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Exercise-induced myokines and their effect on prostate cancer

Nature Reviews Urology volume 18, pages 519–542 (2021)Cite this article

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A Publisher Correction to this article was published on 06 July 2021

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Abstract

Exercise is recognized by clinicians in the field of clinical oncology for its potential role in reducing the risk of certain cancers and in reducing the risk of disease recurrence and progression; yet, the underlying mechanisms behind this reduction in risk are not fully understood. Studies applying post-exercise blood serum directly to various types of cancer cell lines provide insight that exercise might have a role in inhibiting cancer growth via altered soluble and cell-free blood contents. Myokines, which are cytokines produced by muscle and secreted into the bloodstream, might offer multiple benefits to cellular metabolism (such as a reduction in insulin resistance, improved glucose uptake and reduced adiposity), and blood myokine levels can be altered with exercise. Alterations in the levels of myokines such as IL-6, IL-15, IL-10, irisin, secreted protein acidic risk in cysteine (SPARC), myostatin, oncostatin M and decorin might exert a direct inhibitory effect on cancer growth via inhibiting proliferation, promoting apoptosis, inducing cell-cycle arrest and inhibiting the epithermal transition to mesenchymal cells. The association of insulin resistance, hyperinsulinaemia and hyperlipidaemia with obesity can create a tumour-favourable environment; exercise-induced myokines can manipulate this environment by regulating adipose tissue and adipocytes. Exercise-induced myokines also have a critical role in increasing cytotoxicity and the infiltration of immune cells into the tumour.

Key points

  • Exercise improves clinical outcomes in patients with cancer. Preclinical studies suggest the involvement of myokines in exercise-induced tumour suppression.

  • Multiple studies have demonstrated the potential of myokines, such as oncostatin M, secreted protein acidic risk in cysteine (SPARC), irisin and decorin, in decreasing cancer cell proliferation, limiting migration and increasing apoptosis.

  • Myokines such as IL-6, IL-15, irisin and SPARC create a less tumour-favourable environment by reducing whole-body adiposity and adipogenesis.

  • Myokines such as IL-6, IL-10 and IL-8 induce enhancement of the immune system by increasing the number and cytotoxicity of immune cells involved in tumour suppression.

  • Studies examining the effect of myokines on the various phenotypes of prostate cancer cells are required to understand the mechanisms of exercise-induced tumour suppression.

  • Examining myokines in response to various exercise modes, doses and intensities will further improve exercise prescriptions for patients with prostate cancer.

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Fig. 1: Factors involved in prostate cancer growth and the potential effect of exercise.
Fig. 2: The direct effect of serum acquired after a single bout of exercise and prolonged exercise training on various cancer cell lines.
Fig. 3: Direct and indirect mechanisms of exercise-induced myokines on cancer inhibition.

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References

  1. Bray, F. et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68, 394–424 (2018).

    Article  PubMed  Google Scholar 

  2. Anand, P. et al. Cancer is a preventable disease that requires major lifestyle changes. Pharm. Res. 25, 2097–2116 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bourke, L. et al. Exercise for men with prostate cancer: a systematic review and meta-analysis. Eur. Urol. 69, 693–703 (2016).

    Article  PubMed  Google Scholar 

  4. Gunnell, A. S. et al. Physical activity and survival among long-term cancer survivor and non-cancer cohorts. Front. Public Health 5, 19 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Nieto-Vazquez, I., Fernandez-Veledo, S., de Alvaro, C. & Lorenzo, M. Dual role of interleukin-6 in regulating insulin sensitivity in murine skeletal muscle. Diabetes 57, 3211–3221 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Shephard, R. J. Physical activity and prostate cancer: an updated review. Sports Med. 47, 1055–1073 (2017).

    Article  PubMed  Google Scholar 

  7. Kenfield, S. A., Stampfer, M. J., Giovannucci, E. & Chan, J. M. Physical activity and survival after prostate cancer diagnosis in the health professionals follow-up study. J. Clin. Oncol. 29, 726–732 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Datta, D., Aftabuddin, M., Gupta, D. K., Raha, S. & Sen, P. Human prostate cancer hallmarks map. Sci. Rep. 6, 30691 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Potosky, A. L., Miller, B. A., Albertsen, P. C. & Kramer, B. S. The role of increasing detection in the rising incidence of prostate cancer. JAMA 273, 548–552 (1995).

    Article  CAS  PubMed  Google Scholar 

  10. Allott, E. H., Masko, E. M. & Freedland, S. J. Obesity and prostate cancer: weighing the evidence. Eur. Urol. 63, 800–809 (2013).

    Article  CAS  PubMed  Google Scholar 

  11. Jones, L. W. & Alfano, C. M. Exercise-oncology research: past, present, and future. Acta. Oncol. 52, 195–215 (2013).

    Article  PubMed  Google Scholar 

  12. Christensen, J. F., Simonsen, C. & Hojman, P. Exercise training in cancer control and treatment. Compr. Physiol. 9, 165–205 (2018).

    Article  PubMed  Google Scholar 

  13. Fiuza-Luces, C., Garatachea, N., Berger, N. A. & Lucia, A. Exercise is the real polypill. Physiology 28, 330–358 (2013).

    Article  CAS  PubMed  Google Scholar 

  14. Chang, S. et al. Leptin and prostate cancer. Prostate 46, 62–67 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Dethlefsen, C. et al. Exercise-induced catecholamines activate the hippo tumor suppressor pathway to reduce risks of breast cancer development. Cancer Res. 77, 4894–4904 (2017).

    Article  CAS  PubMed  Google Scholar 

  16. Dethlefsen, C. et al. Exercise regulates breast cancer cell viability: systemic training adaptations versus acute exercise responses. Breast Cancer Res. Treat. 159, 469–479 (2016).

    Article  PubMed  Google Scholar 

  17. Dethlefsen, C., Pedersen, K. S. & Hojman, P. Every exercise bout matters: linking systemic exercise responses to breast cancer control. Breast Cancer Res. Treat. 162, 399–408 (2017).

    Article  PubMed  Google Scholar 

  18. Devin, J. L. et al. Acute high intensity interval exercise reduces colon cancer cell growth. J. Physiol. 597, 2177–2184 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kurgan, N. et al. Inhibition of human lung cancer cell proliferation and survival by post-exercise serum is associated with the inhibition of Akt, mTOR, p70 S6K, and Erk1/2. Cancers 9, 46 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  20. Rundqvist, H. et al. Effect of acute exercise on prostate cancer cell growth. PLoS ONE 8, e67579 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pedersen, B. K. & Febbraio, M. A. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat. Rev. Endocrinol. 8, 457–465 (2012).

    Article  CAS  PubMed  Google Scholar 

  22. Aoi, W. et al. A novel myokine, secreted protein acidic and rich in cysteine (SPARC), suppresses colon tumorigenesis via regular exercise. Gut 62, 882–889 (2013).

    Article  CAS  PubMed  Google Scholar 

  23. Hojman, P. et al. Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am. J. Physiol. Endocrinol. Metab. 301, E504–E510 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Pedersen, B. K. The physiology of optimizing health with a focus on exercise as medicine. Annu. Rev. Physiol. 81, 607–627 (2019).

    Article  CAS  PubMed  Google Scholar 

  25. Richman, E. L. et al. Physical activity after diagnosis and risk of prostate cancer progression: data from the cancer of the prostate strategic urologic research endeavor. Cancer Res. 71, 3889–3895 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hayes, S. C., Newton, R. U., Spence, R. R. & Galvão, D. A. The exercise and sports science Australia position statement: exercise medicine in cancer management. J. Sci. Med. Sport 22, 1175–1199 (2019).

