PATHOGENESIS OF HUMAN PROSTATE CARCINOMAS

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The long-term goal of this program is to identify multiple molecular events that interplay in the pathogenesis of human prostate cancer. We obtained evidence for the association of abnormal expression of several genes in prostate cancer. Molecular clones of isoforms of androgen- induced growth factor or FGF8, expressed in human prostate cancer cells, were isolated and characterized. Functional studies with them have suggested that FGF8 expression contributes to biological behavior of prostate cancer cells. In the prostatic malignant epithelium we found overexpression of two other interesting genes: HSF1, a heat shock factor, and L-plastin, an actin-bundling protein isoform. The nuclear transcription factor HSF1 appears to be primarily localized in the cytoplasm of the low risk (stage B) prostate carcinoma cells, while its distribution is increased in the nucleus of high risk (stage C) prostate cancer cells. Inhibition of L-plastin expression results in suppression of motility and invasion of prostate cancer cells. We propose to extend these studies to determine the interactions between FGF8 isoforms and members of the FGF receptor family expressed in stromal and epithelial cells of the prostate, and the role of these interactions in prostate cancer progression. The basis of HSF1 overexpression and potential novel aspects of its subcellular localization will be investigated. Concerning L-plastin, we will specifically examine if prostate cancer invasion and metastasis can be inhibited by high efficiency, tissue specific antisense L-plastin gene expression. To extend our novel finding of the frequent occurrence of intraglandular and intratumor genetic heterogeneity of p53 mutations in prostate tumors, we will also seek to determine if p53 mutations arise to rescue hypoxic prostate cancer cells or whether cells from focal regions with p53 mutations have a higher propensity to metastasize. These studies, in combination, should lead to new insights into the pathogenesis of prostate cancer. Ultimately, an understanding of these molecular events will provide us with new approaches to the treatment and/or management of this increasingly common disease.