Prostate cancer is characterized by an initial phase of well differentiated cells. Upon genetic insult, which seems to focus on oncogene activation, prostate cells become anaplastic, aneuploid and metastatic. The insidiousness of cancer is not in the initial tumor burden, but in its ability to metastasize to sites remote from its point of origin. The differential degree of genotypic expression coincides with a number of phenotypic phenomena which are supportive of tumorigenesis and metastasis. The hypothesis of this investigation is that specific genotypic alterations coincide with specific phenotypic changes that coincide/predict metastasis.
The specific aims of this investigation attempt to understand the interrelationships that exist between the expression of oncogenes (ras, rho) and various phenotypic (cytoskeleton, extracellular matrix) dynamics as tumor progression evolves. The Dunning R-3327 rat dorsal prostatic adenocarcinoma system consist of a number of sublines which serve as an appropriate model to examine this phenomenon. Selected lines will be utilized to examine the genotypic dynamics of specific point mutations and methylation profile in the ras gene as effected by antisense inhibition. Because the metastatic process involves the ability of a proliferative cellular mass to be mobile, rho gene antisense inhibition and differentiation agent treatment of metastatic cells will serve to elucidate changes in cytoskeletal protein levels as well as its effects on the ability of these cells to be attracted to, adhere to and invade components of the extracellular matrix. In addition, confocal and time lapse video microscopy will be used to show the relationship between genotypic and phenotypic components involved in the metastatic process. Data from this investigation should not only serve to further characterize the Dunning model system, but provide information which may be of diagnostic/prognostic/therapeutic value to prostatic adenocarcinoma.
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