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An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination.

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Affiliations

  • 1. Department of Human Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
      Authors
    • Sheinboim D 1
    • Parikh S 1
    • Manich P 1
    • Dahan S 1
    • Parikh R 1
    • Bell RE 1
    • Ruiz SA 1
    • Leibou S 1
    • Arad G 1
    • Mordechai S 1
    • Eldar-Finkelman H 1
    • Levy C 1
    (12 authors)
  • 2. Department of Epidemiology and Preventive Medicine, School of Public Health, Sackler Faculty of Medicine, and Sylvan Adams Sports Institute, Tel Aviv University, Tel Aviv, Israel.
      Authors
    • Markus I 2
    • Stubbs E 2
    • Cohen G 2
    • Gerber Y 2
    • Goldstein N 2
    • Constantini K 2
    • Gepner Y 2
    (7 authors)
  • 3. Institute of Pathology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
      Authors
    • Zemser-Werner V 3
    (1 author)
  • 4. Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.
      Authors
    • Percik R 4
    • Nizri E 4
    • Choshen G 4
    (3 authors)
  • 5. Institute of Oncology, E. Wolfson Medical Center, Holon, Israel.
      Authors
    • Brenner R 5
    (1 author)
    • Show all (18)

Cancer Research, 01 Nov 2022, 82(22):4164-4178
https://doi.org/10.1158/0008-5472.can-22-0237 PMID: 36084256 PMCID: PMC9762351

This article is in the Europe PMC Open access subset. Refer to the copyright information in the article for licensing details.
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A comment on this article appears in "" Cancer Res. 2022 Nov 15;82(22):4124-4125.

Abstract 

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 exercise-induced 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.

Significance

Exercise protects against cancer progression and metastasis by inducing a high nutrient demand in internal organs, indicating that reducing nutrient availability to tumor cells represents a potential strategy to prevent metastasis. See related commentary by Zerhouni and Piskounova, p. 4124.

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Read article at publisher's site: https://doi.org/10.1158/0008-5472.can-22-0237

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    Funding 

    Funders who supported this work.

    European Research Council (1)

    • Grant ID: 726225

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    Israel Cancer Association (1)

    • Grant ID: 01031005

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    Melanoma Research Alliance (1)

    • Grant ID: 402792

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    Tel Aviv University (1)

    • Grant ID: 0601148551

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