This proposal presents a unifying model for the mechanism of normal and abnormal prostatic ductal-acinar development and growth. It is based upon the idea that prostatic epithelial development and growth is elicited not by direct action of androgens, but instead by trophic influences (inductors and/or growth factors) produced by mesenchymal cells under androgenic stimulation. To explore this concept tissue recombinants will be prepared with wild-type urogenital sinus mesenchyme (UGM) and Tfm (testicular feminized) blandder epithelium (BLE). The effects of androgens on these wild-type UGM + Tfm BLE recombinants will be analyzed in terms of morphology, protein, RNA, and DNA synthesis using autoradiographic techniques. The role of mesenchyme is abnormal prostatic growth and development will also be studied in tissue recombinants to determine whether stroma from specimens of benign prostatic hyperplasia (BPH) can induce prostatic growth and development from a test epithelium. Similarly, the abilily of embroyonic UGM (a prostatic inductor) to influence growth and morphology of prostatic adenocarcinomas will be studied to determine whether neoplastic prostatic epithelial cells express a more orderly patter of growth and development when grown in association with a normal prostatic inductor (UGM). Other mesenchymes from bladder, cornea, esophagus, and vagina (which do not support prostatic growth) will be tested for their possible growth inhibitory effects on prostatic carcinoma cells. Finally, studies will be carried out to probe the mechanism of cell-cell interactions in prostatic development. For this purpose, early markers of prostatic induction will be identified and a model biossay system developed. BAsed upon current evidence it is clear that mesenchymal influences are of utmost importance in normal prostatic development and growth. Preliminary evidence indicates that mesenchymal-epithelial interactions continue to be a major regulatory mechanism in adulthood. Therefore, it is quite possible that critical analysis of cell-cell interaction in normal and abnormal prostatic development may be relevant to understanding and developing new therapies for BPH and prostatic cancer.
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