones, L. W. et al. Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy. Cancer Prevention Res. 6, 925–937 (2013). 110. Pearson, M. J. & Smart, N. A. Effect of exercise training on endothelial function in heart failure patients: a systematic review meta-analysis. Int. J. Cardiol. 231, 234–243 (2017).

111. Jain, R. K. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307, 58–62 (2005). 112. Hatfield, S. M. et al. Immunological mechanisms of the antitumor effects of supplemental oxygenation. Sci. Trans. Med. 7, 277ra230 (2015). 113. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011). 114. Kruger, K., Lechtermann, A., Fobker, M., Volker, K. & Mooren, F. C. Exercise-induced redistribution of T lymphocytes is regulated by adrenergic mechanisms. Brain Behav. Immun. 22, 324–338 (2008). 115. Walsh, N. P. et al. Position statement. Part one: Immune function and exercise. Exerc. Immunol. Rev. 17, 6–63 (2011). 116. Timmerman, K. L., Flynn, M. G., Coen, P. M., Markofski, M. M. & Pence, B. D. Exercise traininginduced lowering of inflammatory (CD14+CD16+) monocytes: a role in the anti-inflammatory influence of exercise? J. Leukoc. Biol. 84, 1271–1278 (2008). 117. Sloan, R. P. et al. Aerobic exercise attenuates inducible TNF production in humans. J. Appl. Physiol. 103, 1007–1011 (1985). 118. Pyne, D. B. et al. Effects of an intensive 12‑wk training program by elite swimmers on neutrophil oxidative activity. Med. Sci. Sports Exerc. 27, 536–542 (1995). 119. Hack, V., Strobel, G., Weiss, M. & Weicker, H. PMN cell counts and phagocytic activity of highly trained athletes depend on training period. J. Appl. Physiol. 77, 1731–1735 (1985). 120. Woods, J. A. et al. Effects of 6 months of moderate aerobic exercise training on immune function in the elderly. Mech. Ageing Dev. 109, 1–19 (1999). 121. Kawanishi, N., Yano, H., Yokogawa, Y. & Suzuki, K. Exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from M1 to M2 macrophages in high-fat-diet-induced obese mice. Exerc. Immunol. Rev. 16, 105–118 (2010). 122. Kizaki, T. et al. Adaptation of macrophages to exercise training improves innate immunity. Biochem. Biophys. Res. Commun. 372, 152–156 (2008). 123. Sugiura, H., Nishida, H., Sugiura, H. & Mirbod, S. M. Immunomodulatory action of chronic exercise on macrophage and lymphocyte cytokine production in mice. Acta Physiol. Scand. 174, 247–256 (2002). 124. Engblom, C., Pfirschke, C. & Pittet, M. J. The role of myeloid cells in cancer therapies. Nat. Rev. Cancer 16, 447–462 (2016). 125. Abdalla, D. R., Aleixo, A. A., Murta, E. F. & Michelin, M. A. Innate immune response adaptation in mice subjected to administration of DMBA and physical activity. Oncol. Lett. 7, 886–890 (2014). 126. Murphy, E. A. et al. Effects of moderate exercise and oat beta-glucan on lung tumor metastases and macrophage antitumor cytotoxicity. J. Appl. Physiol. 97, 955–959 (1985). 127. Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014). 128. Bai, J. et al. Contact-dependent carcinoma aggregate dispersion by M2a macrophages via ICAM‑1 and ß2 integrin interactions. Oncotarget 6, 25295–25307 (2015). 129. Almeida, P. W. et al. Swim training suppresses tumor growth in mice. J. Appl. Physiol. 107, 261–265 (1985). 130. Zielinski, M. R., Muenchow, M., Wallig, M. A., Horn, P. L. & Woods, J. A. Exercise delays allogeneic tumor growth and reduces intratumoral inflammation and vascularization. J. Appl. Physiol. 96, 2249–2256 (1985). 131. McClellan, J. L. et al. Exercise effects on polyp burden and immune markers in the ApcMin/+ mouse model of intestinal tumorigenesis. Int. J. Oncol. 45, 861–868 (2014). 132. Fairey, A. S. et al. Randomized controlled trial of exercise and blood immune function in postmenopausal breast cancer survivors. J. Appl. Physiol. 98, 1534–1540 (1985). 133. Pedersen, L. et al. Voluntary running suppresses tumor growth through epinephrine- and IL‑6‑Dependent NK cell mobilization and redistribution. Cell Metab. 23, 554–562 (2016). 134. Simpson, R. J., Florida-James, G. D., Whyte, G. P. & Guy, K. The effects of intensive, moderate and downhill treadmill running on human blood lymphocytes expressing the adhesion/activation molecules CD54 (ICAM‑1), CD18 (ß2 integrin) and CD53. Eur. J. Appl. Physiol. 97, 109–121 (2006). 135. LaVoy, E. C., Bosch, J. A., Lowder, T. W. & Simpson, R. J. Acute aerobic exercise in humans