    Article  PubMed  Google Scholar 

  27. Jones, L. W. Precision oncology framework for investigation of exercise as treatment for cancer. J. Clin. Oncol. 33, 4134–4137 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Sasso, J. P. et al. A framework for prescription in exercise-oncology research. J. Cachexia Sarcopenia Muscle 6, 115–124 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Courneya, K. S. et al. Effects of supervised exercise on progression-free survival in lymphoma patients: an exploratory follow-up of the HELP Trial. Cancer Causes Control. 26, 269–276 (2015).

    Article  PubMed  Google Scholar 

  30. Courneya, K. S. et al. Effects of exercise during adjuvant chemotherapy on breast cancer outcomes. Med. Sci. Sports Exerc. 46, 1744–1751 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Hayes, S. C. et al. Exercise following breast cancer: exploratory survival analyses of two randomised, controlled trials. Breast Cancer Res. Treat. 167, 505–514 (2018).

    Article  CAS  PubMed  Google Scholar 

  32. Rief, H. et al. Resistance training concomitant to radiotherapy of spinal bone metastases - survival and prognostic factors of a randomized trial. Radiat. Oncol. 11, 97 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Galvao, D. A. et al. Enhancing active surveillance of prostate cancer: the potential of exercise medicine. Nat. Rev. Urol. 13, 258–265 (2016).

    Article  PubMed  Google Scholar 

  34. Keilani, M. et al. Effects of resistance exercise in prostate cancer patients: a meta-analysis. Support. Care Cancer 25, 2953–2968 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pak, S. et al. Association of body composition with survival and treatment efficacy in castration-resistant prostate cancer. Front. Oncol. 10, 558 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  36. Galvão, D. A., Taaffe, D. R., Spry, N., Joseph, D. & Newton, R. U. Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial. J. Clin. Oncol. 28, 340–347 (2010).

    Article  PubMed  CAS  Google Scholar 

  37. Lopez, P., Taaffe, D. R., Newton, R. U. & Galvao, D. A. Resistance exercise dosage in men with prostate cancer: Systematic review, meta-analysis, and meta-regression. Med. Sci. Sports Exerc. 53, 459–469 (2020).

    Article  PubMed Central  Google Scholar 

  38. Betof, A. S. et al. Modulation of murine breast tumor vascularity, hypoxia, and chemotherapeutic response by exercise. J. Natl Cancer Inst. 107, djv040 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Jones, L. W. Effects of exercise training on antitumor efficacy of doxorubicin in MDA-MB-231 breast cancer xenografts. Clin. Cancer Res. 11, 6695–6698 (2005).

    Article  CAS  PubMed  Google Scholar 

  40. McCullough, D. J., Stabley, J. N., Siemann, D. W. & Behnke, B. J. Modulation of blood flow, hypoxia, and vascular function in orthotopic prostate tumors during exercise. J. Natl Cancer Inst. 106, dju036 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Schadler, K. L. et al. Tumor vessel normalization after aerobic exercise enhances chemotherapeutic efficacy. Oncotarget 7, 65429–65440 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  42. Schumacher, O. et al. Exercise modulation of tumour perfusion and hypoxia to improve radiotherapy response in prostate cancer. Prostate Cancer Prostatic Dis. 24, 1–14 (2021).

    Article  PubMed  Google Scholar 

  43. Muz, B., de la Puente, P., Azab, F. & Azab, A. K. The role of hypoxia in cancer progression, angiogenesis, metastasis, and resistance to therapy. Hypoxia 3, 83–92 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Barnard, R. J., Ngo, T. H., Leung, P. S., Aronson, W. J. & Golding, L. A. A low-fat diet and/or strenuous exercise alters the IGF axis in vivo and reduces prostate tumor cell growth in vitro. Prostate 56, 201–206 (2003).

    Article  PubMed  Google Scholar 

  45. Leung, P. S., Aronson, W. J., Ngo, T. H., Golding, L. A. & Barnard, R. J. Exercise alters the IGF axis in vivo and increases p53 protein in prostate tumor cells in vitro. J. Appl. Physiol. 96, 450–454 (2004).

    Article  CAS  PubMed  Google Scholar 

  46. Ngo, T. H., Barnard, R. J., Leung, P. S., Cohen, P. & Aronson, W. J. Insulin-like growth factor I (IGF-I) and IGF binding protein-1 modulate prostate cancer cell growth and apoptosis: possible mediators for the effects of diet and exercise on cancer cell survival. Endocrinology 144, 2319–2324 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Yu, M. et al. Exercise activates p53 and negatively regulates IGF-1 pathway in epidermis within a skin cancer model. PLoS ONE 11, e0160939 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Galvao, D. A. et al. Endocrine and immune responses to resistance training in prostate cancer patients. Prostate Cancer Prostatic Dis. 11, 160–165 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Ilagan, E. & Manning, B. D. Emerging role of mTOR in the response to cancer therapeutics. Trends Cancer 2, 241–251 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Sarker, D., Reid, A. H., Yap, T. A. & de Bono, J. S. Targeting the PI3K/AKT pathway for the treatment of prostate cancer. Clin. Cancer. Res. 15, 4799–4805 (2009).

    Article  CAS  PubMed  Google Scholar 

  51. Abylkassov, R. & Xie, Y. Role of Yes-associated protein in cancer: an update. Oncol. Lett. 12, 2277–2282 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Nørgaard-Christensen, N. PO-103 Regulation of prostate cancer cell growth and signalling by exercise. [abstract PO-103]. ESMO Open 3, A61–A61 (2018).

    Article  Google Scholar 

  53. Cohen, D. H. & LeRoith, D. Obesity, type 2 diabetes, and cancer: the insulin and IGF connection. Endocr. Relat. Cancer 19, F27–F45 (2012).

    Article  CAS  PubMed  Google Scholar 

  54. Pedersen, B. K. et al. Searching for the exercise factor: is IL-6 a candidate? J. Muscle Res. Cell Motil. 24, 113–119 (2003).

    Article  CAS  PubMed  Google Scholar 

  55. Pedersen, B. K., Akerstrom, T. C., Nielsen, A. R. & Fischer, C. P. Role of myokines in exercise and metabolism. J. Appl. Physiol. 103, 1093–1098 (2007).

    Article  CAS  PubMed  Google Scholar 

  56. Ruiz-Casado, A. et al. Exercise and the hallmarks of cancer. Trends Cancer 3, 423–441 (2017).

    Article  CAS  PubMed  Google Scholar 

  57. Grant, S. L. & Begley, C. G. The oncostatin M signalling pathway: reversing the neoplastic phenotype? Mol. Med. Today 5, 406–412 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Hutt, J. A. & DeWille, J. W. Oncostatin M induces growth arrest of mammary epithelium via a CCAAT/enhancer-binding protein delta-dependent pathway. Mol. Cancer Ther. 1, 601–610 (2002).

    CAS  PubMed  Google Scholar 

  59. Liu, J. et al. Oncostatin M-specific receptor mediates inhibition of breast cancer cell growth and down-regulation of the c-myc proto-oncogene. Cell Growth Differ. 8, 667–676 (1997).

    CAS  PubMed  Google Scholar 

  60. Hermanns, H. M. Oncostatin M and interleukin-31: Cytokines, receptors, signal transduction and physiology. Cytokine Growth Factor. Rev. 26, 545–558 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Masjedi, A. et al. Oncostatin M: a mysterious cytokine in cancers. Int. Immunopharmacol. 90, 107158 (2021).

