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Exercise-dependent regulation of the tumour microenvironment

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.

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Figure 1: Integrated physiological response to acute exercise.
Figure 2: A simplified model of the adaptive response to exercise in skeletal muscle.
Figure 3: Exercise-dependent regulation of the tumour microenvironment.
Figure 4: Timeline of exercise in cancer research.

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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 anonymous 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.

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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.

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Correspondence to Lee W. Jones.

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PowerPoint slides

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.

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Koelwyn, G., Quail, D., Zhang, X. et al. Exercise-dependent regulation of the tumour microenvironment. Nat Rev Cancer 17, 620–632 (2017). https://doi.org/10.1038/nrc.2017.78

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