Role of Ha-ras activation in superficial papillary pathway of urothelial tumor formation

Urothelial tumors develop along two distinctive phenotypic pathways (superf icial papillary non-invasive tumors versus flat carcinoma in situ lesions), with markedly different biological behavior and prognosis. Although multip le genetic alterations have been identified in human bladder cancer, their cause-effect relationship with the two pathways has not been firmly establi shed, Using a urothelium-specific promoter of the uroplakin TT gene, we sho wed earlier in transgenic mice that the urothelial expression of SV40T anti gen, which inactivates p53 and pRb, induced carcinoma in situ and invasive and metastatic bladder cancer. In striking contrast, we demonstrate here th at the urothelial expression of an activated Ha-ras in transgenic mice caus ed urothelial hyperplasia and superficial papillary non-invasive bladder tu mors. These results provide strong, direct experimental evidence that the t wo phenotypical pathways of bladder tumorigenesis are caused by distinctive genetic defects, Our results indicate that Ha-ras activation can induce ur othelial proliferation in vivo; and that urothelial hyperplasia is a precur sor of low-grade, superficial papillary bladder tumors. Our transgenic mode ls provide unique opportunities to study the detailed molecular events unde rlying different types of bladder neoplasms, and can serve as useful precli nical models for evaluating the in vivo efficacy of preventive and therapeu tic agents that act on various signaling pathways in bladder cancer.