Bladder cancer is a spectrum of diseases ranging from a low grade carcinoma of slow and recurrent course (here referred to as type 1) to a highly invasive carcinoma of aggressive behavior (type 2). It is hypothesized that the grade of malignancy is determined by the dose of carcinogen; exposure to a small dose of carcinogen induces type 1 carcinoma, whereas exposure to a large dose causes type 2 cancer. Type 1 carcinoma may progress to type 2 as a result of re-exposure to carcinogen(s). It is also hypothesized that urine contains a tumor-promoting urinary growth factor(s) (UGF) which is distinct from the epidermal growth factor, and that this factor is responsible for the progression of dormant cancer to a clinically recognizable one and for the seemingly irreversible change in reparative hyperplasia of urothelium. The immediate objectives are 1) to determine whether degree of malignancy of urothelial tumor is determined by the dose and the mode of administration of carcinogen N-methyl-N-nitrosourea (MNU); 2) to determine whether degree of malignancy increases if an MNU-induced low grade tumor is exposed to the carcinogen for the second time; 3) to determine whether contact with urine of regenerating epithelium induces irreversible alteration and also induces an accelerated response to carcinogen; 4) to isolate, purify, and characterize the UGF(s) and 5) to test UGFs on their ability to enhance tumorigenesis in the urinary bladder. All animal studies will be conducted using the heterotopically transplanted rat urinary bladder system. The ultimate goal will be to determine UGF's mechanism of action and to find a means to block its action, so that the same principle may be applied to humans to prevent the recurrence of bladder cancer.