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: 4.25). 09/2008; 10(8):838-46. DOI: 10.1593/neo.08432
Source: PubMed


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.

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    • "Lyophilized BCG was purchased from Sanofi Pasteur Limited (Toronto, CA) and reconstituted as per instructions with sterile PBS and served as positive control. After allowing animals to acclimate to our facility for one week, all animals except five received 0.05% BBN in their drinking water continuously for eight weeks inducing the formation of NMIBC, which is a well-established rodent carcinogen induced BCa model [25]–[30] with marked molecular changes similar to human BCa [31]. After 8 weeks of BBN exposure, animals resumed water without the addition of BBN. "
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    ABSTRACT: Intravesical Bacillus Calmette-Guérin (BCG) has been shown to induce a specific immunologic response (i.e., activation of IL-2 and effector T-cells), while preclinical studies using ALT-803 (mutated IL-15 analogue combined with IL-15Rα-Fc fusion) have shown promising results by prolonging the agent's half-life and stimulating CD8+ T-cells. Based on these results, we hypothesized that the intravesical administration of ALT-803 along with BCG will generate an immunologic response leading to significant bladder tumor burden reduction. Using a well-established carcinogen induced rat non-muscle invasive bladder cancer (NMIBC) model, we studied the effects of intravesical ALT-803 with and without BCG. Rat tissues were evaluated to document treatment response. Intravesical ALT-803 was safe and well tolerated alone and in combination with BCG. As a single treatment agent, ALT-803 reduced tumor burden by 35% compared to control whereas BCG alone only reduced tumor burden by 15%. However, the combination of ALT-803 plus BCG reduced tumor burden by 46% compared to control. Immune monitoring suggested that the antitumor response was linked to the production and secretion of IL-1α, IL-1β and RANTES, which in turn, induced the proliferation and activation of NK cells. Lastly, tumoral responses of the combinational treatment were associated with 76% reduction in angiogenesis, which is significantly higher than when assessed with either agent alone. The enhanced therapeutic index seen with this duplet provides justification for the development of this regimen for future clinical trials.
    Full-text · Article · Jun 2014 · PLoS ONE
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    • "In this report, the chemopreventive efficacy of the selective ER modulator (SERM) tamoxifen in bladder carcinogenesis was evaluated in a mouse model of bladder cancer induced with the organ-specific carcinogen , N -butyl-N -(4-hydroxybutyl)nitrosamine (BBN). This model shares morphologic [46], histologic [47,48], and genetic similarities with higher grades of human bladder cancer [49]. This experiment demonstrates that tamoxifen administered concurrently with carcinogen can significantly reduce the incidence of noninvasive and invasive bladder cancers in female mice, an effect associated with a reduction in urothelial proliferation and suppression of ERα expression induced by exposure to the BBN carcinogen, and suggests that SERMs such as tamoxifen should be evaluated in clinical trials testing a chemoprevention strategy to limit urothelial carcinogenesis in high-risk populations. "
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    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.
    Full-text · Article · Jun 2013 · Translational oncology
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    • "Bladder tumors were chemically induced in vivo in mice capable, or not, of Mfge8 expression (Silvestre et al., 2005). Exposure of mice to N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) leads to development of bladder carcinomas, representative of the highly invasive variants of human carcinomas (Becci et al., 1981; Williams et al., 2008) (Supplementary Figure S2a). As shown in human bladder tumors (Figures 1b and c), we observed a strong increase of Mfge8-gene expression in tumoral urothelium from BBN-treated mouse bladders, as compared with normal urothelium (Figure 3a). "
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    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.
    Full-text · Article · Oct 2010 · Oncogene
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