The Bladder Cancer Program at the University of Southern California/Kenneth Norris Comprehensive Cancer Center is an integrated and multidisciplinary program that has made important contributions in clinical investigations as well as basic and translational research in bladder cancer. Our group has identified important genetic alterations associated with bladder cancer tumorigenesis and progression, including 9q and 17p allelic loss and p53 mutations. More recently, we have identified homozygous deletions and point mutations in p16 (CDKN2) in squamous carcinomas of the bladder, and have found that DNA methylation of exon 1 is associated with loss of expression of the p16 tumor suppressor gene. These studies have led to the development of an evolving model of bladder tumorigenesis and progress. Based on the depth of our clinical and basic science programs, we have developed a strong translational research program; we have recently defined the clinical significance of p53 protein alterations in bladder cancer. While we and others have shown that p53 and Rb are central in bladder cancer progression, the mechanisms by which this occurs are not well understood. The studies proposed here will examine several interrelated molecular and cellular pathways involved in bladder tumor progression, including: (1) the significance of angiogenesis in bladder cancer, including study of the mechanisms of angiogenesis regulation by p53; (2) the relationship of p53 and Rb alterations to bladder cancer progression, mechanisms of loss of tumor suppressor function that do not involve gene mutations or deletions, and the effects of tumor suppressor inactivation; (3) the role of DNA methylation in tumor suppressor gene silencing and as a possible marker for bladder cancer diagnosis and screening; (4) the detection and clinical significance of occult lymph node and bone marrow micrometastases in patients with bladder cancer, and mechanisms by which early tumor dissemination occurs. We further propose that the study of angiogenesis and the detection of occult micrometastases in patients with bladder cancer will be excellent candidates for Bladder Cancer Network collaborative studies. Based on our past work, the progress of our current studies, and our strong ongoing patient and tissue resources, our group is in an excellent position to continue to make important contributions to the study of bladder cancer, and to become valuable collaborators in the Bladder Cancer Network.