    Article  CAS  PubMed  Google Scholar 

  62. Mori, S., Murakami-Mori, K. & Bonavida, B. Oncostatin M (OM) promotes the growth of DU 145 human prostate cancer cells, but not PC-3 or LNCaP, through the signaling of the OM specific receptor. Anticancer. Res. 19, 1011–1015 (1999).

    CAS  PubMed  Google Scholar 

  63. Lee, M. J. et al. Oncostatin M promotes mesenchymal stem cell-stimulated tumor growth through a paracrine mechanism involving periostin and TGFBI. Int. J. Biochem. Cell Biol. 45, 1869–1877 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Sterbova, S., Karlsson, T. & Persson, E. Oncostatin M induces tumorigenic properties in non-transformed human prostate epithelial cells, in part through activation of signal transducer and activator of transcription 3 (STAT3). Biochem. Biophys. Res. Commun. 498, 769–774 (2018).

    Article  CAS  PubMed  Google Scholar 

  65. Catoire, M., Mensink, M., Kalkhoven, E., Schrauwen, P. & Kersten, S. Identification of human exercise-induced myokines using secretome analysis. Physiol. Genomics 46, 256–267 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Nie, J. & Sage, E. H. SPARC inhibits adipogenesis by its enhancement of beta-catenin signaling. J. Biol. Chem. 284, 1279–1290 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Brekken, R. A. & Sage, E. H. SPARC, a matricellular protein: at the crossroads of cell-matrix communication. Matrix Biol. 19, 816–827 (2001).

    Article  CAS  PubMed  Google Scholar 

  68. Puolakkainen, P. A., Brekken, R. A., Muneer, S. & Sage, E. H. Enhanced growth of pancreatic tumors in SPARC-null mice is associated with decreased deposition of extracellular matrix and reduced tumor cell apoptosis. Mol. Cancer Res. 2, 215–224 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Said, N. et al. The role of SPARC in the TRAMP model of prostate carcinogenesis and progression. Oncogene 28, 3487–3498 (2009).

    Article  CAS  PubMed  Google Scholar 

  70. Tai, I. T. & Tang, M. J. SPARC in cancer biology: its role in cancer progression and potential for therapy. Drug Resist. Updat. 11, 231–246 (2008).

    Article  CAS  PubMed  Google Scholar 

  71. Yiu, G. K. et al. SPARC (secreted protein acidic and rich in cysteine) induces apoptosis in ovarian cancer cells. Am. J. Pathol. 159, 609–622 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Said, N. & Motamed, K. Absence of host-secreted protein acidic and rich in cysteine (SPARC) augments peritoneal ovarian carcinomatosis. Am. J. Pathol. 167, 1739–1752 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Shin, M. et al. Exogenous SPARC suppresses proliferation and migration of prostate cancer by interacting with integrin β1. Prostate 73, 1159–1170 (2013).

    Article  CAS  PubMed  Google Scholar 

  74. Kapinas, K. et al. Bone matrix osteonectin limits prostate cancer cell growth and survival. Matrix Biol. 31, 299–307 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Thomas, R., True, L. D., Bassuk, J. A., Lange, P. H. & Vessella, R. L. Differential expression of osteonectin/SPARC during human prostate cancer progression. Clin. Cancer Res. 6, 1140–1149 (2000).

    CAS  PubMed  Google Scholar 

  76. Jeldres, C., Johnston, R. B., Porter, C. R. & Nelson, P. Association of SPARC expression with metastatic progression and prostate cancer-specific mortality after radical prostatectomy. J. Clin. Oncol. 31, 5071–5071 (2013).

    Article  Google Scholar 

  77. Bostrom, P. et al. A PGC1-alpha-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature 481, 463–468 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Huh, J. Y. et al. FNDC5 and irisin in humans: I. Predictors of circulating concentrations in serum and plasma and II. mRNA expression and circulating concentrations in response to weight loss and exercise. Metabolism 61, 1725–1738 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Novelle, M. G., Contreras, C., Romero-Pico, A., Lopez, M. & Dieguez, C. Irisin, two years later. Int. J. Endocrinol. 2013, 746281 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Gannon, N. P., Vaughan, R. A., Garcia-Smith, R., Bisoffi, M. & Trujillo, K. A. Effects of the exercise-inducible myokine irisin on malignant and non-malignant breast epithelial cell behavior in vitro. Int. J. Cancer 136, E197–E202 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Liu, J., Song, N., Huang, Y. & Chen, Y. Irisin inhibits pancreatic cancer cell growth via the AMPK-mTOR pathway. Sci. Rep. 8, 15247 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Shao, L. et al. Irisin suppresses the migration, proliferation, and invasion of lung cancer cells via inhibition of epithelial-to-mesenchymal transition. Biochem. Biophys. Res. Commun. 485, 598–605 (2017).

    Article  CAS  PubMed  Google Scholar 

  83. Tekin, S., Erden, Y., Sandal, S. & Yilmaz, B. Is irisin an anticarcinogenic peptide? Med. Sci. 4, 2172–2180 (2015).

    Article  Google Scholar 

  84. Wang, Y. et al. PI3K inhibitor LY294002, as opposed to wortmannin, enhances AKT phosphorylation in gemcitabine-resistant pancreatic cancer cells. Int. J. Oncol. 50, 606–612 (2017).

    Article  CAS  PubMed  Google Scholar 

  85. Brenmoehl, J. et al. Irisin is elevated in skeletal muscle and serum of mice immediately after acute exercise. Int. J. Biol. Sci. 10, 338–349 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Kim, H. J., So, B., Choi, M., Kang, D. & Song, W. Resistance exercise training increases the expression of irisin concomitant with improvement of muscle function in aging mice and humans. Exp. Gerontol. 70, 11–17 (2015).

    Article  CAS  PubMed  Google Scholar 

  87. Lu, Y. et al. Swimming exercise increases serum irisin level and reduces body fat mass in high-fat-diet fed Wistar rats. Lipids Health Dis. 15, 93 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Miyamoto-Mikami, E. et al. Endurance training-induced increase in circulating irisin levels is associated with reduction of abdominal visceral fat in middle-aged and older adults. PLoS ONE 10, e0120354 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Norheim, F. et al. The effects of acute and chronic exercise on PGC-1alpha, irisin and browning of subcutaneous adipose tissue in humans. FEBS J. 281, 739–749 (2014).

    Article  CAS  PubMed  Google Scholar 

  90. Tsuchiya, Y. et al. High-intensity exercise causes greater irisin response compared with low-intensity exercise under similar energy consumption. Tohoku J. Exp. Med. 233, 135–140 (2014).

    Article  PubMed  Google Scholar 

  91. Yang, X. Q. et al. Swimming intervention mitigates HFD-induced obesity of rats through PGC-1alpha-irisin pathway. Eur. Rev. Med. Pharmacol. Sci. 20, 2123–2130 (2016).

    PubMed  Google Scholar 

  92. Sofeu Feugaing, D. D., Gotte, M. & Viola, M. More than matrix: the multifaceted role of decorin in cancer. Eur. J. Cell Biol. 92, 1–11 (2013).