increases cytokine expression in CD27− but not CD27+ CD8+ T‑cells. Brain Behav. Immun. 27, 54–62 (2013). 136. Silva, L. C. et al. Moderate and intense exercise lifestyles attenuate the effects of aging on telomere length and the survival and composition of T cell subpopulations. Age (Dordr) 38, 24 (2016). 137. Wang, J. et al. Effect of exercise training intensity on murine T‑regulatory cells and vaccination response. Scand. J. Med. Sci. Sports 22, 643–652 (2012). 138. Glass, O. K. et al. Effect of aerobic training on the host systemic milieu in patients with solid tumours: an exploratory correlative study. Br. J. Cancer 112, 825–831 (2015). 139. Angelin, A. et al. Foxp3 reprograms T cell metabolism to function in low-glucose, high-lactate environments. Cell. Metab. 25, 1282–1293.e7 (2017). 140. Facciabene, A. et al. Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and Treg cells. Nature 475, 226–230 (2011). 141. Carmona-Fontaine, C. et al. Emergence of spatial structure in the tumor microenvironment due to the Warburg effect. Proc. Natl Acad. Sci. USA 110, 19402–19407 (2013). 142. Colegio, O. R. et al. Functional polarization of tumourassociated macrophages by tumour-derived lactic acid. Nature 513, 559–563 (2014). 143. Carmona-Fontaine, C. et al. Metabolic origins of spatial organization in the tumor microenvironment. Proc. Natl Acad. Sci. USA 114, 2934–2939 (2017). 144. Roodman, G. D. Mechanisms of bone metastasis. N. Engl. J. Med. 350, 1655–1664 (2004). 145. Jones, L. W. Precision oncology framework for investigation of exercise as treatment for cancer. J. Clin. Oncol. 33, 4134–4137 (2015). 146. Schmitz, K. H. et al. American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Med. Sci. Sports Exerc. 42, 1409–1426 (2010). 147. Sasso, J. P. et al. A framework for prescription in exercise-oncology research. J. Cachexia Sarcopenia Muscle 6, 115–124 (2015). 148. van Waart, H. et al. Effect of low-intensity physical activity and moderate- to high-intensity physical exercise during adjuvant chemotherapy on physical fitness, fatigue, and chemotherapy completion rates: results of the PACES randomized clinical trial. J. Clin. Oncol. 33, 1918–1927 (2015). 149. Courneya, K. S. et al. Effects of exercise dose and type during breast cancer chemotherapy: multicenter randomized trial. J. Natl Cancer Inst. 105, 1821–1832 (2013). 150. Courneya, K. S. et al. Effects of aerobic and resistance exercise in breast cancer patients receiving adjuvant chemotherapy: a multicenter randomized controlled trial. J. Clin. Oncol. 25, 4396–4404 (2007). 151. Courneya, K. S. et al. The colon health and life-long exercise change trial: a randomized trial of the national cancer institute of canada clinical trials group. Curr. Oncol. 15, 279–285 (2008). 152. Kitano, H. Biological robustness. Nat. Rev. Genet. 5, 826–837 (2004). 153. Kitano, H. Cancer robustness: tumour tactics. Nature 426, 125 (2003). 154. Greenhaff, P. L. & Hargreaves, M. ‘Systems biology’ in human exercise physiology: is it something different from integrative physiology? J. Physiol. 589, 1031–1036 (2011). 155. Baker, J. M., De Lisio, M. & Parise, G. Endurance exercise training promotes medullary hematopoiesis. FASEB J. 25, 4348–4357 (2011). 156. David, V. et al. Mechanical loading down-regulates peroxisome proliferator-activated receptor gamma in bone marrow stromal cells and favors osteoblastogenesis at the expense of adipogenesis. Endocrinology 148, 2553–2562 (2007). 157. Wallace, J. M., Ron, M. S. & Kohn, D. H. Short-term exercise in mice increases tibial post-yield mechanical properties while two weeks of latency following exercise increases tissue-level strength. Calcif. Tissue Int. 84, 297–304 (2009). 158. Pichler, K. et al. RANKL is downregulated in bone cells by physical activity (treadmill and vibration stimulation training) in rat with glucocorticoid-induced osteoporosis. Histol. Histopathol. 28, 1185–1196 (2013). 159. Croucher, P. I., McDonald, M. M. & Martin, T. J. Bone metastasis: the importance of the neighbourhood. Nat. Rev. Cancer 16, 373–386 (2016). 160. De Lisio, M. & Parise, G. Characterization of the effects of exercise training on hematopoietic stem cell quantity and function. J. Appl. Physiol. 113, 1576–1584 (1985).



