Physical exercise effects on metastasis: a systematic review and meta-analysis in animal cancer models

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Physical exercise is considered a well-tolerated adjuvant therapy to mitigate cancer-related side effects, but its impact on metastasis is unclear. The present systematic review and meta-analysis aimed to summarize the evidence on the effects of exercise on metastasis in animal cancer models. A systematic search was conducted to identify controlled studies in animals analyzing the impact of exercise interventions on any marker of metastasis incidence or severity. The pooled mean differences (PMD) were calculated for those endpoints for which a minimum of three studies used the same assessment method. We also calculated the pooled odds ratio (OR) of metastases. Twenty-six articles were included in the systematic review, of which 12 could be meta-analyzed. Exercise training in murine cancer models did not significantly modify the number of metastatic foci (PMD = − 3.18; 95% confidence interval [CI] − 8.32, 1.97; p = 0.23), the weight of metastatic tumors (PMD = − 0.03; 95% CI − 0.10, 0.04; p = 0.41), or the risk of developing metastasis (OR = 0.64; 95% CI 0.10, 4.12; p = 0.64). These findings suggest that exercise has no overall influence on any marker of cancer metastasis incidence or severity in animal models. However, the wide methodological heterogeneity observed between studies might be taken into account and the potential exercise effects on metastasis development remain to be determined in pediatric tumors.

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  1. 1.

    Steeg, P. S. (2016). Targeting metastasis. Nature Reviews Cancer, 16, 201–218.

  2. 2.

    Lambert, A. W., Pattabiraman, D. R., & Weinberg, R. A. (2017). Emerging biological principles of metastasis. Cell, 168, 670–691.

  3. 3.

    Nguyen, D. X., Bos, P. D., & Massagué, J. (2009). Metastasis: from dissemination to organ-specific colonization. Nature Reviews Cancer, 9, 274–284.

  4. 4.

    Massagué, J., & Obenauf, A. C. (2016). Metastatic colonization by circulating tumour cells. Nature, 529, 298–306.

  5. 5.

    Pedersen, L., Christensen, J. F., & Hojman, P. (2015). Effects of exercise on tumor physiology and metabolism. Cancer Journal, 21, 111–116.

  6. 6.

    Chen, Y. J., Li, X. X., Ma, H. K., Zhang, X., Wang, B. W., Guo, T. T., et al. (2019). Exercise training for improving patient-reported outcomes in patients with advanced-stage cancer: a systematic review and meta-analysis. Journal of Pain and Symptom Management.

  7. 7.

    Schmitz, K. H., Courneya, K. S., Matthews, C., Demark-Wahnefried, W., Galvão, D. A., Pinto, B. M., Irwin, M. L., Wolin, K. Y., Segal, R. J., Lucia, A., Schneider, C. M., von Gruenigen, V., Schwartz, A. L., & American College of Sports Medicine. (2010). American College of Sports Medicine American College of Sports Medicine roundtable on exercise guidelines for cancer survivors. Medicine & Science in Sports & Exercise, 42, 1409–1426.

  8. 8.

    Morales, J. S., Santana-Sosa, E., Santos-Lozano, A., Baño-Rodrigo, A., Valenzuela, P. L., Rincón-Castanedo, C., et al. (2019). Inhospital exercise benefits in childhood cancer: a prospective cohort study. Scandinavian Journal of Medicine and Science in Sports.

  9. 9.

    Morales, J. S., Valenzuela, P. L., Rincón-Castanedo, C., Takken, T., Fiuza-Luces, C., Santos-Lozano, A., & Lucia, A. (2018). Exercise training in childhood cancer: a systematic review and meta-analysis of randomized controlled trials. Cancer Treatment Reviews, 70, 154–167.

  10. 10.

    Fiuza-Luces, C., Padilla, J. R., Soares-Miranda, L., Santana-Sosa, E., Quiroga, J. V., Santos-Lozano, A., Pareja-Galeano, H., Sanchis-Gomar, F., Lorenzo-González, R., Verde, Z., López-Mojares, L. M., Lassaletta, A., Fleck, S. J., Pérez, M., Pérez-Martínez, A., & Lucia, A. (2017). Exercise intervention in pediatric patients with solid tumors: the physical activity in pediatric cancer trial. Medicine & Science in Sports & Exercise, 49, 223–230.

