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Malignant Transformation of Urinary Bladder in Humans and in N-[4-(5-Nitro-2-furyl)-2-thiazolyl]formamide-exposed Fischer Rats: Ultrastructure of the Major Components of the Permeability Barrier¹

Department of Pathology, Tufts University School of Medicine, Boston, Massachusetts 02111 [F. B. M.], Department of Pathology, Rush Medical College, Chicago, Illinois 60612 [B. U. P., J. A., R. S. W.], and Department of Pathology, the St. Vincent Hospital, Worcester, Massachusetts 01604 [J. B. J., G. H. F.]

Normal urinary bladder transitional epithelium (urothelium) contains a permeability barrier to water and solutes. Electron microscopy studies show that three structural elements of the plasma membranes of superficial urothelial cells, i.e., asymmetrical unit membrane plaques and interplaque membrane at the luminal surface and tight junctions at lateral surfaces, provide the actual barrier. In spontaneous transitional cell carcinomas in humans and in similar appearing tumors in Fischer rats fed the carcinogen N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide, ultrastructure of the luminal membrane is altered, but the observed changes do not appear to adequately account for alterations in permeability. However, modifications in tight junctions are sufficient to account for drastic alterations in transepithelial permeability. In control humans and rats, tight junctions consist of a network of three to five intramembrane strands. In Grade I and II human tumors and in early N-[4-(5-nitro-2-furyl)-2-thiazolyl]formamide-induced rat tumors (26 weeks), tight junctions are focally attenuated to a single strand. In higher-grade human tumors and in late rat tumors (61 weeks), intramembrane strands are often discontinuous. Since the number and distribution of intramembrane strands at tight junctions correlates well with transepithelial permeability in most epithelia (note that there are important exceptions), it is reasonable to conclude that either the incomplete formation and/or rapid turnover of tight junctions is the structural basis of the increased permeability in transitional cell carcinomas.

¹ Presented at the National Bladder Cancer Conference, November 28 to December 1, 1976, Miami Beach, Fla. Supported by Grants CA-14447 and CA-16377 from the National Cancer Institute and by Grant CA-15945 from the National Cancer Institute through the National Bladder Cancer Project.

² Presenter.