PERSPECTIVES 161. Reagan, M. R. & Rosen, C. J. Navigating the bone marrow niche: translational insights and cancer-driven dysfunction. Nat. Rev. Rheumatol 12, 154–168 (2016). 162. Roodman, G. D. Genes associate with abnormal bone cell activity in bone metastasis. Cancer Metastasis Rev. 31, 569–578 (2012). 163. De Lisio, M., Baker, J. M. & Parise, G. Exercise promotes bone marrow cell survival and recipient reconstitution post-bone marrow transplantation, which is associated with increased survival. Exp. Hematol. 41, 143–154 (2013). 164. Shiozawa, Y. et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J. Clin. Invest. 121, 1298–1312 (2011). 165. Pagnotti, G. M. & Styner, M. Exercise regulation of marrow adipose tissue. Front. Endocrinol. (Lausanne) 7, 94 (2016). 166. Emmons, R., Niemiro, G. M., Owolabi, O. & De Lisio, M. Acute exercise mobilizes hematopoietic stem and progenitor cells and alters the mesenchymal stromal cell secretome. J. Appl. Physiol. 120, 624–632 (2016) (1985). 167. Liu, F., Poursine-Laurent, J. & Link, D. C. Expression of the G‑CSF receptor on hematopoietic progenitor cells is not required for their mobilization by G‑CSF. Blood 95, 3025–3031 (2000). 168. Hardaway, A. L., Herroon, M. K., Rajagurubandara, E. & Podgorski, I. Bone marrow fat: linking adipocyte‑induced inflammation with skeletal metastases. Cancer Metastasis Rev. 33, 527–543 (2014). 169. Fazeli, P. K. et al. Marrow fat and bone—new perspectives. J. Clin. Endocrinol. Metab. 98, 935–945 (2013). 170. American Thoracic Society & American College of Chest Physicians. ATS/ACCP Statement on

cardiopulmonary exercise testing. Am. J. Respir. Crit. Care Med. 167, 211–277 (2003). 171. Davis, J. A. Anaerobic threshold: review of the concept and directions for future research. Med. Sci. Sports Exerc. 17, 6–21 (1985). 172. Convertino, V. A. Blood volume response to physical activity and inactivity. Am. J. Med. Sci. 334, 72–79 (2007). 173. Bishop, D. J., Granata, C. & Eynon, N. Can we optimise the exercise training prescription to maximise improvements in mitochondria function and content? Biochim. Biophys. Acta 1840, 1266–1275 (2014). 174. MacDougall, J. D. et al. Muscle performance and enzymatic adaptations to sprint interval training. J. Appl. Physiol. 84, 2138–2142 (1985). 175. Hickson, R. C., Hagberg, J. M., Ehsani, A. A. & Holloszy, J. O. Time course of the adaptive responses of aerobic power and heart rate to training. Med. Sci. Sports Exerc. 13, 17–20 (1981). 176. Kreher, J. B. & Schwartz, J. B. Overtraining syndrome: a practical guide. Sports Health 4, 128–138 (2012). 177. Fry, R. W., Morton, A. R. & Keast, D. Periodisation of training stress—a review. Can. J. Sport Sci. 17, 234–240 (1992). 178. Fry, R. W., Morton, A. R. & Keast, D. Periodisation and the prevention of overtraining. Can. J. Sport Sci. 17, 241–248 (1992). 179. Rusch, H. P. & Kline, B. E. The effect of exercise on the growth of a mouse tumor. Cancer Res. 4, 116–118 (1944). 180. Winningham, M. L., MacVicar, M. G., Bondoc, M., Anderson, J. I. & Minton, J. P. Effect of aerobic exercise on body weight and composition in patients with breast cancer on adjuvant chemotherapy. Oncol. Nurs. Forum 16, 683–689 (1989). 181. Segal, R. et al. Structured exercise improves physical functioning in women with stages I and II breast

cancer: results of a randomized controlled trial. J. Clin. Oncol. 19, 657–665 (2001). 182. Brown, J. K. et al. Nutrition and physical activity during and after cancer treatment: an American Cancer Society guide for informed choices. CA Cancer J. Clin. 53, 268–291 (2003). 183. Holmes, M. D., Chen, W. Y., Feskanich, D., Kroenke, C. H. & Colditz, G. A. Physical activity and survival after breast cancer diagnosis. JAMA 293, 2479–2486 (2005). 184. Meyerhardt, J. A. et al. Interaction of molecular markers and physical activity on mortality in patients with colon cancer. Clin. Cancer Res. 15, 5931–5936 (2009).

Acknowledgements

L.W.J. is supported by research grants from the National Cancer Institute, AKTIV Against Cancer and the Memorial Sloan Kettering Cancer Center Support Grant/Core Grant (P30 CA008748). The authors would like to thank N. Eves and anony mous reviewers for insights and feedback on earlier versions of this manuscript as well as W. Underwood for administrative support. The authors apologize to the many authors whose work we were unable to cite owing to space constraints.

Author contributions

G.J.K., D.F.Q. and L.W.J. researched data for the article, made substantial contributions to the discussion of content and wrote the manuscript. All authors reviewed and edited the manuscript before submission. G.J.K. and D.F.Q. are joint first authors.

Competing interests statement

The authors declare no competing interests.

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.



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