  11. 11.

    Schmitz, K. H., Campbell, A. M., Stuiver, M. M., Pinto, B. M., Schwartz, A. L., Morris, G. S., Ligibel, J. A., Cheville, A., Galvão, D. A., Alfano, C. M., Patel, A. V., Hue, T., Gerber, L. H., Sallis, R., Gusani, N. J., Stout, N. L., Chan, L., Flowers, F., Doyle, C., Helmrich, S., Bain, W., Sokolof, J., Winters-Stone, K. M., Campbell, K. L., & Matthews, C. E. (2019). Exercise is medicine in oncology: engaging clinicians to help patients move through cancer. CA: a Cancer Journal for Clinicians, 69, 468–484.

  12. 12.

    Dai, J. Y., Wang, B., Wang, X., Cheng, A., Kolb, S., Stanford, J. L., & Wright, J. L. (2019). Vigorous physical activity is associated with lower risk of metastatic-lethal progression in prostate cancer and hypomethylation in the CRACR2A gene. Cancer Epidemiology, Biomarkers & Prevention, 28, 258–264.

  13. 13.

    Guercio, B. J., Zhang, S., Ou, F. S., Venook, A. P., Niedzwiecki, D., Lenz, H. J., Innocenti, F., O’Neil, B. H., Shaw, J. E., Polite, B. N., Hochster, H. S., Atkins, J. N., Goldberg, R. M., Sato, K., Ng, K., van Blarigan, E., Mayer, R. J., Blanke, C. D., O'Reilly, E. M., Fuchs, C. S., & Meyerhardt, J. A. (2019). Associations of physical activity with survival and progression in metastatic colorectal cancer: results from Cancer and Leukemia Group B (Alliance)/SWOG 80405. Journal of Clinical Oncology, 37, 2620–2631.

  14. 14.

    Brown, J. C., Rhim, A. D., Manning, S. L., Brennan, L., Mansour, A. I., Rustgi, A. K., Damjanov, N., Troxel, A. B., Rickels, M. R., Ky, B., Zemel, B. S., Courneya, K. S., & Schmitz, K. H. (2018). Effects of exercise on circulating tumor cells among patients with resected stage I-III colon cancer. PLoS One, 13, e0204875.

  15. 15.

    Jinnah, A. H., Zacks, B. C., Gwam, C. U., & Kerr, B. A. (2018). Emerging and established models of bone metastasis. Cancers (Basel), 10.

  16. 16.

    Ashcraft, K. A., Peace, R. M., Betof, A. S., Dewhirst, M. W., & Jones, L. W. (2016). Efficacy and mechanisms of aerobic exercise on cancer initiation, progression, and metastasis: a critical systematic review of in vivo preclinical data. Cancer Research, 76, 4032–4050.

  17. 17.

    Ruiz-Casado, A., Martín-Ruiz, A., Pérez, L. M., Provencio, M., Fiuza-Luces, C., & Lucia, A. (2017). Exercise and the hallmarks of cancer. Trends in Cancer, 3, 423–441.

  18. 18.

    Betof, A. S., Dewhirst, M. W., & Jones, L. W. (2013). Effects and potential mechanisms of exercise training on cancer progression: a translational perspective. Brain, Behavior, and Immunity, 30, S75–S87.

  19. 19.

    Moher, D., Shamseer, L., Clarke, M., Ghersi, D., Liberati, A., Petticrew, M., Shekelle, P., Stewart, L. A., & PRISMA-P Group. (2015). Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Systematic Reviews, 4, 1.

  20. 20.

    Goh, J., Tsai, J., Bammler, T. K., Farin, F. M., Endicott, E., & Ladiges, W. C. (2013). Exercise training in transgenic mice is associated with attenuation of early breast cancer growth in a dose-dependent manner. PLoS One, 8, e80123.

  21. 21.

    Hooijmans, C. R., Rovers, M. M., de Vries, R. B. M., Leenaars, M., Ritskes-Hoitinga, M., & Langendam, M. W. (2014). SYRCLE’s risk of bias tool for animal studies. BMC Medical Research Methodology, 14, 43.

