You have accessJournal of UrologyBladder Cancer: Basic Research I1 Apr 2010785 COMPENSATORY TUMOR DEFENSES IN UROTHELIUM DURING TUMOR SUPPRESSOR DEFICIENCY: IMPLICATION ON THE REQUIREMENT OF MULTI-GENE DEFECTS IN INVASIVE CARCINOMA FORMATION Feng He, Lan Mo, Eva Lee, Herbert Lepor, Tung-Tien Sun, and Xue-Ru Wu Feng HeFeng He New York, NY More articles by this author , Lan MoLan Mo New York, NY More articles by this author , Eva LeeEva Lee Irvine, CA More articles by this author , Herbert LeporHerbert Lepor New York, NY More articles by this author , Tung-Tien SunTung-Tien Sun New York, NY More articles by this author , and Xue-Ru WuXue-Ru Wu New York, NY More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.1434AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Urothelium, one of the slowest proliferating epithelia, is under the tight control of multiple growth inhibitors that act as tumor barriers. Overcoming these barriers is considered a prerequisite to transform urothelial cells into full-fledged carcinomas. However, the identity of the barriers and precisely how they operate during tumorigenesis have not been elucidated. METHODS We assessed the expression of key tumor suppressors in normal mouse urothelia using real-time PCR, in situ hybridization, immunohistochemical staining and Western blotting. We also examined the urothelial responses to tumor suppressor loss using urothelium-specific knockout mice. Additionally, we studied whether multi-gene defects were necessary for invasive urothelial tumor initiation. Finally, we determined whether the combinatorial molecular defects identified in mice have correlates in humans. RESULTS Unlike p53 which was undetectable in normal mouse urothelium, all pRb family proteins (pRb, p107 and p130) were highly expressed in all urothelial layers. E2F1, a potent growth stimulator whose activity is suppressed by pRb, was expressed at a very low level. Functionally ablating pRb in mouse urothelium provoked a marked increase of p107 as well as p53 pathway components (p53 itself, p19, p21, Bak and Bax). Instead of proliferation, pRb-deficient urothelial cells underwent apoptosis, due to dual (p107 and p53) compensatory tumor defenses. Removal of p53 from pRb-deficient cells bypassed p53-pathway activation, leading to late-onset hyperplasia. Treating mice lacking both pRb and p53 with a bladder-specific carcinogen elicited high-frequency invasive urothelial carcinomas, where p107 was markedly down-regulated. These results suggest that combined deficiency of pRb, p107 and p53 is necessary for invasive urothelial tumorigenesis. A follow-up immunohistochemical survey identified human muscle-invasive urothelial carcinomas that had the same molecular defects as in mice. CONCLUSIONS Our data reveal important mechanisms of urothelial cells in tumor defense and demonstrate a new concept for invasive urothelial tumorigenesis. They also suggest that a combination of pRb, p107 and p53 may be more accurate prognostic predictors for patients with muscle-invasive bladder cancer. © 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e307 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Feng He New York, NY More articles by this author Lan Mo New York, NY More articles by this author Eva Lee Irvine, CA More articles by this author Herbert Lepor New York, NY More articles by this author Tung-Tien Sun New York, NY More articles by this author Xue-Ru Wu New York, NY More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...