While significant progress has been made upon defining the molecular steps in androgen action in prostatic tissue, there are a series of major controversies which have not been resolved particularly with regard to the importance of cell/cell interaction in such androgen action. One of the most significant of these controversies involves whether androgen action in the normal vs neoplastic prostate involves an intracrine, autocrine, or paracrine pathway. Since prostatic glandular cells express the androgen receptor, originally it was assumed that androgen action involves a completely intracellular (i.e., intracrine) pathway. In this intracrine model, once testosterone is converted to DHT within glandular cells it binds to the androgen receptor and the binding of the dihydrotestosterone (DHT) androgen receptor complex to androgen response elements within the promoter region of specific androgen responsive genes leads to the production of specific mRNAs whose expression results in proteins retained within the glandular cell itself to generate specific signals either to maintain secretory function and suppress programmed death to proliferate. Recent studies have questioned whether androgens act directly within the prostatic glandular cells themselves. These studies suggest that the critical DHT-androgen receptor interactions actually occur in prostatic stromal cells inducing these stromal cells to synthesize and release soluble factors whose functions are to regulate the balance between proliferation and death of the prostatic glandular cells. Since during the development of both BPH and prostate cancer, this balance is abnormally disrupted, there is a critical need to resolve the role of stromal cells in androgen regulated normal and abnormal growth of the prostate. This is particularly critical since there is experimental data supporting the idea that during prostatic neoplastic progression, there is a shift from the normal paracrine to an autocrine or intracrine mechanism of androgen action. Resolving this issue is critical since depending on the answer, the choice of theoretical, as well as practical targets and/or methods to prevent the development of these prostatic disorders would be profoundly different. Based upon this realization, the present RFA specifically has called for applications to study cell/cell interaction and prostate growth. In the present application, a series of unique xenograft and molecular biologic methods will be used to clarify the role of stromal cell interactions in the androgen regulation of the in vivo growth of normal, BPH, and malignant human prostate tissues.
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