The Urology Research Group at the University of Oklahoma is a multidisciplinary group of scientists working on a multicenter translational research program in bladder cancer biomarkers. The hypothesis being tested is that metastasis requires several functional phenotypic traits to be simultaneously present in cells, and that these phenotypes can be defined by quantitatively measured biomarkers representing functional phenotypes. This approach depends upon integrating model system studies of bladder cancer cells of defined metastatic potential grown on natural connective tissue matrix and in nude mice with small-scale retrospective studies of known outcome to identify markers for functional phenotypes needed for mestastasis. The model systems allow specific mechanisms of metastasis to be investigated and manipulated in vitro and in animal models to assess the response of selected biomarkers. The small-scale retrospective studies with patient samples identify specific mechanisms to be investigated. The functional phenotypes being evaluated include markers for matrix degradation (matrix metalloproteinases, MMP and their inhibitors, TIMP), motility (autocrine motility factor receptor, AMFR), weak cell adhesion (E-cadherin, integrins), evasion of apoptosis (transglutaminase), cytoskeletal changes (actin), biomarkers associated with angiogenesis (bFGF), and biomarkers of modulation of epithelial-stromal interactions (TGF-b). The marker profiles found most useful in these basic mechanistic studies of markers and mechanisms will be evaluated further in retrospective studies of patients with known outcomes to begin to develop a panel of biomarkers to identify metastatic risk. Because the emphasis is on identification of clinically useful markers, these studies will involve 50 or fewer patients because markers that are not clearly useful in a study of this size have minimal potential for use as clinical markers. The objective of these studies is to assess sensitivity and specificity, identify which markers cluster together or provide independent information on metastatic risk. The emphasis will be on Grade 2 tumors because for this group, stage and grade are least useful. The results of this study should generate biomarker profiles that are based in basic, mechanistic understanding of metastasis that can subsequently be tested in controlled clinical studies.
