Epithelial-stromal interactions in normal and chemical carcinogen-treated adult bladder.

Abstract

Summary Tumor formation in the adult rat urinary bladder may be induced by multiple intraurethral instillations of N -methyl- N -nitrosourea (MNU), and this bladder-chemical carcinogen system has been adapted for study of tissue interactive processes in neoplastic change. Responsiveness of transitional epithelium to stromal influences can be determined by scanning electron microscopic analysis of cell membrane changes on the luminal aspect of the urothelium in vivo and in long-term organ cultures (0 to 100 days in vitro ) of normal and chemical carcinogen-treated bladders and of homotypic and heterotypic recombinations of the isolated epithelial and stromal components from normal and MNU-treated bladders. Individual globular surface processes, their chain-like arrangement, and amalgamation to form the characteristic angular membrane of the superficial cell identify the cell surface maturation sequence of normal urothelium in vivo . This is reproduced in vitro but only where epithelium is in association with homotypic stroma. Absence of stoma leads to atypical epithelial cell differentiation, with numerous irregular microvilli of varying size and orientation patterning the cell surface; this implies epithelial dependence on stoma for normal cytodifferentiation. In MNU-induced benign and preneoplastic hyperplasia of the urothelium, short swollen microvilli cover the luminal surface, whereas surface differentiation of preneoplastic epithelium to overt neoplasia and tumor formation is associated with the appearance of increasingly complex and bizarre pleomorphic microvilli providing a convenient marker of cell abnormality. Production of pleomorphic microvilli is not reversed when neoplastic epithelium is placed in heterotypic combination with normal bladder stroma, suggesting epithelial independence of stromal influence. By contrast, abnormal pleomorphic microvilli develop on the surface of normal urothelium associated with stroma from MNU-treated bladder; this implies a stromal effect on the epithelium and suggests that MNU may elicit new epithelial behavior by causing a derangement of stromal function.