Sex differences in the MB49 syngeneic, murine model of bladder cancer
Main Article Content
urinary bladder neoplasms, chorionic gonadotropin, testosterone, MB49, sex differences
Objective: The MB49 syngeneic, murine model of bladder cancer has been widely used for more than 35 years. In humans, bladder cancer is one third as prevalent in women as in men, with a trend toward lower prevalence in parous compared to nulliparous women. Our objective was to determine if the MB49 bladder cancer model reproduces the sex differences observed in humans, and to determine its sensitivity to testosterone and the pregnancy hormone, human chorionic gonadotropin (hCG).
Methods: Male and female C57BL/6 mice were implanted with MB49 murine bladder cancer cells, and observed for tumor growth. MB49 dose responses to hCG and dihydrotestosterone were determined in vitro.
Results: MB49 tumor growth was significantly greater in male mice than female mice. Pregnancy did not affect MB49 tumor growth in female mice. MB49 cells did not proliferate in response to hCG in vitro and the functional receptor for gonadotropins was absent. Dihydrotestosterone strongly stimulated growth of MB49 cells in vitro.
Conclusions: The MB49 murine model of bladder cancer reproduced some aspects of the sex differences observed in humans. Our results suggest that testosterone may stimulate MB49 cell proliferation, which may explain the more rapid MB49 tumor growth observed in male mice.
2. P. Hartge, E.B. Harvey, W.M. Linehan, et al., "Unexplained excess risk of bladder cancer in men," Journal of the National Cancer Institute, vol. 82, no.20, pp. 1636-1640, 1990.
3. J.E. Castelao, J.M. Yuan, P.L. Skipper, et al.,, "Gender- and smoking-related bladder cancer risk," Journal of the National Cancer Institute, vol. 93, no.7, pp. 538-545, 2001.
4. M. McGrath, D.S. Michaud, I. De Vivo, "Hormonal and reproductive factors and the risk of bladder cancer in women," American journal of epidemiology, vol. 163, no.3, pp. 236-244, 2006.
5. S.E. Daugherty, J.V. Lacey, Jr., R.M. Pfeiffer, et al.,, "Reproductive factors and menopausal hormone therapy and bladder cancer risk in the NIH-AARP diet and health study," International journal of cancer. Journal international du cancer, vol. 133, no.2, pp. 462-472, 2013.
6. I.C. Summerhayes and L.M. Franks. "Effects of donor age on neoplastic transformation of adult mouse bladder epithelium in vitro." J Natl Cancer Inst 1979; 62:1017e1023.
7. V.T. Fabris, C. Lodillinsky, M.B. Pampena, D. Belgorosky, C. Lanari, A.M. Eijan. “Cytogenetic characterization of the murine bladder cancer model MB49 and the derived invasive line MB49-I” Cancer Genetics 205 (2012) 168-176.
8. A. Bohle, A. Jurczok, P. Ardelt, et al.,"Inhibition of bladder carcinoma cell adhesion by oligopeptide combinations in vitro and in vivo," The Journal of urology, vol. 167, no.1, pp. 357-363, 2002.
9. M.R. Rossi, J.R. Masters, S. Park, J.H. Todd, S.H. Garrett, M.A. Sens. "The immortalized UROtsa cell line as a potential cell culture model of human urothelium." Environ Health Perspect. 2001;109:801–808.
10. M.M. Tomayko, C.P. Reynolds, "Determination of subcutaneous tumor size in athymic (nude) mice," Cancer chemotherapy and pharmacology, vol. 24, no.3, pp. 148-154, 1989.
11. G.A. Maston, M. Ruvolo, "Chorionic gonadotropin has a recent origin within primates and an evolutionary history of selection," Molecular biology and evolution, vol. 19, no.3, pp. 320-335, 2002.
12. A. Zaravinos, G.I. Lambrou, I. Boulalas, et al.,, "Identification of common differentially expressed genes in urinary bladder cancer," PloS one, vol. 6, no.4, pp. e18135, 2011.
13. G.J. Vergara, M.H. Irwin, R.J. Moffatt, et al., "In vitro fertilization in mice: Strain differences in response to superovulation protocols and effect of cumulus cell removal," Theriogenology, vol. 47, no.6, pp. 1245-1252, 1997.
14. X.N. Wang, G.S. Greenwald, "Human chorionic gonadotropin or human recombinant follicle-stimulating hormone (fsh)-induced ovulation and subsequent fertilization and early embryo development in hypophysectomized fsh-primed mice," Endocrinology, vol. 132, no.5, pp. 2009-2016, 1993.
15. D.J. Gillott, R.K. Iles, T. Chard, "The effects of beta-human chorionic gonadotrophin on the in vitro growth of bladder cancer cell lines," British journal of cancer, vol. 73, no.3, pp. 323-326, 1996.
16. L.A. Cole, S. Butler, "Hyperglycosylated hcg, hcgbeta and hyperglycosylated hcgbeta: Interchangeable cancer promoters," Molecular and cellular endocrinology, vol. 349, no.2, pp. 232-238, 2012.