    Article  CAS  PubMed  Google Scholar 

  93. Bozoky, B. et al. Decreased decorin expression in the tumor microenvironment. Cancer Med. 3, 485–491 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Hu, Y. et al. Decorin suppresses prostate tumor growth through inhibition of epidermal growth factor and androgen receptor pathways. Neoplasia 11, 1042–1053 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Santra, M., Eichstetter, I. & Iozzo, R. V. An anti-oncogenic role for decorin. Down-regulation of ErbB2 leads to growth suppression and cytodifferentiation of mammary carcinoma cells. J. Biol. Chem. 275, 35153–35161 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Seidler, D. G. et al. Decorin protein core inhibits in vivo cancer growth and metabolism by hindering epidermal growth factor receptor function and triggering apoptosis via caspase-3 activation. J. Biol. Chem. 281, 26408–26418 (2006).

    Article  CAS  PubMed  Google Scholar 

  97. Shi, X., Liang, W., Yang, W., Xia, R. & Song, Y. Decorin is responsible for progression of non-small-cell lung cancer by promoting cell proliferation and metastasis. Tumour Biol. 36, 3345–3354 (2015).

    Article  CAS  PubMed  Google Scholar 

  98. Xu, W. et al. The systemic delivery of an oncolytic adenovirus expressing decorin inhibits bone metastasis in a mouse model of human prostate cancer. Gene Ther. 22, 247–256 (2015).

    Article  CAS  PubMed  Google Scholar 

  99. Heinemeier, K. M., Bjerrum, S. S., Schjerling, P. & Kjaer, M. Expression of extracellular matrix components and related growth factors in human tendon and muscle after acute exercise. Scand. J. Med. Sci. Sports 23, e150–e161 (2013).

    Article  CAS  PubMed  Google Scholar 

  100. Kanzleiter, T. et al. The myokine decorin is regulated by contraction and involved in muscle hypertrophy. Biochem. Biophys. Res. Commun. 450, 1089–1094 (2014).

    Article  CAS  PubMed  Google Scholar 

  101. Di Lorenzo, G. et al. Expression of epidermal growth factor receptor correlates with disease relapse and progression to androgen-independence in human prostate cancer. Clin. Cancer Res. 8, 3438–3444 (2002).

    PubMed  Google Scholar 

  102. Pignon, J. C. et al. Androgen receptor controls EGFR and ERBB2 gene expression at different levels in prostate cancer cell lines. Cancer Res. 69, 2941–2949 (2009).

    Article  CAS  PubMed  Google Scholar 

  103. Chung, T. D., Yu, J. J., Spiotto, M. T., Bartkowski, M. & Simons, J. W. Characterization of the role of IL-6 in the progression of prostate cancer. Prostate 38, 199–207 (1999).

    Article  CAS  PubMed  Google Scholar 

  104. Hobisch, A. et al. Interleukin-6 regulates prostate-specific protein expression in prostate carcinoma cells by activation of the androgen receptor. Cancer Res. 58, 4640–4645 (1998).

    CAS  PubMed  Google Scholar 

  105. Jia, L. et al. Androgen receptor signaling: mechanism of interleukin-6 inhibition. Cancer Res. 64, 2619–2626 (2004).

    Article  CAS  PubMed  Google Scholar 

  106. Lee, S. O., Chun, J. Y., Nadiminty, N., Lou, W. & Gao, A. C. Interleukin-6 undergoes transition from growth inhibitor associated with neuroendocrine differentiation to stimulator accompanied by androgen receptor activation during LNCaP prostate cancer cell progression. Prostate 67, 764–773 (2007).

    Article  CAS  PubMed  Google Scholar 

  107. Lin, D. L., Whitney, M. C., Yao, Z. & Keller, E. T. Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression. Clin. Cancer Res. 7, 1773–1781 (2001).

    CAS  PubMed  Google Scholar 

  108. Spiotto, M. T. & Chung, T. D. STAT3 mediates IL-6-induced neuroendocrine differentiation in prostate cancer cells. Prostate 42, 186–195 (2000).

    Article  CAS  PubMed  Google Scholar 

  109. Wallner, L. et al. Inhibition of interleukin-6 with CNTO328, an anti-interleukin-6 monoclonal antibody, inhibits conversion of androgen-dependent prostate cancer to an androgen-independent phenotype in orchiectomized mice. Cancer Res. 66, 3087–3095 (2006).

    Article  CAS  PubMed  Google Scholar 

  110. Farmawati, A. et al. Characterization of contraction-induced IL-6 up-regulation using contractile C2C12 myotubes. Endocr. J. 60, 137–147 (2013).

    Article  CAS  PubMed  Google Scholar 

  111. Febbraio, M. A. et al. Hepatosplanchnic clearance of interleukin-6 in humans during exercise. Am. J. Physiol. Endocrinol. Metab. 285, E397–E402 (2003).

    Article  CAS  PubMed  Google Scholar 

  112. Hiscock, N., Chan, M. H., Bisucci, T., Darby, I. A. & Febbraio, M. A. Skeletal myocytes are a source of interleukin-6 mRNA expression and protein release during contraction: evidence of fiber type specificity. FASEB J. 18, 992–994 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Jonsdottir, I. H. et al. Muscle contractions induce interleukin-6 mRNA production in rat skeletal muscles. J. Physiol. 528, 157–163 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Keller, C. et al. Transcriptional activation of the IL-6 gene in human contracting skeletal muscle: influence of muscle glycogen content. FASEB J. 15, 2748–2750 (2001).

    Article  CAS  PubMed  Google Scholar 

  115. Ostrowski, K., Schjerling, P. & Pedersen, B. K. Physical activity and plasma interleukin-6 in humans — effect of intensity of exercise. Eur. J. Appl. Physiol. 83, 512–515 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Steensberg, A. et al. IL-6 and TNF-alpha expression in, and release from, contracting human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 283, E1272–E1278 (2002).

    Article  CAS  PubMed  Google Scholar 

  117. Bruun, J. M., Helge, J. W., Richelsen, B. & Stallknecht, B. Diet and exercise reduce low-grade inflammation and macrophage infiltration in adipose tissue but not in skeletal muscle in severely obese subjects. Am. J. Physiol. Endocrinol. Metab. 290, E961–E967 (2006).

    Article  CAS  PubMed  Google Scholar 

  118. Goldhammer, E. et al. Exercise training modulates cytokines activity in coronary heart disease patients. Int. J. Cardiol. 100, 93–99 (2005).

    Article  PubMed  Google Scholar 

  119. Kohut, M. L. et al. Aerobic exercise, but not flexibility/resistance exercise, reduces serum IL-18, CRP, and IL-6 independent of beta-blockers, BMI, and psychosocial factors in older adults. Brain Behav. Immun. 20, 201–209 (2006).

    Article  CAS  PubMed  Google Scholar 

  120. Adachi, M. et al. Androgen-insensitivity syndrome as a possible coactivator disease. N. Engl. J. Med. 343, 856–862 (2000).

    Article  CAS  PubMed  Google Scholar 

  121. Iyengar, N. M., Hudis, C. A. & Dannenberg, A. J. Obesity and cancer: local and systemic mechanisms. Annu. Rev. Med. 66, 297–309 (2015).

    Article  CAS  PubMed  Google Scholar 

  122. Cox, M. E. et al. Insulin receptor expression by human prostate cancers. Prostate 69, 33–40 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Venkateswaran, V. et al. Association of diet-induced hyperinsulinemia with accelerated growth of prostate cancer (LNCaP) xenografts. J. Natl Cancer Inst. 99, 1793–1800 (2007).

