Moderate swimming suppressed the growth and metastasis of the transplanted liver cancer in mice model: with reference to nervous system

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Abstract

Physical activity has been shown to suppress tumor initiation and progression. The neurotransmitter dopamine (DA) is closely related to movement and exhibits antitumor properties. However, whether the suppressive effects of physical activity on tumors was mediated by the nervous system via increased DA level remains unknowns. Here we show that regular moderate swimming (8 min/day, 9 weeks) raised DA levels in the prefrontal cortex, serum and tumor tissue, suppressed growth, reduced lung metastasis of transplanted liver cancer, and prolonged survival in a C57BL/6 mouse model, while overload swimming (16 and 32 min/day, 9 weeks) had the opposite effect. In nude mice that were orthotopically implanted with human liver cancer cell lines, DA treatment significantly suppressed growth and lung metastasis by acting on the D2 receptor (DR2). Furthermore, DR2 blockade attenuated the suppressive effect of moderate swimming on liver cancer. Both moderate swimming and DA treatment suppressed the transforming growth factor-beta (TGF-β1)-induced epithelial–mesenchymal transition of transplanted liver cancer cells. At the molecular level, DR2 signaling inhibited extracellular signal-regulated kinase phosphorylation and expression of TGF-β1 in vitro. Together, these findings demonstrated a novel mechanism by which the moderate exercise suppressed liver cancer through boosting DR2 activity, while overload exercise had the opposite effect, highlighting the possible importance of the dopaminergic system in tumor growth and metastasis of liver cancer.

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References

  1. 1

    Tang ZY, Ye SL, Liu YK, Qin LX, Sun HC, Ye QH et al. A decade's studies on metastasis of hepatocellular carcinoma. J Cancer Res Clin Oncol 2004; 130: 187–196.

  2. 2

    Wan D, Gong Y, Qin W, Zhang P, Li J, Wei L et al. Large-scale cDNA transfection screening for genes related to cancer development and progression. Proc Natl Acad Sci USA 2004; 101: 15724–15729.

  3. 3

    Tang ZY . Fighting against cancer by integrative medicine. Chin J Integr Med 2012; 18: 323–324.

  4. 4

    WHO Global Recommendations on Physical Activity for Health. World Health Organization: Geneva, 2010, p 10.

  5. 5

    Heinen MM, Verhage BA, Goldbohm RA, Lumey LH, van den Brandt PA . Physical activity, energy restriction, and the risk of pancreatic cancer: a prospective study in the Netherlands. Am J Clin Nutr 2011; 94: 1314–1323.

  6. 6

    Friedenreich CM, Woolcott CG, McTiernan A, Ballard-Barbash R, Brant RF, Stanczyk FZ et al. Alberta physical activity and breast cancer prevention trial: sex hormone changes in a year-long exercise intervention among postmenopausal women. J Clin Oncol 2010; 28: 1458–1466.

  7. 7

    Ballard-Barbash R, Friedenreich CM, Courneya KS, Siddiqi SM, McTiernan A, Alfano CM . Physical activity, biomarkers, and disease outcomes in cancer survivors: a systematic review. J Natl Cancer Inst 2012; 104: 815–840.

  8. 8

    Giovannucci EL . Physical activity as a standard cancer treatment. J Natl Cancer Inst 2012; 104: 797–799.

  9. 9

    Hoglinger GU, Rizk P, Muriel MP, Duyckaerts C, Oertel WH, Caille I et al. Dopamine depletion impairs precursor cell proliferation in Parkinson disease. Nat Neurosci 2004; 7: 726–735.

  10. 10

    Klaissle P, Lesemann A, Huehnchen P, Hermann A, Storch A, Steiner B . Physical activity and environmental enrichment regulate the generation of neural precursors in the adult mouse substantia nigra in a dopamine-dependent manner. BMC Neurosci 2012; 13: 132.

  11. 11

    He SB, Tang WG, Tang WJ, Kao XL, Zhang CG, Wong XT . Exercise intervention may prevent depression. Int J Sports Med 2012; 33: 525–530.

  12. 12

    Missale C, Nash SR, Robinson SW, Jaber M, Caron MG . Dopamine receptors: from structure to function. Physiol Rev 1998; 78: 189–225.

