Epidemiological research suggests that regular physical activity confers beneficial effects that mediate an anti-tumor response and may reduce cancer recurrence. It is unclear what amount of physical activity is necessary to exert such a protective effect and what mechanisms are involved. We investigated the effects of voluntary wheel running on tumor progression and cytokine gene expression in the transgenic polyoma middle T oncoprotein (PyMT) mouse model of invasive breast cancer. Runners showed significantly reduced tumor sizes compared with non-runners after 3 weeks of running (p≤0.01), and the greater the running distance the smaller the tumor size (Pearson's r = ？0.61, p≤0.04, R2 = 0.38). Mice running greater than 150 km per week had a significantly attenuated tumor size compared with non-runners (p≤0.05). Adipose tissue mass was inversely correlated with tumor size in runners (Pearson's r = ？0.77, p = 0.014) but not non-runners. Gene expression of CCL22, a cytokine associated with recruitment of immunosuppressive T regulatory cells, was decreased in tumors of runners compared to non-runners (p≤0.005). No differences in tumor burden or metastatic burden were observed between runners and non-runners after ten weeks of running when the study was completed. We conclude that voluntary wheel running in PyMT mice correlates with an attenuation in tumor progression early during the course of invasive breast cancer. This effect is absent in the later stages of overwhelming tumor burden even though cytokine signaling for immunosuppressive regulatory T cells was down regulated. These observations suggest that the initiation of moderate exercise training for adjunctive therapeutic benefit early in the course of invasive breast cancer should be considered for further investigation.
References
[1]
Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA (2005) Physical activity and survival after breast cancer diagnosis. JAMA 293: 2479–2486.
[2]
Irwin ML, McTiernan A, Manson JE, Thomson CA, Sternfeld B, et al. (2011) Physical activity and survival in postmenopausal women with breast cancer: results from the women's health initiative. Cancer Prev Res 4: 522–529.
[3]
Chen X, Lu W, Zheng W, Gu K, Matthews CE, et al. (2011) Exercise after diagnosis of breast cancer in association with survival. Cancer Prev Res 4: 1409–1418.
[4]
Murphy EA, Davis JM, Barrileaux TL, McClellan JL, Steiner JL, et al. (2011) Benefits of exercise training on breast cancer progression and inflammation in C3(1) SV40 Tag mice. Cytokine 55: 274–279.
[5]
Steiner JL, Davis JM, McClellan JL, Enos RT, Murphy EA. (2013) Effects of voluntary exercise on tumorigenesis in the C3(1)/SV40Tag transgenic mouse model of breast cancer. Int J Oncol DOI:10.3892/ijo.2013.1827
[6]
Colbert LH, Westerlind KC, Perkins SN, Haines DC, Berrigan D, et al. (2009) Exercise effects on tumorigenesis in a p53-deficient mouse model of breast cancer. Med Sci Sports Exerc 8: 1597–1605.
[7]
Balkwill FR, Mantovani A (2012) Cancer-related inflammation: common themes and therapeutic opportunities. Sem Cancer Biol 22: 33–40.
[8]
Sica A, Allavena P, Mantovani A (2008) Cancer related inflammation: the macrophage connection. Cancer Lett 264: 204–215.
[9]
Watkins SK, Egilmez NK, Suttles J, Stout RD (2007) IL-12 rapidly alters the functional profile of tumor-associated and tumor-infiltrating macrophages in vitro and in vivo. J Immunol 178: 1357–1362.
[10]
Goh J, Kirk EA, Lee SX, Ladiges WC (2012) Exercise, physical activity and breast cancer: the role of tumor-associated macrophages. Exerc Immunol Rev 18: 157–175.
[11]
Boimel PJ, Smirnova T, Zhou ZN, Wyckoff J, Park H, et al. (2012) Contribution of CXCL12 secretion to invasion of breast cancer cells. Breast Cancer Res 14: R23.
[12]
Muller A, Homey B, Soto H, Ge N, Catron D, et al. (2001) Involvement of chemokine receptors in breast cancer metastasis. Nature 410: 50–56.
[13]
De Palma M, Lewis CE (2013) Macrophage regulation of tumor responses to anticancer therapies. Cancer Cell 23: 277–286.
[14]
Yan M, Jene N, Byrne D, Millar EK, O'Toole SA, et al. (2011) Recruitment of regulatory T cells is correlated with poor prognosis in basal-like breast cancers. Breast Cancer Res 13: R47.
[15]
Menetrier-Caux C, Faget J, Biota C, Gobert M, Blay JY, et al. (2012) Innate immune recognition of breast tumor cells mediates CCL22 secretion favoring Treg recruitment within tumor environment. OncoImmunol 1: 759–761.
[16]
Ohara M, Yamaguchi Y, Matsuura K, Murakami S, Arihiro K, et al. (2009) Possible involvement of regulatory T cells in tumor onset and progression in primary breast cancer. Cancer Immunol Immunother 58: 441–447.