  22. 22.

    Bax, L., Yu, L. M., Ikeda, N., Tsuruta, H., & Moons, K. G. M. (2006). Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Medical Research Methodology, 6, 50.

  23. 23.

    Smeda, M., Przyborowski, K., Proniewski, B., Zakrzewska, A., Kaczor, D., Stojak, M., Buczek, E., Nieckarz, Z., Zoladz, J. A., Wietrzyk, J., & Chlopicki, S. (2017). Breast cancer pulmonary metastasis is increased in mice undertaking spontaneous physical training in the running wheel; a call for revising beneficial effects of exercise on cancer progression. American Journal of Cancer Research, 7, 1926–1936.

  24. 24.

    MacNeil, B., & Hoffman-Goetz, L. (1993). Exercise training and tumour metastasis in mice: influence of time of exercise onset. Anticancer Research, 13, 2085–2088.

  25. 25.

    Hoffmann-Goetz, L., MacNeil, B., & Arumugam, Y. (1994). Tissue distribution of radiolabelled tumor cells in wheel exercised and sedentary mice. International Journal of Sports Medicine, 15, 249–253.

  26. 26.

    Jadeski, L., & Hoffman-Goetz, L. (1996). Exercise and in vivo natural cytotoxicity against tumour cells of varying metastatic capacity. Clinical & Experimental Metastasis, 14, 138–144.

  27. 27.

    Jee, H., Chang, J. E., & Yang, E. J. (2016). Positive prehabilitative effect of intense treadmill exercise for ameliorating cancer cachexia symptoms in a mouse model. Journal of Cancer, 7, 2378–2387.

  28. 28.

    Tsai, M. S., Kuo, M. L., Chang, C. C., & Wu, Y. T. (2013). The effects of exercise training on levels of vascular endothelial growth factor in tumor-bearing mice. Cancer Biomarkers, 13, 307–313.

  29. 29.

    Uhlenbruck, G., & Order, U. (1991). Can endurance sports stimulate immune mechanisms against cancer and metastasis? International Journal of Sports Medicine, 12(Suppl 1), S63–S68.

  30. 30.

    MacNeil, B., & Hoffman-Goetz, L. (1993). Effect of exercise on natural cytotoxicity and pulmonary tumor metastases in mice. Medicine & Science in Sports & Exercise, 25, 922–928.

  31. 31.

    Murphy, E. A., Davis, J. M., Brown, A. S., Carmichael, M. D., Mayer, E. P., & Ghaffar, A. (2004). Effects of moderate exercise and oat beta-glucan on lung tumor metastases and macrophage antitumor cytotoxicity. Journal of Applied Physiology, 97, 955–959.

  32. 32.

    Pedersen, L., Idorn, M., Olofsson, G. H., Lauenborg, B., Nookaew, I., Hansen, R. H., Johannesen, H. H., Becker, J. C., Pedersen, K. S., Dethlefsen, C., Nielsen, J., Gehl, J., Pedersen, B. K., Thor Straten, P., & Hojman, P. (2016). Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metabolism, 23, 554–562.

  33. 33.

    Alvarado, A., Gil da Costa, R. M., Faustino-Rocha, A. I., Ferreira, R., Lopes, C., Oliveira, P. A., & Colaço, B. (2017). Effects of exercise training on breast cancer metastasis in a rat model. International Journal of Experimental Pathology, 98, 40–46.

  34. 34.

    Hoffman-Goetz, L., May, K. M., & Arumugam, Y. (1994). Exercise training and mouse mammary tumour metastasis. Anticancer Research, 14, 2627–2631.

  35. 35.

    Higgins, K. A., Park, D., Lee, G. Y., Curran, W. J., & Deng, X. (2014). Exercise-induced lung cancer regression: mechanistic findings from a mouse model. Cancer, 120, 3302–3310.

  36. 36.

    Assi, M., Kenawi, M., Ropars, M., & Rébillard, A. (2017). Interleukin-6, C/EBP-β and PPAR-γ expression correlates with intramuscular liposarcoma growth in mice: the impact of voluntary physical activity levels. Biochemical and Biophysical Research Communications, 490, 1026–1032.