    Article  PubMed  Google Scholar 

  124. Pollak, M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat. Rev. Cancer 12, 159–169 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Di Sebastiano, K. M., Pinthus, J. H., Duivenvoorden, W. C. M. & Mourtzakis, M. Glucose impairments and insulin resistance in prostate cancer: the role of obesity, nutrition and exercise. Obes. Rev. 19, 1008–1016 (2018).

    Article  PubMed  CAS  Google Scholar 

  126. Michalaki, V., Syrigos, K., Charles, P. & Waxman, J. Serum levels of IL-6 and TNF-alpha correlate with clinicopathological features and patient survival in patients with prostate cancer. Br. J. Cancer 90, 2312–2316 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Shariat, S. F. et al. Plasma levels of interleukin-6 and its soluble receptor are associated with prostate cancer progression and metastasis. Urology 58, 1008–1015 (2001).

    Article  CAS  PubMed  Google Scholar 

  128. Shariat, S. F. et al. Association of preoperative plasma levels of vascular endothelial growth factor and soluble vascular cell adhesion molecule-1 with lymph node status and biochemical progression after radical prostatectomy. J. Clin. Oncol. 22, 1655–1663 (2004).

    Article  CAS  PubMed  Google Scholar 

  129. Uehara, H. et al. Adipose tissue: critical contributor to the development of prostate cancer. J. Med. Invest. 65, 9–17 (2018).

    Article  PubMed  Google Scholar 

  130. Uehara, H., Takahashi, T., Oha, M., Ogawa, H. & Izumi, K. Exogenous fatty acid binding protein 4 promotes human prostate cancer cell progression. Int. J. Cancer 135, 2558–2568 (2014).

    Article  CAS  PubMed  Google Scholar 

  131. Laurent, V. et al. Periprostatic adipocytes act as a driving force for prostate cancer progression in obesity. Nat. Commun. 7, 10230 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Ferro, M. et al. The emerging role of obesity, diet and lipid metabolism in prostate cancer. Future Oncol. 13, 285–293 (2017).

    Article  CAS  PubMed  Google Scholar 

  133. Ito, Y. et al. Adipocyte-derived monocyte chemotactic protein-1 (MCP-1) promotes prostate cancer progression through the induction of MMP-2 activity. Prostate 75, 1009–1019 (2015).

    Article  CAS  PubMed  Google Scholar 

  134. Xu, A. et al. Adipocyte fatty acid-binding protein is a plasma biomarker closely associated with obesity and metabolic syndrome. Clin. Chem. 52, 405–413 (2006).

    Article  CAS  PubMed  Google Scholar 

  135. Mohamed-Ali, V. et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-alpha, in vivo. J. Clin. Endocrinol. Metab. 82, 4196–4200 (1997).

    CAS  PubMed  Google Scholar 

  136. Bastard, J. P. et al. Elevated levels of interleukin 6 are reduced in serum and subcutaneous adipose tissue of obese women after weight loss. J. Clin. Endocrinol. Metab. 85, 3338–3342 (2000).

    CAS  PubMed  Google Scholar 

  137. Roytblat, L. et al. Raised interleukin-6 levels in obese patients. Obes. Res. 8, 673–675 (2000).

    Article  CAS  PubMed  Google Scholar 

  138. Rotter, V., Nagaev, I. & Smith, U. Interleukin-6 (IL-6) induces insulin resistance in 3T3-L1 adipocytes andis, like IL-8 and tumor necrosis factor-alpha, overexpressed in human fat cells from insulin-resistant subjects. J. Biol. Chem. 278, 45777–45784 (2003).

    Article  CAS  PubMed  Google Scholar 

  139. van Hall, G. et al. Interleukin-6 stimulates lipolysis and fat oxidation in humans. J. Endocrinol. Metab. 88, 3005–3010 (2003).

    Article  CAS  Google Scholar 

  140. Wedell-Neergaard, A. S. et al. Exercise-induced changes in visceral adipose tissue mass are regulated by IL-6 signaling: a randomized controlled trial. Cell Metab. 29, 844–855.e3 (2019).

    Article  CAS  PubMed  Google Scholar 

  141. Ikeda, S. I. et al. Exercise-induced increase in IL-6 level enhances GLUT4 expression and insulin sensitivity in mouse skeletal muscle. Biochem. Biophys. Res. Commun. 473, 947–952 (2016).

    Article  CAS  PubMed  Google Scholar 

  142. Almendro, V. et al. Interleukin-15 increases calcineurin expression in 3T3-L1 cells: possible involvement on in vivo adipocyte differentiation. Int. J. Mol. Med. 24, 453–458 (2009).

    CAS  PubMed  Google Scholar 

  143. Barra, N. G. et al. Interleukin-15 contributes to the regulation of murine adipose tissue and human adipocytes. Obesity 18, 1601–1607 (2010).

    Article  CAS  PubMed  Google Scholar 

  144. Carbo, N. et al. Interleukin-15 mediates reciprocal regulation of adipose and muscle mass: a potential role in body weight control. Biochim. Biophys. Acta. 1526, 17–24 (2001).

    Article  CAS  PubMed  Google Scholar 

  145. Quinn, L. S., Anderson, B. G., Strait-Bodey, L., Stroud, A. M. & Argiles, J. M. Oversecretion of interleukin-15 from skeletal muscle reduces adiposity. Am. J. Physiol. Endocrinol. Metab. 296, E191–E202 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Raschke, S., Eckardt, K., Bjorklund Holven, K., Jensen, J. & Eckel, J. Identification and validation of novel contraction-regulated myokines released from primary human skeletal muscle cells. PLoS ONE 8, e62008 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Nielsen, A. R. et al. Expression of interleukin-15 in human skeletal muscle effect of exercise and muscle fibre type composition. J. Physiol. 584, 305–312 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Bazgir, B., Salesi, M., Koushki, M. & Amirghofran, Z. Effects of eccentric and concentric emphasized resistance exercise on IL-15 serum levels and its relation to inflammatory markers in athletes and non-athletes. Asian J. Sports Med. 6, e27980 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  149. Crane, J. D. et al. Exercise-stimulated interleukin-15 is controlled by AMPK and regulates skin metabolism and aging. Aging Cell 14, 625–634 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Perez-Lopez, A. et al. Skeletal muscle IL-15/IL-15Ralpha and myofibrillar protein synthesis after resistance exercise. Scand. J. Med. Sci. Sports 28, 116–125 (2018).

    Article  CAS  PubMed  Google Scholar 

  151. Riechman, S. E., Balasekaran, G., Roth, S. M. & Ferrell, R. E. Association of interleukin-15 protein and interleukin-15 receptor genetic variation with resistance exercise training responses. J. Appl. Physiol. 97, 2214–2219 (2004).

    Article  CAS  PubMed  Google Scholar 

  152. Pierce, J. R., Maples, J. M. & Hickner, R. C. IL-15 concentrations in skeletal muscle and subcutaneous adipose tissue in lean and obese humans: local effects of IL-15 on adipose tissue lipolysis. Am. J. Physiol. Endocrinol. Metab. 308, E1131–E1139 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Tamura, Y. et al. Upregulation of circulating IL-15 by treadmill running in healthy individuals: is IL-15 an endocrine mediator of the beneficial effects of endurance exercise? Endocr. J. 58, 211–215 (2011).

    Article  CAS  PubMed  Google Scholar 

  154. Noda, T. et al. Longterm exposure to leptin enhances the growth of prostate cancer cells. Int. J. Oncol. 46, 1535–1542 (2015).