  13. 13

    Wise RA . Dopamine and reward: the anhedonia hypothesis 30 years on. Neurotox Res 2008; 14: 169–183.

  14. 14

    Moreno-Smith M, Lu C, Shahzad MM, Pena GN, Allen JK, Stone RL et al. Dopamine blocks stress-mediated ovarian carcinoma growth. Clin Cancer Res 2011; 17: 3649–3659.

  15. 15

    Ishibashi M, Fujisawa M, Furue H, Maeda Y, Fukayama M, Yamaji T . Inhibition of growth of human small cell lung cancer by bromocriptine. Cancer Res 1994; 54: 3442–3446.

  16. 16

    Ganguly S, Basu B, Shome S, Jadhav T, Roy S, Majumdar J et al. Dopamine, by acting through its D2 receptor, inhibits insulin-like growth factor-I (IGF-I)-induced gastric cancer cell proliferation via up-regulation of Kruppel-like factor 4 through down-regulation of IGF-IR and AKT phosphorylation. Am J Pathol 2010; 177: 2701–2707.

  17. 17

    Chakroborty D, Sarkar C, Mitra RB, Banerjee S, Dasgupta PS, Basu S . Depleted dopamine in gastric cancer tissues: dopamine treatment retards growth of gastric cancer by inhibiting angiogenesis. Clin Cancer Res 2004; 10: 4349–4356.

  18. 18

    Chakroborty D, Chowdhury UR, Sarkar C, Baral R, Dasgupta PS, Basu S . Dopamine regulates endothelial progenitor cell mobilization from mouse bone marrow in tumor vascularization. J Clin Invest 2008; 118: 1380–1389.

  19. 19

    Pickett M, Mock V, Ropka ME, Cameron L, Coleman M, Podewils L . Adherence to moderate-intensity exercise during breast cancer therapy. Cancer Pract 2002; 10: 284–292.

  20. 20

    Moderate exercise may reduce ovarian cancer risk. Mayo Clin Womens Healthsource 2006; 10: 3.

  21. 21

    Murphy EA, Davis JM, Brown AS, Carmichael MD, Mayer EP, Ghaffar A . Effects of moderate exercise and oat beta-glucan on lung tumor metastases and macrophage antitumor cytotoxicity. J Appl Physiol (1985) 2004; 97: 955–959.

  22. 22

    Thompson HJ . Effect of exercise intensity and duration on the induction of mammary carcinogenesis. Cancer Res 1994; 54: 1960s–1963s.

  23. 23

    Wang J, Song H, Tang X, Yang Y, Vieira VJ, Niu Y et al. Effect of exercise training intensity on murine T-regulatory cells and vaccination response. Scand J Med Sci Sports 2012; 22: 643–652.

  24. 24

    Demarzo MM, Garcia SB . Exhaustive physical exercise increases the number of colonic preneoplastic lesions in untrained rats treated with a chemical carcinogen. Cancer Lett 2004; 216: 31–34.

  25. 25

    Tian F, DaCosta Byfield S, Parks WT, Yoo S, Felici A, Tang B et al. Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Res 2003; 63: 8284–8292.

  26. 26

    Massague J . TGFbeta in cancer. Cell 2008; 134: 215–230.

  27. 27

    Lee J, Roh KB, Kim SC, Park D . Soy peptide-induced stem cell proliferation: involvement of ERK and TGF-beta1. J Nutr Biochem 2012; 23: 1341–1351.

  28. 28

    Mulder KM . Role of Ras and Mapks in TGFbeta signaling. Cytokine Growth Factor Rev 2000; 11: 23–35.

  29. 29

    Aguirre-Ghiso JA, Estrada Y, Liu D, Ossowski L . ERK (MAPK) activity as a determinant of tumor growth and dormancy; regulation by p38(SAPK). Cancer Res 2003; 63: 1684–1695.

  30. 30

    Peng H, Dara L, Li TW, Zheng Y, Yang H, Tomasi ML et al. MAT2B-GIT1 interplay activates MEK1/ERK 1 and 2 to induce growth in human liver and colon cancer. Hepatology 2013; 57: 2299–2313.

  31. 31

    Almeida PW, Gomes-Filho A, Ferreira AJ, Rodrigues CE, Dias-Peixoto MF, Russo RC et al. Swim training suppresses tumor growth in mice. J Appl Physiol (1985) 2009; 107: 261–265.