17. P.M. Apaja, J.T. Tuusa, E.M. Pietila, et al., "Luteinizing hormone receptor ectodomain splice variant misroutes the full-length receptor into a subcompartment of the endoplasmic reticulum," Molecular biology of the cell, vol. 17, no.5, pp. 2243-2255, 2006.
18. A.E. Chambers, P.F. Stanley, H. Randeva, et al., "Microvesicle-mediated release of soluble lh/hcg receptor (lhcgr) from transfected cells and placenta explants," Reproductive biology and endocrinology : RB&E, vol. 9, no., pp. 64, 2011.
19. A.M. Johnson, M.J. O'Connell, E.M. Messing, et al.,"Decreased bladder cancer growth in parous mice," Urology, vol. 72, no.3, pp. 470-473, 2008.
20. J.S. Bertram, A.W. Craig, "Specific induction of bladder cancer in mice by butyl-(4-hydroxybutyl)-nitrosamine and the effects of hormonal modifications on the sex difference in response," European journal of cancer, vol. 8, no.6, pp. 587-594, 1972.
21. H. Miyamoto, Z. Yang, Y.T. Chen, et al., "Promotion of bladder cancer development and progression by androgen receptor signals," Journal of the National Cancer Institute, vol. 99, no.7, pp. 558-568, 2007.
22. K. Izumi, M. taguri, H. Miyamoto, Y. Hara, T. Kishida, K. Chiba, T. Murali, K. Hirai, K. Suzuki, K. Fujinami, T. Ueki, K. Udagawa, K. Kitami, M. Moriyama, Y. Myoshi, F. Tsuchiya, I. Ikeda, K. Kobayashi, M. Sato, S. Morita, K. Noguchi, and H. Uemura. "Androgen deprivation therapy prevents bladder cancer recurrence." Oncotarget, 5(24):12665-74, 2014.
23. K. Dietrich, E. Demidenko, A. Schned, et al., "Parity, early menopause and the incidence of bladder cancer in women: A case-control study and meta-analysis," European journal of cancer, vol. 47, no.4, pp. 592-599, 2011.
24. M.M. Cantwell, J.V. Lacey, Jr., C. Schairer, et al., "Reproductive factors, exogenous hormone use and bladder cancer risk in a prospective study," International journal of cancer. Journal international du cancer, vol. 119, no.10, pp. 2398-2401, 2006.
25. C.E. Weibull, S. Eloranta, D. Altman, et al., "Childbearing and the risk of bladder cancer: A nationwide population-based cohort study," European urology, vol. 63, no.4, pp. 733-738, 2013.
26. C.A. Davis-Dao, K.D. Henderson, J. Sullivan-Halley, et al.,, "Lower risk in parous women suggests that hormonal factors are important in bladder cancer etiology," Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, vol. 20, no.6, pp. 1156-1170, 2011.
27. D. Li, X. Wen, L. Ghali, et al., "Hcg beta expression by cervical squamous carcinoma--in vivo histological association with tumour invasion and apoptosis," Histopathology, vol. 53, no.2, pp. 147-155, 2008.
28. T. Shah, R. Srirajaskanthan, M. Bhogal, et al., "Alpha-fetoprotein and human chorionic gonadotrophin-beta as prognostic markers in neuroendocrine tumour patients," British journal of cancer, vol. 99, no.1, pp. 72-77, 2008.
29. M.T. Sheaff, J.E. Martin, D.F. Badenoch, et al., "Beta hcg as a prognostic marker in adenocarcinoma of the prostate," Journal of clinical pathology, vol. 49, no.4, pp. 329-332, 1996.
30. K. Hotakainen, S. Lintula, R. Jarvinen, et al., "Overexpression of human chorionic gonadotropin beta genes 3, 5 and 8 in tumor tissue and urinary cells of bladder cancer patients," Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine, vol. 28, no.1, pp. 52-56, 2007.
31. S. GoriS. Porrozzi, F. Roila, et al., "Germ cell tumours of the testis," Critical reviews in oncology/hematology, vol. 53, no.2, pp. 141-164, 2005.
32. A. Kuorelahti, S. Rulli, I. Huhtaniemi, et al.,, "Human chorionic gonadotropin (hcg) up-regulates wnt5b and wnt7b in the mammary gland, and hcgbeta transgenic female mice present with mammary gland tumors exhibiting characteristics of the wnt/beta-catenin pathway activation," Endocrinology, vol. 148, no.8, pp. 3694-3703, 2007.
33. M. Zygmunt, F. Herr, S. Keller-Schoenwetter, et al., "Characterization of human chorionic gonadotropin as a novel angiogenic factor," The Journal of clinical endocrinology and metabolism, vol. 87, no.11, pp. 5290-5296, 2002.
34. R.M. Michel, J.L. Aguilar, O. Arrieta, "Human chorionic gonadotropin as an angiogenic factor in breast cancer during pregnancy," Medical hypotheses, vol. 68, no.5, pp. 1035-1040, 2007.