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.
“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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Wang, Y., Zhang, Z., Jiao, W., Wang, Y., Wang, X., Zhao, Y., Fan, X., Tian, L., Li, X., & Mi, J. (2022) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2022.1051866 · Cited by 57 · see citing works
“, 2005), and the latter can participate in a versatile of physiological and pathological processes such as inflammation regulation, insulin sensitivity, tumor growth inhibition and cognitive improvement (Pedersen and Febbraio, 2008; Hong et al., 2009; Ellingsgaard et al., 2011; Hojman et al., 2011; Wrann et al., 2013).”
BackgroundExercise and colorectal cancer: prevention and molecular mechanisms
Amirsasan, R., Akbarzadeh, M., & Akbarzadeh, S. (2022) · Cancer Cell International · doi:10.1186/s12935-022-02670-3 · Cited by 53 · see citing works
The role of myokines in cancer: crosstalk between skeletal muscle and tumor
Park, S.-Y., Hwang, B.-O., & Song, N. (2023) · BMB Reports · doi:10.5483/bmbrep.2023-0064 · Cited by 52 · see citing works
Prostate cancer and physical activity: Adaptive response to oxidative stress
Rébillard, A., Lefeuvre‐Orfila, L., Guéritat, J., & Cillard, J. (2013) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2013.02.009 · Cited by 52 · see citing works
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“Moreover, brain-derived neurotrophic factor (BDNF; reviewed in [100]), leukemia inhibitory factor (LIF; [101]), oncostatin M (OSM; [102]) chemokine CXC motif ligand 1 (CXCL-1; [103]) and myonectin (CTRP15; [104]) have also been described.”
BackgroundColetta, A. M., Agha, N. H., Baker, F. L., Niemiro, G. M., Mylabathula, P. L., Brewster, A. M., Bevers, T. B., Fuentes‐Mattei, E., Basen-Engquist, K. M., Gilchrist, S. C., et al. (2021) · Breast Cancer Research and Treatment · doi:10.1007/s10549-021-06111-z · Cited by 51 · see citing works
Physical Exercise and the Hallmarks of Breast Cancer: A Narrative Review
García‐Chico, C., López‐Ortiz, S., Peñín‐Grandes, S., Pinto-Fraga, J., Valenzuela, P. L., Emanuele, E., Ceci, C., Graziani, G., Fiuza‐Luces, C., Lista, S., et al. (2023) · Cancers · doi:10.3390/cancers15010324 · Cited by 50 · see citing works
“Available research shows that among myokines, aerobic exercise releases oncostatin M (OSM), thus resulting in lower tumor volume in breast cancer mice [58].”
BackgroundGoh, J., & Ladiges, W. (2014) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2014.06.004 · Cited by 50 · see citing works
Kudou, K., Saeki, H., Nakashima, Y., Sasaki, S., Jogo, T., Hirose, K., Hu, Q., Tsuda, Y., Kimura, K., Nakanishi, R., et al. (2018) · The American Journal of Surgery · doi:10.1016/j.amjsurg.2018.07.003 · Cited by 48 · see citing works
Kim, J., Wilson, R. L., Taaffe, D. R., Galvao, D. A., Gray, E. S., & Newton, R. U. (2021) · Medicine & Science in Sports & Exercise · doi:10.1249/mss.0000000000002783 · Cited by 49 · see citing works
“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…”
BackgroundShamsi, M. M., Chekachak, S., Soudi, S., Gharakhanlou, R., Quinn, L. S., Ranjbar, K., Rezaei, S., Shirazi, F. J., Allahmoradi, B., Yazdi, M. H., et al. (2018) · Nutrition · doi:10.1016/j.nut.2018.05.022 · Cited by 47 · see citing works
Redox Signaling in Widespread Health Benefits of Exercise
Louzada, R. A. N., Bouvière, J., Matta, L., Werneck‐de‐Castro, J. P., Dupuy, C., de Carvalho, D. P., & Fortunato, R. S. (2020) · Antioxidants and Redox Signaling · doi:10.1089/ars.2019.7949 · Cited by 47 · see citing works
“By screening 28 potential candidate molecules upregulated in serum after swimming exercise, Oncostatin M has emerged as a candidate for reducing mammary cancer cells growth (78).”