[17]
Lin EY, Jones JG, Li P, Zhu L, Whitney KD, et al. (2003) Progression to malignancy in the Polyoma Middle T Oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 163: 2113–2126.
[18]
Green JE, Shibata MA, Yoshidome K, Liu ML, Jorcyk C, et al. (2000) The C3(1)/SV40 T-antigen transgenic mouse model of mammary cancer: ductal epithelial cell targeting with multistage progression to carcinoma. Oncogene 19: 1020–1027.
[19]
Guy CT, Cardiff RD, Muller WJ (1992) Induction of mammary tumors by expression of polyomavirus middle T oncogene- a transgenic mouse model for metastatic disease. Mol Cell Biol 12: 954–961.
[20]
Goh J, Enns L, Fatemie S, Hopkins H, Morton J, et al. (2011) Mitochondrial targeted catalase suppresses invasive breast cancer in mice. BMC Cancer 11: 191.
[21]
Goh J, Ladiges W (2013) A novel long term short interval physical activity regime improves body composition in mice. BMC Res Notes 6: 66.
[22]
Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, et al. (2011) HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PIGF. Cancer Cell 19: 31–44.
[23]
Ruffell B, Affara NI, Coussens LM (2012) Differential macrophage programming in the tumor microenvironment. Trends Immunol 33: 119–126.
[24]
Hattermann K, Meintlein R. (2012) An infernal trio: the chemokine CXCL12 and its receptors CXCR4 and CXCR7 in tumor biology. Ann Anat12 : doi:pii: S0940-9602(12)00170-7. 10.1016/j.aanat.2012.10.013.
[25]
Chen B (2011) Lipid mobilization in cachexia: mechanisms and mediators. Curr Op Support Palliat Care 5: 356–360.
[26]
Allen DL, Harrison BC, Maass A, Bell ML, Byrnes WC, et al. (2001) Cardiac and skeletal muscle adaptations to voluntary wheel running in the mouse. J Appl Physiol 90: 1900–1908.
[27]
Faget J, Biota C, Bachelot T, Gobert M, Treilleux I, et al. (2011) Early detection of tumor cells by innate immune cells lead to T(Reg) recruitment through CCl22 production by tumor cells. Cancer Res 71: 6143–6152.
[28]
Movahedi K, Laoui D, Gysemans C, Baeten M, Stange G, et al. (2010) Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6c (high) monocytes. Cancer Res 70: 5728–5739.
[29]
Abdalla DR, Murta EFC, Michelin MA (2013) The influence of physical activity on the profile of immune response cells and cytokine synthesis in mice with experimental breast tumors induced by 7,12-dimethylbenzanthracene. Eur J Cancer Prev 22: 251–258.
[30]
Hampas SS, Nesline M, Wallace PK, Odunsi K, Furlani N, et al.. (2012) Predictors of immunosuppressive regulatory T lymphocytes in healthy women. J cancer Epidemiol 2012: DOI: 10.1155/2012/191090.
[31]
Biswas SK, Sica A, Lewis CE (2008) Plasticity of macrophage function during tumor progression: regulation by distinct molecular mechanisms. J Immunol 180: 2011–2017.
[32]
Burger JA, Kipps TJ (2006) CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood 107: 1761–1767.
[33]
Thompson HJ, Ronan AM, Ritaco KA, Tagliaferro AR, Meeker LD (1988) Effect of exercise on the induction of mammary carcinogenesis. Cancer Res 48: 2720–2723.
[34]
Thompson HJ, Ronan AM, Ritacco KA, Tagliaferro AR (1989) Effect of type and amount of dietary fat on the enhancement of rat mammary tumorigenesis by exercise. Cancer Res 49: 1904–1908.
[35]
Thompson HJ, Westerlind KC, Snedden J, Briggs S, Singh M (1995) Exercise intensity dependent inhibition of 1-methyl-1 nitrosourea induced mammary carcinogenesis in female F-344 rats. Carcinogenesis 16: 1783–1786.
[36]
Hoffman-Goetz L (2003) Physical activity and cancer prevention: animal-tumor models. Med Sci Sports Exerc 35: 1828–1833.
[37]
Pulaski BA, Ostrand-Rosenberg S (2000) Mouse 4T1 breast tumor model. Curr Protoc Immunol 20(2): 1–16.
[38]
Jones LW, Eves ND, Courneya KS, Chiu BK, Baracos Ve, et al. (2005) Effects of exercise training on antitumor efficacy of doxorubicin in MDA-MB-231 breast cancer xenografts. Clin Cancer Res 11: 6695–6698.
[39]
Jones LW, Viglianti BL, Tashjian JA, Kothadia SM, Keir ST, et al. (2009) Effect of aerobic exercise on tumor physiology in an animal model of human breast cancer. J Appl Physiol 108: 343–348.