    Article  CAS  PubMed  Google Scholar 

  155. Busquets, S., Figueras, M., Almendro, V., Lopez-Soriano, F. J. & Argiles, J. M. Interleukin-15 increases glucose uptake in skeletal muscle. An antidiabetogenic effect of the cytokine. Biochim. Biophys. Acta. 1760, 1613–1617 (2006).

    Article  CAS  PubMed  Google Scholar 

  156. Gray, S. R. & Kamolrat, T. The effect of exercise induced cytokines on insulin stimulated glucose transport in C2C12 cells. Cytokine 55, 221–228 (2011).

    Article  CAS  PubMed  Google Scholar 

  157. Krolopp, J. E., Thornton, S. M. & Abbott, M. J. IL-15 activates the Jak3/STAT3 signaling pathway to mediate glucose uptake in skeletal muscle cells. Front. Physiol. 7, 626 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Quinn, L. S., Anderson, B. G., Conner, J. D. & Wolden-Hanson, T. IL-15 overexpression promotes endurance, oxidative energy metabolism, and muscle PPARdelta, SIRT1, PGC-1alpha, and PGC-1beta expression in male mice. Endocrinology 154, 232–245 (2013).

    Article  CAS  PubMed  Google Scholar 

  159. Ferrannini, E. et al. Effect of insulin on the distribution and disposition of glucose in man. J. Clin. Invest. 76, 357–364 (1985).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Schnyder, S. & Handschin, C. Skeletal muscle as an endocrine organ: PGC-1alpha, myokines and exercise. Bone 80, 115–125 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Marshall, A. et al. Mighty is a novel promyogenic factor in skeletal myogenesis. Exp. Cell Res. 314, 1013–1029 (2008).

    Article  CAS  PubMed  Google Scholar 

  162. Zhu, J. et al. Relationships between transforming growth factor-beta1, myostatin, and decorin: implications for skeletal muscle fibrosis. J. Biol. Chem. 282, 25852–25863 (2007).

    Article  CAS  PubMed  Google Scholar 

  163. Hittel, D. S. et al. Myostatin decreases with aerobic exercise and associates with insulin resistance. Med. Sci. Sports Exerc. 42, 2023–2029 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Konopka, A. R. et al. Molecular adaptations to aerobic exercise training in skeletal muscle of older women. J. Gerontol. A Biol. Sci. Med. Sci. 65, 1201–1207 (2010).

    Article  PubMed  CAS  Google Scholar 

  165. Kopple, J. D. et al. Effect of exercise on mRNA levels for growth factors in skeletal muscle of hemodialysis patients. J. Ren. Nutr. 16, 312–324 (2006).

    Article  PubMed  Google Scholar 

  166. Laurentino, G. C. et al. Strength training with blood flow restriction diminishes myostatin gene expression. Med. Sci. Sports Exerc. 44, 406–412 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Louis, E., Raue, U., Yang, Y., Jemiolo, B. & Trappe, S. Time course of proteolytic, cytokine, and myostatin gene expression after acute exercise in human skeletal muscle. J. Appl. Physiol. 103, 1744–1751 (2007).

    Article  CAS  PubMed  Google Scholar 

  168. Mascher, H. et al. Repeated resistance exercise training induces different changes in mRNA expression of MAFbx and MuRF-1 in human skeletal muscle. Am. J. Physiol. Endocrinol. Metab. 294, E43–E51 (2008).

    Article  CAS  PubMed  Google Scholar 

  169. Matsakas, A., Friedel, A., Hertrampf, T. & Diel, P. Short-term endurance training results in a muscle-specific decrease of myostatin mRNA content in the rat. Acta. Physiol. Scand. 183, 299–307 (2005).

    Article  CAS  PubMed  Google Scholar 

  170. Roth, S. M. et al. Myostatin gene expression is reduced in humans with heavy-resistance strength training: a brief communication. Exp. Biol. Med. 228, 706–709 (2003).

    Article  CAS  Google Scholar 

  171. Seyedi, S. H. & Ramezanpour, M. R. The effect of a single bout of resistance exercise on serum level of myostatin and follistatin in elderly men. Cibtech J. Zool. 4, 19–26 (2015).

    Google Scholar 

  172. White, T. A. & LeBrasseur, N. K. Myostatin and sarcopenia: opportunities and challenges — a mini-review. Gerontology 60, 289–293 (2014).

    Article  CAS  PubMed  Google Scholar 

  173. McPherron, A. C. & Lee, S. J. Suppression of body fat accumulation in myostatin-deficient mice. J. Clin. Invest. 109, 595–601 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Zhang, C. et al. Inhibition of myostatin protects against diet-induced obesity by enhancing fatty acid oxidation and promoting a brown adipose phenotype in mice. Diabetologia 55, 183–193 (2012).

    Article  CAS  PubMed  Google Scholar 

  175. Dong, J. et al. Inhibition of myostatin in mice improves insulin sensitivity via irisin-mediated cross talk between muscle and adipose tissues. Int. J. Obes. 40, 434–442 (2016).

    Article  CAS  Google Scholar 

  176. Shan, T., Liang, X., Bi, P. & Kuang, S. Myostatin knockout drives browning of white adipose tissue through activating the AMPK-PGC1alpha-Fndc5 pathway in muscle. FASEB J. 27, 1981–1989 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Akpan, I. et al. The effects of a soluble activin type IIB receptor on obesity and insulin sensitivity. Int. J. Obes. 33, 1265–1273 (2009).

    Article  CAS  Google Scholar 

  178. Bernardo, B. L. et al. Postnatal PPARdelta activation and myostatin inhibition exert distinct yet complimentary effects on the metabolic profile of obese insulin-resistant mice. PLoS ONE 5, e11307 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  179. Freedland, S. J., Williams, C. D. & Masko, E. M. Adiponectin and prostate cancer mortality: to be or not to be skinny? Clin. Chem. 56, 1–3 (2010).

    Article  CAS  PubMed  Google Scholar 

  180. Mistry, T., Digby, J. E., Desai, K. M. & Randeva, H. S. Obesity and prostate cancer: a role for adipokines. Eur. Urol. 52, 46–53 (2007).

    Article  CAS  PubMed  Google Scholar 

  181. Reddy, N. L., Tan, B. K., Barber, T. M. & Randeva, H. S. Brown adipose tissue: endocrine determinants of function and therapeutic manipulation as a novel treatment strategy for obesity. BMC Obes. 1, 13 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  182. Arhire, L. I., Mihalache, L. & Covasa, M. Irisin: a hope in understanding and managing obesity and metabolic syndrome. Front. Endocrinol. 10, 524 (2019).

    Article  Google Scholar 

  183. Zhang, Y. et al. Irisin stimulates browning of white adipocytes through mitogen-activated protein kinase p38 MAP kinase and ERK MAP kinase signaling. Diabetes 63, 514–525 (2014).

    Article  CAS  PubMed  Google Scholar 

  184. Mazur-Bialy, A. I., Bilski, J., Pochec, E. & Brzozowski, T. New insight into the direct anti-inflammatory activity of a myokine irisin against proinflammatory activation of adipocytes. Implication for exercise in obesity. J. Physiol. Pharmacol. 68, 243–251 (2017).

    CAS  PubMed  Google Scholar 

  185. Kamei, N. et al. Overexpression of monocyte chemoattractant protein-1 in adipose tissues causes macrophage recruitment and insulin resistance. J. Biol. Chem. 281, 26602–26614 (2006).

    Article  CAS  PubMed  Google Scholar 

  186. Kanda, H. et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J. Clin. Invest. 116, 1494–1505 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Spiegelman, B. M. & Ginty, C. A. Fibronectin modulation of cell shape and lipogenic gene expression in 3T3-adipocytes. Cell 35, 657–666 (1983).

