TY - JOUR
T1 - An Exercise-Induced Metabolic Shield in Distant Organs Blocks Cancer Progression and Metastatic Dissemination
AU - Sheinboim, Danna
AU - Parikh, Shivang
AU - Manich, Paulee
AU - Markus, Irit
AU - Dahan, Sapir
AU - Parikh, Roma
AU - Stubbs, Elisa
AU - Cohen, Gali
AU - Zemser-Werner, Valentina
AU - Bell, Rachel E.
AU - Ruiz, Sara Arciniegas
AU - Percik, Ruth
AU - Brenner, Ronen
AU - Leibou, Stav
AU - Vaknine, Hananya
AU - Arad, Gali
AU - Gerber, Yariv
AU - Keinan-Boker, Lital
AU - Shimony, Tal
AU - Bikovski, Lior
AU - Goldstein, Nir
AU - Constantini, Keren
AU - Labes, Sapir
AU - Mordechai, Shimonov
AU - Doron, Hila
AU - Lonescu, Ariel
AU - Ziv, Tamar
AU - Nizri, Eran
AU - Choshen, Guy
AU - Eldar-Finkelman, Hagit
AU - Tabach, Yuval
AU - Helman, Aharon
AU - Ben-Eliyahu, Shamgar
AU - Erez, Neta
AU - Perlson, Eran
AU - Geiger, Tamar
AU - Ben-Zvi, Danny
AU - Khaled, Mehdi
AU - Gepner, Yftach
AU - Levy, Carmit
N1 - Publisher Copyright:
© 2022 TheAuthors.
PY - 2022/11/15
Y1 - 2022/11/15
N2 - UNLABELLED: 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.
AB - UNLABELLED: 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.
UR - http://www.scopus.com/inward/record.url?scp=85141936442&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-22-0237
DO - 10.1158/0008-5472.CAN-22-0237
M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???
C2 - 36084256
AN - SCOPUS:85141936442
SN - 0008-5472
VL - 82
SP - 4164
EP - 4178
JO - Cancer Research
JF - Cancer Research
IS - 22
ER -