Kim, J., Taaffe, D. R., Galvao, D. A., Clay, T. D., Redfern, A. D., Hart, N. H., Gray, E. S., Ryan, C. J., Kenfield, S. A., Fred Saad, C., et al. (2022) · Prostate Cancer and Prostatic Diseases · doi:10.1038/s41391-022-00624-4 · Cited by 44 · see citing works
The effect of acute exercise on circulating immune cells in newly diagnosed breast cancer patients
Koivula, T., Lempiäinen, S., Rinne, P., Rannikko, J. H., Hollmén, M., Sundberg, C. J., Rundqvist, H., Minn, H. R. I., & HEINONEN, I. H. A. (2023) · Scientific Reports · doi:10.1038/s41598-023-33432-4 · Cited by 44 · see citing works
Physical activity and breast cancer risk by pathological subtype
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 · see citing works
Non‐pharmacological interventions in non‐alcoholic fatty liver disease patients
Ratziu, V. (2017) · Liver International · doi:10.1111/liv.13311 · Cited by 44 · see citing works
Impact of cancer rehabilitation on the prognosis of patients with hepatocellular carcinoma
Hashida, R., Kawaguchi, T., Koya, S., Hirota, K., Goshima, N., Yoshiyama, T., Otsuka, T., Bekki, M., Iwanaga, S., Nakano, D., et al. (2020) · Oncology Letters · doi:10.3892/ol.2020.11345 · Cited by 43 · see citing works
“Oncostatin M was reported to have an anti-proliferative and apoptotic effect on breast-cancer cells in an in vivo study (46).”
Kudou, K., Nakashima, Y., Haruta, Y., Nambara, S., Tsuda, Y., Kusumoto, E., Ando, K., Kimura, Y., Hashimoto, K., Yoshinaga, K., et al. (2020) · Annals of Surgical Oncology · doi:10.1245/s10434-020-08821-y · Cited by 43 · see citing works
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 42 · see citing works
The cytokine interleukin-11 crucially links bone formation, remodeling and resorption
Kespohl, B., Schumertl, T., Bertrand, J., Lokau, J., & Garbers, C. (2021) · Cytokine & Growth Factor Reviews · doi:10.1016/j.cytogfr.2021.04.002 · Cited by 42 · see citing works
Lee, J. K., Park, Y. S., Lee, K., Youn, S. I., Won, Y., Min, S.-H., Ahn, S., Park, D. J., & Kim, H. (2021) · Journal of Cachexia Sarcopenia and Muscle · doi:10.1002/jcsm.12793 · Cited by 42 · see citing works
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Muscle-Derived Cytokines Reduce Growth, Viability and Migratory Activity of Pancreatic Cancer Cells
Schwappacher, R., Dieterich, W., Reljic, D., Pilarsky, C. P., Mukhopadhyay, D., Chang, D. K.-F., Biankin, A. V., Siebler, J., Herrmann, H. J., Neurath, M. F., et al. (2021) · Cancers · doi:10.3390/cancers13153820 · Cited by 39 · see citing works
“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 · see citing works
Orange, S. T., Jordan, A., & Saxton, J. (2020) · Physiological Reports · doi:10.14814/phy2.14635 · Cited by 35 · see citing works
“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, A., Maridaki, M., Zagouri, F., Dimopoulos, M., Koutsilieris, M., & Philippou, A. (2022) · Cancers · doi:10.3390/cancers14081892 · Cited by 34 · see citing works
“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].”
BackgroundConroy, S. M., Courneya, K. S., Brenner, D. R., Shaw, E., O’Reilly, R., Yasui, Y., Woolcott, C. G., & Friedenreich, C. M. (2016) · Cancer Medicine · doi:10.1002/cam4.836 · Cited by 33 · see citing works
“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).”
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Hypothalamus-skeletal muscle crosstalk during exercise and its role in metabolism modulation
Ibeas, K., Herrero, L., Mera, P., & Serra, D. (2021) · Biochemical Pharmacology · doi:10.1016/j.bcp.2021.114640 · Cited by 35 · see citing works
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Exercise Training in Elderly Cancer Patients: A Systematic Review
Giallauria, F., Testa, C., Cuomo, G., di Lorenzo, A. D., Venturini, E., Lauretani, F., Maggio, M., Iannuzzo, G., & Vigorito, C. (2023) · Cancers · doi:10.3390/cancers15061671 · Cited by 26 · see citing works
“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 Training in Cancer Control and Treatment
Christensen, J. F., Simonsen, C., & Højman, P. (2019) · Comprehensive physiology · doi:10.1002/j.2040-4603.2019.tb00064.x · Cited by 31 · see citing works
Exercise shapes redox signaling in cancer
Assi, M., Dufresne, S., & Rébillard, A. (2020) · Redox Biology · doi:10.1016/j.redox.2020.101439 · Cited by 31 · see citing works
“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 31 · see citing works
Kim, M. K., Kim, Y., Park, S.-H., Kim, E., Kim, Y., Kim, Y., & Kim, J. (2020) · Integrative Cancer Therapies · doi:10.1177/1534735420949678 · Cited by 31 · see citing works
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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].”
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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 32 · see citing works
“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.”
Background
- 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 › Rehabilitation › Exercise and Physiological Responses
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Oncology › 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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