    Article  CAS  PubMed  Google Scholar 

  188. Liu, J. et al. Changes in integrin expression during adipocyte differentiation. Cell Metab. 2, 165–177 (2005).

    Article  PubMed  CAS  Google Scholar 

  189. Nagaraju, G. P. & Sharma, D. Anti-cancer role of SPARC, an inhibitor of adipogenesis. Cancer Treat. Rev. 37, 559–566 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Bradshaw, A. D., Graves, D. C., Motamed, K. & Sage, E. H. SPARC-null mice exhibit increased adiposity without significant differences in overall body weight. Proc. Natl Acad. Sci. USA 100, 6045–6050 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Kang, S. et al. Wnt signaling stimulates osteoblastogenesis of mesenchymal precursors by suppressing CCAAT/enhancer-binding protein alpha and peroxisome proliferator-activated receptor gamma. J. Biol. Chem. 282, 14515–14524 (2007).

    Article  CAS  PubMed  Google Scholar 

  192. Laukkanen, J. A. et al. Metabolic syndrome and the risk of prostate cancer in Finnish men: a population-based study. Cancer Epidemiol. Biomarkers Prev. 13, 1646–1650 (2004).

    Article  CAS  PubMed  Google Scholar 

  193. Gacci, M. et al. Meta-analysis of metabolic syndrome and prostate cancer. Prostate Cancer Prostatic Dis. 20, 146–155 (2017).

    Article  CAS  PubMed  Google Scholar 

  194. Saylor, P. J. & Smith, M. R. Metabolic complications of androgen deprivation therapy for prostate cancer. J. Urol. 189, S34–S42; discussion S43–44 (2013).

    Article  CAS  PubMed  Google Scholar 

  195. Caliskan, S. et al. The effect of metabolic syndrome on prostate cancer final pathology. J. Cancer Res. Ther. 15, S47–S50 (2019).

    Article  CAS  PubMed  Google Scholar 

  196. Yu, Y. R. & Ho, P. C. Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting. Clin. Exp. Immunol. 197, 153–160 (2019).

    Article  CAS  PubMed  Google Scholar 

  197. Engelhardt, J. J. et al. Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells. Cancer Cell 21, 402–417 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Gallina, G. et al. Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells. J. Clin. Invest. 116, 2777–2790 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Kuang, D. M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Kusmartsev, S., Nagaraj, S. & Gabrilovich, D. I. Tumor-associated CD8+ T cell tolerance induced by bone marrow-derived immature myeloid cells. J. Immunol. 175, 4583–4592 (2005).

    Article  CAS  PubMed  Google Scholar 

  202. Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Cascone, T. et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 27, 977–987 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Ho, P. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  205. Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Doedens, A. L. et al. Hypoxia-inducible factors enhance the effector responses of CD8+ T cells to persistent antigen. Nat. Immunol. 14, 1173–1182 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Kruijsen-Jaarsma, M., Revesz, D., Bierings, M. B., Buffart, L. M. & Takken, T. Effects of exercise on immune function in patients with cancer: a systematic review. Exer. Immunol. Rev. 19, 120–143 (2013).

    Google Scholar 

  208. Shephard, R. J. & Shek, P. N. Effects of exercise and training on natural killer cell counts and cytolytic activity: a meta-analysis. Sports Med. 28, 177–195 (1999).

    Article  CAS  PubMed  Google Scholar 

  209. Timmons, B. W. & Cieslak, T. Human natural killer cell subsets and acute exercise: a brief review. Exerc. Immunol. Rev. 14, 8–23 (2008).

    PubMed  Google Scholar 

  210. Pedersen, L. et al. Voluntary running suppresses tumor growth through epinephrine- and IL-6-dependent NK cell mobilization and redistribution. Cell Metab. 23, 554–562 (2016).

    Article  CAS  PubMed  Google Scholar 

  211. Clahsen, T. & Schaper, F. Interleukin-6 acts in the fashion of a classical chemokine on monocytic cells by inducing integrin activation, cell adhesion, actin polymerization, chemotaxis, and transmigration. J. Leukoc. Biol. 84, 1521–1529 (2008).

    Article  CAS  PubMed  Google Scholar 

  212. Fisher, D. T. et al. IL-6 trans-signaling licenses mouse and human tumor microvascular gateways for trafficking of cytotoxic T cells. J. Clin. Invest. 121, 3846–3859 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Idorn, M. & Hojman, P. Exercise-dependent regulation of NK cells in cancer protection. Trends Mol. Med. 22, 565–577 (2016).

    Article  CAS  PubMed  Google Scholar 

  214. Kaplanski, G., Marin, V., Montero-Julian, F., Mantovani, A. & Farnarier, C. IL-6: a regulator of the transition from neutrophil to monocyte recruitment during inflammation. Trends Immunol. 24, 25–29 (2003).

    Article  CAS  PubMed  Google Scholar 

  215. Madden, K. S. & Felten, D. L. Experimental basis for neural-immune interactions. Physiol. Rev. 75, 77–106 (1995).

    Article  CAS  PubMed  Google Scholar 

  216. Nagao, F., Suzui, M., Takeda, K., Yagita, H. & Okumura, K. Mobilization of NK cells by exercise: downmodulation of adhesion molecules on NK cells by catecholamines. Am. J. Physiol. Regul. Integr. Comp. Physiol. 279, R1251–R1256 (2000).

    Article  CAS  PubMed  Google Scholar 

  217. Robinson, T. O. & Schluns, K. S. The potential and promise of IL-15 in immuno-oncogenic therapies. Immunol. Lett. 190, 159–168 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Kennedy, M. K. et al. Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J. Exp. Med. 191, 771–780 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Lodolce, J. P. et al. IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9, 669–676 (1998).

    Article  CAS  PubMed  Google Scholar 

  220. Tang, F. et al. Activity of recombinant human interleukin-15 against tumor recurrence and metastasis in mice. Cell Mol. Immunol. 5, 189–196 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  221. Morris, J. C. et al. Vaccination with tumor cells expressing IL-15 and IL-15Rα inhibits murine breast and prostate cancer. Gene. Ther. 21, 393–401 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Cabral-Santos, C. et al. Inflammatory cytokines and BDNF response to high-intensity intermittent exercise: effect the exercise volume. Front. Physiol. 7, 509 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  223. Chupel, M. U. et al. Strength training decreases inflammation and increases cognition and physical fitness in older women with cognitive impairment. Front. Physiol. 8, 377 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Dorneles, G. P. et al. High intensity interval exercise decreases IL-8 and enhances the immunomodulatory cytokine interleukin-10 in lean and overweight-obese individuals. Cytokine 77, 1–9 (2016).

    Article  CAS  PubMed  Google Scholar 

  225. Ghafourian, M., Ashtary-Larky, D., Chinipardaz, R., Eskandary, N. & Mehavaran, M. Inflammatory biomarkers’ response to two different intensities of a single bout exercise among soccer players. Iran. Red. Crescent Med. J. 18, e21498 (2016).

    PubMed  PubMed Central  Google Scholar 

  226. Ouyang, W., Rutz, S., Crellin, N. K., Valdez, P. A. & Hymowitz, S. G. Regulation and functions of the IL-10 family of cytokines in inflammation and disease. Annu. Rev. Immunol. 29, 71–109 (2011).

