The main goal of this proposal is to investigate the cellular and molecular mechanisms of smooth muscle-epithelial interactions in normal and malignant prostatic epithelial growth and differentiation. The rationale of the overall approach of this proposal is that the initial differentiation of smooth muscle in the developing prostate is induced and maintained through interactions with epithelium. During prostatic carcinogenesis the ability of epithelium to induce and maintain smooth muscle differentiation will diminish as signaling from epithelium to smooth muscle becomes abnormal. Hypothesis: This proposal is based upon the hypothesis that normal and malignant prostatic epithelium cell growth and differentiation as regulated by smooth muscle-epithelial cell interactions medicated by paracrine growth or differentiation factors. This hypothesis will be examined through pursuit of the following specific aims. (Specific aim #1) Analysis of expression of prostatic smooth muscle markers during normal prostatic development and prostatic carcinogenesis. Overall strategy for specific aim #1 will include: (a) to examine the sequential expression of smooth muscle differentiation markers during normal prostatic development in rat and human by immunohistochemistry and western blot. (b) to examine expression of smooth muscle differentiation markers in malignant human prostate and during prostatic carcinogenesis in rats. (Specific aim #2) Analysis of induction and maintenance of prostatic smooth muscle differentiation by normal and malignant prostatic epithelial cells. The overall strategy will include: (a) Analysis of cellular mechanisms of induction and maintenance of smooth muscle differentiation. (b) Analysis of hormonal mechanisms of induction of smooth muscle differentiation. (c) Analysis of molecular mechanisms of induction of smooth muscle differentiation. (Specific aim #3) Analysis of prostatic smooth muscle and Dunning tumor stroma as regulators of normal and malignant prostatic epithelial growth and differentiation. (Specific aim #4) Development and utilization of new methods of prostate carcinogenesis. The long-term objective of this research project is to develop the best strategy for regulation of human prostatic cancer growth by understanding the cellular and molecular mechanisms of smooth muscle-epithelial interactions.
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