Abstract
Activation of oncogenes or inactivation of tumor suppressors in urothelium is considered critical for development of urothelial cancer. Here we report cloning of the urothelium-specific promoter uroplakin-II (UPK II) and generation of transgenic mice in which expression of SV40 large T antigen is driven by UPK II promoter. Inactivation of tumor suppressor p53 and pRb in urothelium by SV40 T antigen resulted in urothelial carcinoma, resembling human high-grade carcinoma in situ. Specific deletion of p53 in urothelial cells using the newly generated UPK II-Cre mice results in normal bladders without any evidence of cancer. The high-grade carcinoma in situ in the UPK II-SV40 mice is associated with significant activation of angiogenic signals consisting of hypoxia-inducible factor-1α (HIF-1α) and VEGF and a down-regulation of thrombospondin-1. Interestingly, such pro-angiogenic activity was not associated with progression to invasive cancer. Analysis of bladder-associated microRNAs in carcinoma in situ lesions reveals a pro-angiogenic profile, with specific overexpression of miR-18a and miR-19a and down-regulation of miR-107. A group of microRNAs (miRs) identified as associated with invasive human urothelial cancer remained unchanged in this mouse model. Collectively, our results support the notion that activation of angiogenesis and loss of p53 are not sufficient for progression to invasive cancer. Our studies identify a new mouse model for bladder cancer that can be used to study factors that determine progression to an invasive phenotype of bladder cancer.
Highlights
Urothelial carcinomas of the bladder are among the most frequent human cancers and account for more than 14,000 deaths annually in the United States [1]
The molecular basis of urothelial bladder cancer is being progressively unveiled, and the generation of transgenic mouse models of bladder cancer obtained through the urothelial expression of oncogenes (SV40) [3] or deletion of tumor suppressor genes remains a viable strategy for unraveling this mechanism
Urothelium-specific Expression of SV40 T Antigen Leads to Development of Bladder Carcinoma in Situ—SV40 T large antigen expression is able to inactivate both p53 and pRb, and its uroplakin II conditional expression has been previously shown to induce the development of bladder carcinomas in situ (CIS) [3]
Summary
Urothelial carcinomas of the bladder are among the most frequent human cancers and account for more than 14,000 deaths annually in the United States [1]. Angiogenesis is among the biological factors that have been studied as potential predictors of progression to invasive tumors in superficial bladder carcinoma and is considered by some groups as a useful biomarker [10] In this regard, some clinical studies have suggested that elevated microvessel density, an indicator of angiogenic phenotype, is associated with progression of carcinoma in situ to invasive cancer, but some other clinical observations did not confirm these results [11, 12]. We generated a new transgenic mouse, UPK II-SV40, and observed that the development of high-grade urothelial carcinoma in situ was associated with a significant activation of angiogenic signals This pro-angiogenic phenotype was independent of invasion and associated with specific changes in the profile of microRNAs regulating angiogenesis, without any effect on urothelial expression of invasion-related microRNA (miR). These results suggest that progression to invasive bladder cancer is not solely dependent on angiogenesis, and the notion that markers of angiogenesis or angiogenesis-related miRs may serve as useful markers to predict invasive bladder cancer needs to be carefully evaluated
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