  37. 37.

    Zhang, Q. B., Zhang, B. H., Zhang, K. Z., Meng, X. T., Jia, Q. A., Zhang, Q. B., Bu, Y., Zhu, X. D., Ma, D. N., Ye, B. G., Zhang, N., Ren, Z. G., Sun, H. C., & Tang, Z. Y. (2016). Moderate swimming suppressed the growth and metastasis of the transplanted liver cancer in mice model: with reference to nervous system. Oncogene, 35, 4122–4131.

  38. 38.

    Zhang, Q. B., Meng, X. T., Jia, Q. A., Bu, Y., Ren, Z. G., Zhang, B. H., & Tang, Z. Y. (2016). Herbal compound songyou yin and moderate swimming suppress growth and metastasis of liver cancer by enhancing immune function. Integrative Cancer Therapies, 15, 368–375.

  39. 39.

    Wolff, G., Davidson, S. J., Wrobel, J. K., & Toborek, M. (2015). Exercise maintains blood-brain barrier integrity during early stages of brain metastasis formation. Biochemical and Biophysical Research Communications, 463, 811–817.

  40. 40.

    Hoffman-Goetz, L., MacNeil, B., Arumugam, Y., & Randall Simpson, J. (1992). Differential effects of exercise and housing condition on murine natural killer cell activity and tumor growth. International Journal of Sports Medicine, 13, 167–171.

  41. 41.

    Colbert, L. H., Westerlind, K. C., Perkins, S. N., Haines, D. C., Berrigan, D., Donehower, L. A., Fuchs-Young, R., & Hursting, S. D. (2009). Exercise effects on tumorigenesis in a p53-deficient mouse model of breast cancer. Medicine & Science in Sports & Exercise, 41, 1597–1605.

  42. 42.

    Bryner, R., Riggs, D., Donley, D., White, J., Ullrich, I., Lamm, D., et al. (1998). Effects of voluntary running wheel exercise on the growth and metastasis of transplanted prostate cancer in rats. Journal of Exercise Physiology Online, 1, 1–9.

  43. 43.

    Yan, L., & Demars, L. C. (2011). Effects of non-motorized voluntary running on experimental and spontaneous metastasis in mice. Anticancer Research, 31, 3337–3344.

  44. 44.

    Davis, J. M., Kohut, M. L., Jackson, D. A., Colbert, L. H., Mayer, E. P., & Ghaffar, A. (1998). Exercise effects on lung tumor metastases and in vitro alveolar macrophage antitumor cytotoxicity. American Journal of Physiology, 274, R1454–R1459.

  45. 45.

    MacNeil, B., & Hoffman-Goetz, L. (1993). Chronic exercise enhances in vivo and in vitro cytotoxic mechanisms of natural immunity in mice. Journal of Applied Physiology, 74, 388–395.

  46. 46.

    Khori, V., Amani Shalamzari, S., Isanejad, A., Alizadeh, A. M., Alizadeh, S., Khodayari, S., Khodayari, H., Shahbazi, S., Zahedi, A., Sohanaki, H., Khaniki, M., Mahdian, R., Saffari, M., & Fayad, R. (2015). Effects of exercise training together with tamoxifen in reducing mammary tumor burden in mice: possible underlying pathway of miR-21. European Journal of Pharmacology, 765, 179–187.

  47. 47.

    Jones, L. W., Antonelli, J., Masko, E. M., Broadwater, G., Lascola, C. D., Fels, D., Dewhirst, M. W., Dyck, J. R., Nagendran, J., Flores, C. T., Betof, A. S., Nelson, E. R., Pollak, M., Dash, R. C., Young, M. E., & Freedland, S. J. (2012). Exercise modulation of the host-tumor interaction in an orthotopic model of murine prostate cancer. Journal of Applied Physiology, 113, 263–272.

  48. 48.

    Garzia, L., Kijima, N., Morrissy, A. S., De Antonellis, P., Guerreiro-Stucklin, A., Holgado, B. L., et al. (2018). A hematogenous route for medulloblastoma leptomeningeal metastases. Cell, 172, 1050–1062.e14.

