Molecular Credentialing of Rodent Bladder Carcinogenesis Models 1

Department of Public Health Sciences, Division of Biostatistics, University of Virginia School of Medicine, Charlottesville, VA 22908-0717, USA.
Neoplasia (New York, N.Y.) (Impact Factor: 5.4). 09/2008; 10(8):838-46. DOI: 10.1593/neo.08432
Source: PubMed

ABSTRACT Cancer of the urinary bladder is often a result of exposure to chemical carcinogens. Models of this disease have been developed by exposing rodents to N-butyl-N-(4-hydroxybutyl)-nitrosamine (OH-BBN). The resultant tumors are histologically similar to human disease, but little is known about genetic similarities to the latter. Such knowledge would help identify or corroborate genes found important in human bladder cancer and suggest biologically appropriate mechanistic studies. We address this need by comparing gene expression profiles associated with urothelial carcinoma for three different species: mouse, rat, and human. We find that many human genes homologous to those differentially expressed in carcinogen-induced rodent tumors are also differentially expressed in human disease and are preferentially associated with progression from non-muscle-invasive to muscle-invasive disease. We also find that overall gene expression profiles of rodent tumors correspond more closely with those of invasive human tumors rather than non-muscle-invasive tumors. Finally, we provide a list of genes that are likely candidates for driving this disease process by virtue of their concordant regulation in tumors of all three species.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Bladder cancer is the fifth most frequent tumor in men and ninth in women in the United States. Due to a high likelihood of recurrence, effective chemoprevention is a significant unmet need. Estrogen receptors (ERs), primarily ERβ, are expressed in normal urothelium and urothelial carcinoma, and blocking ER function with selective ER modulators such as tamoxifen inhibits bladder cancer cell proliferation in vitro. Herein, the chemoprotective potential of tamoxifen was evaluated in female mice exposed to the bladder-specific carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). Carcinogen treatment resulted in a 76% tumor incidence and increased mean bladder weights in comparison to controls. In contrast, mice receiving tamoxifen concurrent (8–20 weeks) or concurrent and subsequent (8–32 weeks) to BBN administration had no change in bladder weight and only 10% to 14% incidence of tumors. Non–muscle-invasive disease was present in animals treated with tamoxifen before (5–8 weeks) or after (20–32 weeks) BBN exposure, while incidence of muscle-invasive bladder carcinoma was reduced. ERβ was present in all mice and thus is a potential mediator of the tamoxifen chemoprotective effect. Surprisingly, ERα expression, which was detected in 74% of the mice exposed to BBN alone but not in any controlmice, was correlated with tumor incidence, indicating a possible role for this receptor in carcinogen-induced urothelial tumorigenesis. Thus, these data argue that both ERα and ERβ play a role in modulating carcinogen-induced bladder tumorigenesis. Administration of tamoxifen should be tested as a chemopreventive strategy for patients at high risk for bladder cancer recurrence.
    Translational oncology 06/2013; 6(6):244-255. DOI:10.1593/tlo.13247 · 3.40 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Milk fat globule-epidermal growth factor-factor VIII (MFGE8), also called lactadherin or SED1, is a secreted integrin-binding protein that promotes elimination of apoptotic cells by phagocytes leading to tolerogenic immune responses, and vascular endothelial growth factor (VEGF)-induced angiogenesis: two important processes for cancer development. Here, by transcriptomic analysis of 228 biopsies of bladder carcinomas, we observed overexpression of MFGE8 during tumor development, correlated with expression of genes involved in cell adhesion or migration and in immune responses, but not in VEGF-mediated angiogenesis. To test whether MFGE8 expression was instrumental in bladder tumor development, or a simple consequence of this development, we used genetic ablation in a mouse model of carcinogen-induced bladder carcinoma. We showed that Mfge8 was also upregulated in mouse carcinoma, and that in its absence, Mfge8-deficient animals developed less advanced tumors. Angiogenesis was similar in carcinogen-treated Mfge8-expressing or -deficient bladders, thus ruling out a major role of the proangiogenic function of Mfge8 for its protumoral role. By contrast, the tumor-promoting role of Mfge8 was not observed anymore in mice devoid of adaptive immune system, and human tumors overexpressing MFGE8 where invaded with macrophages and regulatory T cells, thus suggesting that MFGE8/lactadherin favors development of bladder tumors at least partly by an immune system-dependent mechanism. Our observations suggest future use of MFGE8-inhibiting molecules as therapies of bladder carcinomas, and of a limited number of other human cancers, in which our analysis of public databases also revealed overexpression of MFGE8.
    Oncogene 10/2010; 30(6):642-53. DOI:10.1038/onc.2010.446 · 8.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cancer research on animals is an important complement to clinical investigations. Particularly, the use of animal models in researches on urinary tract cancer has a primary role in demonstrating that carcinogenesis is a multiple-stage process. These models are used to induce tumors in order to analyze the development of immunity, chemotherapy, and new techniques. This article discusses the role of animal models using rodents in urothelial carcinoma, the validity of animal models in carcinogen-induced tumors, the primary animal models available of transitional cell carcinoma and carcinoma of the upper urinary tract, and the advantages and disadvantages of the main experimental models in use.


Available from