    Article  CAS  PubMed  Google Scholar 

  227. Mannino, M. H. et al. The paradoxical role of IL-10 in immunity and cancer. Cancer Lett. 367, 103–107 (2015).

    Article  CAS  PubMed  Google Scholar 

  228. Fiorentino, D. F., Bond, M. W. & Mosmann, T. R. Two types of mouse T helper cell. IV. Th2 clones secrete a factor that inhibits cytokine production by Th1 clones. J. Exp. Med. 170, 2081–2095 (1989).

    Article  CAS  PubMed  Google Scholar 

  229. Groux, H., Bigler, M., de Vries, J. E. & Roncarolo, M. G. Inhibitory and stimulatory effects of IL-10 on human CD8+ T cells. J. Immunol. 160, 3188–3193 (1998).

    Article  CAS  PubMed  Google Scholar 

  230. MacNeil, I. A., Suda, T., Moore, K. W., Mosmann, T. R. & Zlotnik, A. IL-10, a novel growth cofactor for mature and immature T cells. J. Immunol. 145, 4167–4173 (1990).

    Article  CAS  PubMed  Google Scholar 

  231. Moore, K. W., de Waal Malefyt, R., Coffman, R. L. & O’Garra, A. Interleukin-10 and the interleukin-10 receptor. Annu. Rev. Immunol. 19, 683–765 (2001).

    Article  CAS  PubMed  Google Scholar 

  232. Groux, H. et al. A transgenic model to analyze the immunoregulatory role of IL-10 secreted by antigen-presenting cells. J. Immunol. 162, 1723–1729 (1999).

    Article  CAS  PubMed  Google Scholar 

  233. Berman, R. M. et al. Systemic administration of cellular IL-10 induces an effective, specific, and long-lived immune response against established tumors in mice. J. Immunol. 157, 231–238 (1996).

    Article  CAS  PubMed  Google Scholar 

  234. Fujii, S., Shimizu, K., Shimizu, T. & Lotze, M. T. Interleukin-10 promotes the maintenance of antitumor CD8+ T-cell effector function in situ. Blood 98, 2143–2151 (2001).

    Article  CAS  PubMed  Google Scholar 

  235. Smith, M. R. et al. Changes in body composition during androgen deprivation therapy for prostate cancer. J. Clin. Endocrinol. Metab. 87, 599–603 (2002).

    Article  CAS  PubMed  Google Scholar 

  236. Schmitz, K. H. et al. Exercise is medicine in oncology: engaging clinicians to help patients move through cancer. CA Cancer J. Clin. 69, 468–484 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  237. Hojan, K. et al. Physical exercise for functional capacity, blood immune function, fatigue, and quality of life in high-risk prostate cancer patients during radiotherapy: a prospective, randomized clinical study. Eur. J. Phys. Rehabil. Med. 52, 489–501 (2016).

    PubMed  Google Scholar 

  238. Park, J. et al. Effects of progressive resistance training on post-surgery incontinence in men with prostate cancer. J. Clin. Med. 7, 292 (2018).

    Article  PubMed Central  Google Scholar 

  239. Newton, R. U. et al. Intense exercise for survival among men with metastatic castrate-resistant prostate cancer (INTERVAL-GAP4): a multicentre, randomised, controlled phase III study protocol. BMJ Open 8, e022899 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  240. Campbell, K. L. et al. Exercise guidelines for cancer survivors: consensus statement from international multidisciplinary roundtable. Med. Sci. Sports Exerc. 51, 2375–2390 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  241. Ajuwon, K. M. & Spurlock, M. E. Direct regulation of lipolysis by interleukin-15 in primary pig adipocytes. Am. J. Physiol. Regul. Integr. Comp. Physiol. 287, R608–R611 (2004).

    Article  CAS  PubMed  Google Scholar 

  242. Gao, S. et al. Effects and molecular mechanism of GST-irisin on lipolysis and autocrine function in 3T3-L1 adipocytes. PLoS ONE 11, e0147480 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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Authors and Affiliations

  1. Exercise Medicine Research Institute, Edith Cowan University, Joondalup, WA, Australia

    Jin-Soo Kim, Daniel A. Galvão, Robert U. Newton & Dennis R. Taaffe

  2. School of Medical and Health Sciences, Edith Cowan University, Joondalup, WA, Australia

    Jin-Soo Kim, Daniel A. Galvão, Robert U. Newton, Elin Gray & Dennis R. Taaffe

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  1. Jin-Soo Kim
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  2. Daniel A. Galvão
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  3. Robert U. Newton
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Contributions

D.A.G., J.-S.K., R.U.N., E.G. and D.R.T. researched data for the article, J.-S.K. wrote the article, D.A.G., J.-S.K., R.U.N., E.G. and D.R.T. made a substantial contribution to discussion of the content of the article and D.A.G., J.-S.K., R.U.N., E.G. and D.R.T. reviewed and edited the manuscript prior to submission.

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Correspondence to Daniel A. Galvão.

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Glossary

Secretomes

Proteins that are expressed and secreted by tissues into the extracellular space.

Metabolic disease

A disease or disorder that disrupts the normal process of energy conversion at a cellular level.

Crosstalk

Organ-to-organ, organ-to-system and organ-to-body interactions.

Moderate-intensity physical activity

Physical activity requiring moderate effort (e.g. 55 to <70% maximum heart rate).

Epithelial–mesenchymal transition

(EMT). The process of epithelial cells losing cell polarity and gaining migratory, invasive and mesenchymal properties.

Resistance exercise

Strength training, exercises requiring muscle contraction against an external resistance.

Hippo tumour-suppressor pathway

The cellular pathway for cell growth; restricts tissue enlargement and organ size by limiting cell growth.

IGF1 axis

A complex system involving insulin-like growth factor 1 (IGF1) and insulin-like growth factor-binding proteins (IGFBPs) that cells use to communicate with the physiological environment.

Proliferating cell nuclear antigen

(PCNA). A nuclear protein that has a key role in DNA replication in cells; used as a marker of cell proliferation.

p53 protein

Also known as TP53, which has a role as a tumour-suppressing protein.

Metallopeptidases

Protease enzymes that involve a metal, such as zinc or calcium, during catalytic responses.

Matricellular proteins

Non-structural proteins presented in the extracellular matrix.

Cyclin D1

A cell cycle regulatory protein required for cell-cycle progression.

Caspase

A family of protease enzymes that regulate programmed cell death.

Fibronectin type III domain-containing 5

(FNDC5). A precursor of irisin; FNDC5 is upregulated by exercise and cleaved to irisin through a post-translational process.

Mitochondrial uncoupling portion

(UCP1). An integral membrane protein found in the inner membrane of mitochondria that induces non-shivering thermogenesis.

E-cadherin

A cell-to-cell adhesion protein that is downregulated during epithelial–mesenchymal transition.

LY294002

A potential phosphoinositide-3 kinase (PI3K) inhibitor, which induces AKT phosphorylation.

Phosphatase and tensin homologue

(PTEN). A cell-cycle regulator, preventing cell growth and division.

C2C12 cell

Mouse myoblast cell line.

Adiponectin

An adipose tissue produced and secreted protein regulating glucose levels and fatty acid breakdown.

Integrins

Cell-to-cell and cell-to-extracellular matrix adhesion transmembrane receptors.

Anaerobic glycolysis

The process of glucose transformation to lactate without oxygen.

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Kim, JS., Galvão, D.A., Newton, R.U. et al. Exercise-induced myokines and their effect on prostate cancer. Nat Rev Urol 18, 519–542 (2021). https://doi.org/10.1038/s41585-021-00476-y

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