  49. 49.

    McTiernan, A. (2008). Mechanisms linking physical activity with cancer. Nature Reviews Cancer, 8, 205–211.

  50. 50.

    Theriau, C. F., Shpilberg, Y., Riddell, M. C., & Connor, M. K. (2016). Voluntary physical activity abolishes the proliferative tumor growth microenvironment created by adipose tissue in animals fed a high fat diet. Journal of Applied Physiology, 121, 139–153.

  51. 51.

    Bianco, T. M., Abdalla, D. R., Desidério, C. S., Thys, S., Simoens, C., Bogers, J. P., Murta, E. F. C., & Michelin, M. A. (2017). The influence of physical activity in the anti-tumor immune response in experimental breast tumor. Immunology Letters, 190, 148–158.

  52. 52.

    Koelwyn, G. J., Quail, D. F., Zhang, X., White, R. M., & Jones, L. W. (2017). Exercise-dependent regulation of the tumour microenvironment. Nature Reviews Cancer, 17, 620–632.

  53. 53.

    Jones, L. W., Fels, D. R., West, M., Allen, J. D., Broadwater, G., Barry, W. T., Wilke, L. G., Masko, E., Douglas, P. S., Dash, R. C., Povsic, T. J., Peppercorn, J., Marcom, P. K., Blackwell, K. L., Kimmick, G., Turkington, T. G., & Dewhirst, M. W. (2013). Modulation of circulating angiogenic factors and tumor biology by aerobic training in breast cancer patients receiving neoadjuvant chemotherapy. Cancer Prevention Research, 6, 925–937.

  54. 54.

    Pearson, M. J., & Smart, N. A. (2017). Aerobic training intensity for improved endothelial function in heart failure patients: a systematic review and meta-analysis. Cardiology Research and Practice, 2017, 2450202.

  55. 55.

    Hojman, P., Gehl, J., Christensen, J. F., & Pedersen, B. K. (2018). Molecular mechanisms linking exercise to cancer prevention and treatment. Cell Metabolism, 27, 10–21.

  56. 56.

    Goetz, J. G. (2018). Metastases go with the flow. Science, 362, 999–1000.

  57. 57.

    Shachar, S. S., Williams, G. R., Muss, H. B., & Nishijima, T. F. (2016). Prognostic value of sarcopenia in adults with solid tumours: a meta-analysis and systematic review. European Journal of Cancer, 57, 58–67.

  58. 58.

    Wolin, K. Y., Ruiz, J. R., Tuchman, H., & Lucia, A. (2010). Exercise in adult and pediatric hematological cancer survivors: an intervention review. Leukemia, 24, 1113–1120.

  59. 59.

    Pei, Y., Moore, C. E., Wang, J., Tewari, A. K., Eroshkin, A., Cho, Y. J., Witt, H., Korshunov, A., Read, T. A., Sun, J. L., Schmitt, E. M., Miller, C. R., Buckley, A. F., McLendon, R., Westbrook, T. F., Northcott, P. A., Taylor, M. D., Pfister, S. M., Febbo, P. G., & Wechsler-Reya, R. J. (2012). An animal model of MYC-driven medulloblastoma. Cancer Cell, 21, 155–167.

  60. 60.

    Weiss, W. A., Aldape, K., Mohapatra, G., Feuerstein, B. G., & Bishop, J. M. (1997). Targeted expression of MYCN causes neuroblastoma in transgenic mice. EMBO Journal, 16, 2985–2995.

  61. 61.

    Sweet-Cordero, E. A., & Biegel, J. A. (2019). The genomic landscape of pediatric cancers: implications for diagnosis and treatment. Science, 363, 1170–1175.

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Rincón-Castanedo, C., Morales, J.S., Martín-Ruiz, A. et al. Physical exercise effects on metastasis: a systematic review and meta-analysis in animal cancer models. Cancer Metastasis Rev (2020) doi:10.1007/s10555-020-09851-4

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  • Dissemination
  • Physical activity
  • Metastasis
  • Exercise
  • Spontaneous model
  • Induction model