Urothelium-specific expression of an oncogene in transgenic mice induced the formation of carcinoma in situ and invasive transitional cell carcinoma.
Although many genetic alterations are known to be associated with human transitional cell carcinoma (TCC) of the urinary bladder, relatively little is known about the roles of these molecular defects, singular or in combination, in bladder tumorigenesis. We have developed a transgenic mouse model of bladder tumorigenesis using a 3.6-kb promoter of uroplakin II gene to drive the urotheliums-specific expression of oncogenes. In this study, we demonstrate that transgenic mice bearing a low copy number of SV40T transgene developed bladder carcinoma in situ (CIS), whereas those bearing high copies developed CIS as well as invasive and metastatic TCCs. These results indicate that the SV40T inactivation of p53 and retinoblastoma gene products, defects frequently found in human bladder CIS and invasive TCCs, can cause the aggressive form of TCC. Our results also provide experimental proof that CIS is a precursor of invasive TCCs, thus supporting the concept of two distinct pathways of bladder tumorigenesis (papillary versus CIS/invasive TCC). This transgenic system can be used for the systematic dissection of the roles of individual or combinations of specific molecular events in bladder tumorigenesis.
Zhang
Z T
ZT
Department of Urology, Kaplan Comprehensive Cancer Center, New York University School of Medicine, New York 10016, USA.
Pak
J
J
Shapiro
E
E
Sun
T T
TT
Wu
X R
XR
D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000096:biosynthesis / Q000235:genetics*; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D002291:Carcinoma, Papillary / Q000235:genetics; D002295:Carcinoma, Transitional Cell / Q000235:genetics* / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002472:Cell Transformation, Viral / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016161:Genes, Retinoblastoma; D016158:Genes, p53; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D009857:Oncogenes; D009928:Organ Specificity; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013539:Simian virus 40 / Q000235:genetics; D019076:Transgenes; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology; D060170:Uroplakin II; D019459:Urothelium / Q000378:metabolism*
D000952:Antigens, Polyomavirus Transforming; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; C554658:UPK2 protein, human; C554659:Upk2 protein, mouse; D060170:Uroplakin II