MOLECULAR CHANGES DURING PROSTATE CARCINOMA PROGRESSION

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Prostate carcinoma is now the most common visceral malignancy in males. It is variable in its clinical progression. The cause(s) of this variability are unknown, but are likely due to differences in the efficiency of cellular invasion and metastatic spread. Cellular invasion is a three step process: 1) attachment of the cells to components of the extracellular matrix; 2) release of proteolytic enzymes and/or their specific inhibitors (TIMPs); and, 3) migration of the cells through the tissue to invade the vascular bed. In this proposal we will examine the relationship of the extracellular matrix molecules (ECM) (fibronectin, vitronectin, tenascin, laminin, and type IV collagen) as they relate to tumor progression in the various stages of premalignant and malignant disease. In addition We will examine the expression of the adhesive integrin molecules on the surface of normal human prostate glands, and the changes observed with tumor progression. We will also investigate the relationship of integrin expression to the intermediate filaments of the cytoskeleton. Finally, we will examine the expression of three of the known members of the multigene collagenase family in the human prostate in the various stages of premalignant and malignant disease. Expression of the extracellular matrix molecules, surface integrin molecules, and metalloproteinase will be detected in tissue using indirect immunofluorescence with specific antibodies. The detection of the metalloproteinases will also be examined at the transcriptional level in frozen sections using in situ hybridization as well as northern blot analysis using extracted total RNA. The relationship of these molecules will be compared to tumor grade and pathologic stage. The role of these molecules will be investigated in attachment and early invasion by injecting various variant prostate cell lines into the SCID mice.