  32. 32

    Sasvari M, Taylor AW, Gaal D, Radak Z . The effect of regular exercise on development of sarcoma tumor and oxidative damage in mice liver. J Sports Sci Med 2011; 10: 93–96.

  33. 33

    Gray JR, Braver TS, Raichle ME . Integration of emotion and cognition in the lateral prefrontal cortex. Proc Natl Acad Sci USA 2002; 99: 4115–4120.

  34. 34

    Herz DM, Siebner HR, Hulme OJ, Florin E, Christensen MS, Timmermann L . Levodopa reinstates connectivity from prefrontal to premotor cortex during externally paced movement in Parkinson's disease. Neuroimage 2014; 90: 15–23.

  35. 35

    Muller HK, Wegener G, Popoli M, Elfving B . Differential expression of synaptic proteins after chronic restraint stress in rat prefrontal cortex and hippocampus. Brain Res 2011; 1385: 26–37.

  36. 36

    Saez Mdel C, Barriga C, Garcia JJ, Rodriguez AB, Ortega E . Exercise-induced stress enhances mammary tumor growth in rats: beneficial effect of the hormone melatonin. Mol Cell Biochem 2007; 294: 19–24.

  37. 37

    Goldacre MJ, Kurina LM, Wotton CJ, Yeates D, Seagroat V . Schizophrenia and cancer: an epidemiological study. Br J Psychiatry 2005; 187: 334–338.

  38. 38

    Pacheco R, Prado CE, Barrientos MJ, Bernales S . Role of dopamine in the physiology of T-cells and dendritic cells. J Neuroimmunol 2009; 216: 8–19.

  39. 39

    Padua D, Zhang XH, Wang Q, Nadal C, Gerald WL, Gomis RR et al. TGFbeta primes breast tumors for lung metastasis seeding through angiopoietin-like 4. Cell 2008; 133: 66–77.

  40. 40

    Li Y, Tang Y, Ye L, Liu B, Liu K, Chen J et al. Establishment of a hepatocellular carcinoma cell line with unique metastatic characteristics through in vivo selection and screening for metastasis-related genes through cDNA microarray. J Cancer Res Clin Oncol 2003; 129: 43–51.

  41. 41

    Zhang QB, Sun HC, Zhang KZ, Jia QA, Bu Y, Wang M et al. Suppression of natural killer cells by sorafenib contributes to prometastatic effects in hepatocellular carcinoma. PLoS One 2013; 8: e55945.

  42. 42

    Zhang W, Sun HC, Wang WQ, Zhang QB, Zhuang PY, Xiong YQ et al. Sorafenib down-regulates expression of HTATIP2 to promote invasiveness and metastasis of orthotopic hepatocellular carcinoma tumors in mice. Gastroenterology 2012; 143: 1641–1649.e5.

  43. 43

    Zhang W, Zhu XD, Sun HC, Xiong YQ, Zhuang PY, Xu HX et al. Depletion of tumor-associated macrophages enhances the effect of sorafenib in metastatic liver cancer models by antimetastatic and antiangiogenic effects. Clin Cancer Res 2010; 16: 3420–3430.

  44. 44

    Jia QA, Wang ZM, Ren ZG, Bu Y, Xie XY, Wang YH et al. Herbal compound "Songyou Yin" attenuates hepatoma cell invasiveness and metastasis through downregulation of cytokines secreted by activated hepatic stellate cells. BMC Complement Altern Med 2013; 13: 89.

  45. 45

    Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS et al. Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol 2007; 25: 2586–2593.

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Acknowledgements

This project was supported by the National Natural Science Foundation of China (grant number: 81372314), the National Key Project for Infectious Diseases of China (2012ZX10002012-004) and the Shanghai Natural Science Fund for Youth Scholars (12ZR1442300). The authors appreciate the instruction in writing of the manuscript provided by Professor Hong Tu and Assistant Professor Yu Gan (State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, China).

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Correspondence to Z-Y Tang.

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Zhang, Q., Zhang, B., Zhang, K. et al. Moderate swimming suppressed the growth and metastasis of the transplanted liver cancer in mice model: with reference to nervous system. Oncogene 35, 4122–4131 (2016). https://doi.org/10.1038/onc.2015.484

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