Neovascularization in the Development of Epithelial Proliferative Lesions of the Rat Urinary Bladder: A Light Microscopic, Immunohistochemical and Ultrastructural Study.

Abstract

Neovascularization was studied during the development of epithelial proliferative lesions of rat urinary bladder induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) using an immunohistochemical and electron microscopical approach. Male 6-week old F344 rats were treated with 0.05% BBN in the drinking water for 12 weeks and then maintained without BBN for 8 weeks (total of 20 weeks observation). At intervals of 2 weeks during carcinogen administration period and at 16 and 20 weeks, groups of rats were killed and urinary bladder lesions were examined. Neovascularization appeared early in simple hyperplasia and capillary intrusion into the mucosal layer, accompanied by stromal cells and extracellular matrix formation, occurred in papillary or nodular (PN) hyperplasia, and with pronounced growth of tumor stroma within papillomas and carcinomas. However, bFGF, a potent angiogenic growth factor could not be demonstrated in the epithelial lesions at any time point's during the course of carcinogenesis. An important feature was that the basement membranes between epithelial and endothelial cells were maintained at the base of the mucosal layer but became obscure with more intrusive neovasculariza-tion. The findings indicate that stromal cells and the extracellular matrix are important factors for neovascularization during the course of rat bladder carcinogenesis.