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Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth
Abstract
Regular physical activity protects against the development of breast and colon cancer, since it reduces the risk of developing these by 25-30%. During exercise, humoral factors are released from the working muscles for endocrinal signaling to other organs. We hypothesized that these myokines mediate some of the inhibitory effects of exercise on mammary cancer cell proliferation. Serum and muscles were collected from mice after an exercise bout. Incubation with exercise-conditioned serum inhibited MCF-7 cell proliferation by 52% and increased caspase activity by 54%. A similar increase in caspase activity was found after incubation of MCF-7 cells with conditioned media from electrically stimulated myotubes. PCR array analysis (CAPM-0838E; SABiosciences) revealed that seven genes were upregulated in the muscles after exercise, and of these oncostatin M (OSM) proved to inhibit MCF-7 proliferation by 42%, increase caspase activity by 46%, and induce apoptosis. Blocking OSM signaling with anti-OSM antibodies reduced the induction of caspase activity by 51%. To verify that OSM was a myokine, we showed that it was significantly upregulated in serum and in three muscles, tibialis cranialis, gastronemius, and soleus, after an exercise bout. In contrast, OSM expression remained unchanged in subcutaneous and visceral adipose tissue, liver, and spleen (mononuclear cells). We conclude that postexercise serum inhibits mammary cancer cell proliferation and induces apoptosis of these cells. We suggest that one or more myokines secreted from working muscles may be mediating this effect and that OSM is a possible candidate. These findings emphasize that role of physical activity in cancer treatment, showing a direct link between exercise-induced humoral factors and decreased tumor cell growth.
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“A few mechanistic studies have demonstrated a potential role of other myokines, including Oncostatin M, irisin, and SPARC in the suppression of breast and colon cancer growth (41, 224-227).”
From Muscle–Organ Crosstalk: The Emerging Roles of Myokines (2020) · cites this paper as [224]
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“Furthermore, preclinical studies that have applied myokines, such as secreted protein acidic and rich in cysteine (SPARC) (25–27), oncostatin M (OSM) (28,29), decorin (30,31), IL-6 (32), IL-15 (33), and irisin (34,35), to various types of cancer cell lines have also provided evidence for the potential direct tumor-sup…”
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Lope, V., Martín, M., Castelló, A., Casla, S., Ruı́z, A., Baena-Cañada, J. M., Casas, A. M., Calvo, L., Bermejo, B., Muñoz-Mateu, M., et al. (2017) · Gynecologic Oncology · doi:10.1016/j.ygyno.2016.12.014 · Cited by 44
Non‐pharmacological interventions in non‐alcoholic fatty liver disease patients
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Impact of cancer rehabilitation on the prognosis of patients with hepatocellular carcinoma
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“Oncostatin M was reported to have an anti-proliferative and apoptotic effect on breast-cancer cells in an in vivo study (46).”
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Irisin, an exercise myokine, potently suppresses tumor proliferation, invasion, and growth in glioma
Huang, C., Chang, Y., Lee, H., Wu, J., Huang, J., Chung, Y., Hsu, S.-T., Chow, L., Wei, K., & Huang, F. (2020) · The FASEB Journal · doi:10.1096/fj.202000573rr · Cited by 43
The cytokine interleukin-11 crucially links bone formation, remodeling and resorption
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Muscle-Derived Cytokines Reduce Growth, Viability and Migratory Activity of Pancreatic Cancer Cells
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“Further examination revealed that the myokine oncostatin M is involved in exercise-induced apoptosis in breast cancer cells [2].”
BackgroundInfluentialExercise training improves radiotherapy efficiency in a murine model of prostate cancer
Dufresne, S., Guéritat, J., Chiavassa, S., Noblet, C., Assi, M., Rioux-Leclercq, N. C., Rannou‐Bekono, F., Lefeuvre‐Orfila, L., Paris, F., & Rébillard, A. (2020) · The FASEB Journal · doi:10.1096/fj.201901728r · Cited by 35
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“Administration of IL-6 and oncostatin M has been shown to suppress breast cancer growth in vitro (Chiu et al., 1996; Hojman et al., 2011), suggesting that IL-6 and other myokines could have a direct role in reducing cancer progression by modulating key signaling pathways involved in cancer cell proliferation.”
Physical Exercise Restrains Cancer Progression through Muscle-Derived Factors
Papadopetraki, Α., Maridaki, M. D., Zagouri, F., Dimopoulos, M. A., Koutsilieris, M., & Philippou, Α. (2022) · Cancers · doi:10.3390/cancers14081892 · Cited by 36
“Indeed, it has been reported that the incubation of human breast cancer cells with a post-exercise human serum containing OSM inhibited cell proliferation and induced apoptosis, while the blockage of OSM mitigated the anti-tumor effects of exercise-conditioned serum [9].”
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“Furthermore, exercise- induced musclederived cytokines have been found to inhibit mammary cancer cell growth in vitro [28].”
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“There is profound evidence that physical training directly affects cancer cells via serum factors; this was demonstrated in cell culture experiments using exercise-conditioned serum from healthy humans and mice (Hojman et al. 2011; Aoi et al. 2013; Rundqvist et al. 2013).”
