Differential Expression of Cell Cycle Regulators in Phenotypic Variants of Transgenically Induced Bladder Tumors: Implications for Tumor Behavior

Abstract

Proteins controlling cell growth, differentiation, apoptosis, and oncogenic stress are often deregulated in tumor cells. However, whether such deregulations affect tumor behavior remains poorly understood in many tumor types. We recently showed that the urothelium-specific expression of activated Hras and SV40 T antigen in transgenic mice produced two distinctive types of tumors strongly resembling the human superficial papillary tumors and carcinoma in situ of the bladder, respectively. Here we assessed the expression of a key set of cell cycle regulators in these mouse tumors and in a new transgenic line expressing a cyclin D1 oncogene in the urothelium. We found that urothelia of the wild-type and cyclin D1 transgenic mice exhibited a profile of cell cycle regulators found in quiescent (G 0 ) cells, indicating that urothelium overexpressing the cyclin D1 (an 8-fold increase) is reminiscent of normal urothelium and remains slowcycling. Low-grade superficial papillary tumors induced by activated H-ras had no detectable Rb family proteins (Rb, p107, and p130) and late cell cycle cyclins and kinases (cyclin A, E, and CDK1), but had increased level of p16, p53, and MDM2. These data suggest that the inactivation of the Rb pathway plays an important role in H-ras-induced superficial papillary tumors and that oncogenic H-ras can induce a compensatory activation of alternative tumor suppressor pathways. In contrast, carcinoma in situ of the bladder induced by SV40 T antigen had increased expression of cell cycle regulators mainly active in post-G 1 phases. The fact that phenotypically different bladder tumors exhibit different patterns of cell cycle regulators may explain why these tumors have different propensity to progress to invasive tumors. Our results indicate that the transgenic mouse models can be used not only for studying tumorigenesis but also for evaluating therapeutic strategies that target specific cell cycle regulators.

Altered phenotype of cultured urothelial and other stratified epithelial cells: implications for wound healing

“…2B) (55,57,109,112). In addition, recent studies indicate that uroplakin Ia may serve as the urothelial receptor for type 1-fimbriated Escherichia coli that causes Ͼ90% of urinary tract infections (111,117) and that the use of a urothelium-specific uroplakin II promoter made possible detailed analyses of the roles of specific oncogenes and tumor suppressor genes in bladder tumorigenesis (27,29,65,116).…”

Interferon-γ induces regression of epithelial cell carcinoma: critical roles of IRF-1 and ICSBP transcription factors

“…Although significant in-roads have been made in development of anticancer agents, few therapies with proven efficacy are available for highly aggressive epithelial cell carcinomas and for majority of these patients, prognosis following diagnosis is poor (Vilchez and Butel, 2004;Young and Rickinson, 2004;Hughes, 2005). Targeting expression of proteins that control cell cycle progression or promote apoptosis into neoplastic cells localized in specific tissues of TR mice provides a powerful tool for validating the efficacy of potential antineoplastic agents Gabril et al, 2005;Garcia-Espana et al, 2005).…”

Archetype and Rearranged Non-coding Control Regions in Urothelial Bladder Carcinoma of Immunocompetent Individuals

“…After primary infection, both BKPyV and JCPyV remain latent lifelong in the epithelium of the urinary tract (40). Two reports showed that the urothelium-specific expression of polyomavirus SV40 TAg in transgenic mice produced tumors strongly resembling human carcinoma in situ of the bladder (15,16 detected was significantly associated with urinary bladder carcinoma (14,41). Furthermore, a statistically significant association between urine cytological evidence of PyV infection (decoy cells) and BC was also demonstrated in immunocompetent patients (18).…”

“…Recently, viral infections have also been associated with this pathology. BC has been observed in SV40 T antigen (TAg) transgenic mice (15,16). Geetha and colleagues found a strong BKV DNA detection in neoplastic tissue but not in the surrounding non-dysplastic urothelium (17), whereas Weinreb et al demonstrated a strong association between a prior PyV infection and the subsequent diagnosis of bladder carcinoma (18).…”