UROPLAKIN-II GENE IS EXPRESSED IN TRANSITIONAL-CELL CARCINOMA BUT NOTIN BILHARZIAL BLADDER SQUAMOUS-CELL CARCINOMA - ALTERNATIVE PATHWAYS OF BLADDER EPITHELIAL DIFFERENTIATION AND TUMOR-FORMATION

Uroplakins (UPs) are integral membrane proteins that are synthesized a s the major differentiation products of mammalian urothelium. We have cloned the human UP-II gene and localized it on chromosome 11q23. A su rvey of 50 transitional cell carcinomas (TCCs) revealed a UP-II polymo rphism but no tumor-specific mutations. Immunohistochemical staining u sing rabbit antisera against a synthetic peptide of UP-II and against total UPs showed UP reactivity in 39.5% (17 of 43 cases) of convention al TCCs, 12.8% (5 of 39) of bilharzial-related TCCs, and 2.7% (1 of 36 ) of bilharzial-related squamous cell carcinomas (SCCs). The finding t hat fewer bilharzial TCCs express UPs than conventional TCCs (12.8 ver sus 40%) raised the possibility that the former are heterogeneous, exp ressing SCC features to varying degrees. Our data strongly support the hypothesis that urothelium can undergo at least three pathways of dif ferentiation: (a) urothelium-type pathway; (b) epidermis-type pathway; and (c) glandular-type pathway, characterized by the production of UP s, K1/K10 keratins, and secreted glycoproteins, respectively. Vitamin A deficiency and mesenchymal factors may play a role in determining th e relative contributions of these pathways to urothelial differentiati on as well as to the formation of TCC, SCC, and adenocarcinoma, or a m ixture thereof.