A molecular genetic model of human bladder carcinogenesis.

Human bladder carcinogenesis stands as a paradigm for research on the molecular genetic mechanisms of chemical carcinogenesis. The pathogenesis of bladder cancer is multistage with a typical onset later in life. Epidemiological studies associate occupational exposure to aromatic amines with increased bladder cancer risk. Biochemical studies show aromatic amine metabolism, covalent binding, and DNA adduct formation in human uroepithelial cells (HUC). Smoking increases bladder cancer risk. A possible link with certain strains of human papilloma virus (HPV) infection has recently been suggested. Molecular analyses of bladder cancers reveal multiple genetic alterations, including mutational activation of oncogenes and inactivation of suppressor genes. A working hypothesis proposes that bladder carcinogens cause mutations in cancer genes (oncogenes and suppressor genes) in HUC that, possibly together with HPV infection and viral DNA integration, lead to the development of bladder cancer. In this review, we describe how this model is currently being tested using a multistep HUC in vitro transformation system.