BackgroundInfluentialKatsui, K., Ogata, T., Sugiyama, S., Yoshio, K., Kuroda, M., Hiraki, T., Kiura, K., Maeda, Y., Toyooka, S., & Kanazawa, S. (2021) · Scientific Reports · doi:10.1038/s41598-021-91449-z · Cited by 32
Hypothalamus-skeletal muscle crosstalk during exercise and its role in metabolism modulation
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Exercise Training in Elderly Cancer Patients: A Systematic Review
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“Interestingly, a study has shown that the combination of exercise and cyclophosphamide reduced the growth of mouse breast cancer compared to a cycle of cyclophosphamide alone [53].”
BackgroundInfluentialExercise shapes redox signaling in cancer
Assi, M., Dufresne, S., & Rébillard, A. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101439 · Cited by 34
“costatin M (OSM) as a myokine produced after exercise and able to reduce the proliferation of MCF7 breast cancer cells in vitro [85].”
BackgroundThe role of obesity and bariatric surgery-induced weight loss in breast cancer
Bohm, M. S., Sipe, L. M., Pye, M. E., Davis, M. J., Pierre, J. F., & Makowski, L. (2022) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10050-6 · Cited by 33
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“Furthermore, the PRT group will have samples taken before and after training sessions to investigate whether a bout of resistance training will release myokines and NK-cells as it is known from endurance exercise [27, 57, 58].”
BackgroundHunt, L., & White, J. (2016) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-27511-6_3 · Cited by 31
Anti-carcinogenic effects of exercise-conditioned human serum: evidence, relevance and opportunities
Metcalfe, R. S., Kemp, R. N., Heffernan, S. M., Churm, R., Chen, Y., Ruffino, J. S., Conway, G. E., Tornillo, G., & Orange, S. T. (2021) · European Journal of Applied Physiology · doi:10.1007/s00421-021-04680-x · Cited by 33
“Indeed, both SPARC and OSM were also associated with increased apoptosis and caspase activity in these animal studies (Aoi et al. 2013; Hojman et al. 2011) and current human data suggests that apoptosis is not increased in cancer cells treated with exercise-condition serum (Devin et al.”
BackgroundExercise-Induced Extracellular Vesicles Delay the Progression of Prostate Cancer
Sadovska, L., Auders, J., Keiša, L., Romanchikova, N., Silamiķele, L., Kreišmane, M., Zayakin, P., Takahashi, S., Kalniņa, Z., & Linē, A. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2021.784080 · Cited by 26
“Myokines have been shown to act as tumor suppressors and may impact several hallmark features of cancer (Hojman et al., 2011; Ruiz-Casado et al., 2017), whereas glycolytic enzymes might induce changes in the metabolic activity of cancer cells (Pedersen et al.”
BackgroundExercise-induced crosstalk between immune cells and adipocytes in humans: Role of oncostatin-M
Dollet, L., Lundell, L. S., Chibalin, A., Pendergrast, L. A., Pillon, N. J., Lansbury, E., Elmastas, M., Frendo‐Cumbo, S., Jalkanen, J., Barbosa, T. D. C., et al. (2023) · Cell Reports Medicine · doi:10.1016/j.xcrm.2023.101348 · Cited by 28
“…mice, oncostatin-M has been reported to increase after exercise in skeletal muscle and has been implicated in the recruitment of M2 macrophages, 46,47 while oncostatin-M expression was not found to be regulated by exercise in adipose tissue, 48 underlining the species speci-ficity of…”
Kim, H., Lee, T., Park, W., Lee, J. W., Kim, J., Lee, B.-Y., Ahn, H., Moon, S., Cho, S., Do, K. T., et al. (2013) · DNA Research · doi:10.1093/dnares/dst010 · Cited by 28
“Furthermore, using mice experiment, it was recently shown that exercise-conditioned serum is capable of inducing apoptosis.(56) Although we did not find apoptosis-related KEGG pathway enrichment of the URGs in blood, apoptosis-related genes seem to be highly enriched in those of blood tissues on the basis of the GO en…”
Metadata
- Authors
- Hojman, P., Dethlefsen, C., Brandt, C., Hansen, J., Pedersen, L., & Pedersen, B. K.
- Affiliations
- Centre of Inflammation and Metabolism at the Department of Infectious Diseases, Rigshospitalet, University of Copenhagen, Cophenhagen; and
- University of Copenhagen (DK)
- Venue
- American Journal of Physiology-Endocrinology and Metabolism
- Publisher
- American Physiological Society
- Published
- 2011-09
- Volume
- 301
- Issue
- 3
- Pages
- E504-E510
- ISSN
- 0193-1849 (ISSN-L)
- 1522-1555
- OpenAlex
- W2137928272
- Cited by
- 259
- References
- 27
- Citations by year
- 2026: 11 · 2025: 25 · 2024: 24 · 2023: 21 · 2022: 29 · 2021: 20 · 2020: 26 · 2019: 16 · 2018: 14 · 2017: 15 · 2016: 13 · 2015: 11 · 2014: 8 · 2013: 18 · 2012: 7
- FWCI
- 10.83
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- American Journal of Physiology-Endocrinology and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Topics
- Health Sciences › Medicine › Physiology (medical) › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
- Keywords
- physical activity, myokines, oncostatin M, breast cancer, MCF-7 cells, apoptosis, caspase activity, tumor cell proliferation
- MeSH terms
- Animals, Cells, Cultured, Humans, Physical Conditioning, Animal, Up-Regulation, Cytokines, Muscle, Skeletal, Cell Line, Tumor, Cell Proliferation, Mice
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