Exercise prevents cancer incidence and recurrence, yet the underlying mechanism behind this relationship remains mostly unknown. Here we report that exercise induces the metabolic reprogramming of internal organs that increases nutrient demand and protects against metastatic colonization by limiting nutrient availability to the tumor, generating an exercise-induced metabolic shield. Proteomic and ex vivo metabolic capacity analyses of murine internal organs revealed that exercise induces catabolic processes, glucose uptake, mitochondrial activity, and GLUT expression. Proteomic analysis of routinely active human subject plasma demonstrated increased carbohydrate utilization following exercise. Epidemiologic data from a 20-year prospective study of a large human cohort of initially cancer-free participants revealed that exercise prior to cancer initiation had a modest impact on cancer incidence in low metastatic stages but significantly reduced the likelihood of highly metastatic cancer. In three models of melanoma in mice, exercise prior to cancer injection significantly protected against metastases in distant organs. The protective effects of exercise were dependent on mTOR activity, and inhibition of the mTOR pathway with rapamycin treatment ex vivo reversed the exerciseinduced metabolic shield. Under limited glucose conditions, active stroma consumed significantly more glucose at the expense of the tumor. Collectively, these data suggest a clash between the metabolic plasticity of cancer and exercise-induced metabolic reprogramming of the stroma, raising an opportunity to block metastasis by challenging the metabolic needs of the tumor.
Bibliographical noteFunding Information:
C. Levy and Y. Gepner acknowledge grant support from the Israeli Cancer Association (01031005), the collaboration grant between schools at the Faculty of Medicine (0601148551). C. Levy acknowledges grant support from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 726225), the I-CORE Gene Regulation in Complex Human Disease Center (no. 41/11), the Melanoma Research Alliance (MRA; grant 402792), and Israel Science Foundation (grant 129/13). C. Levy would like to thank Baruch the glazier from Givataim for his humble support in the technical obstacles of the primary experiment.
© 2022 TheAuthors.
ASJC Scopus subject areas
- Cancer Research