The goal of this research is to study the role of stromal-epithelial interactions in prostatic carcinogenesis. The overall hypothesis is that tumorigenic growth is the sum of individual growth processes and inductive tissue interactions inepithelial and stromal tissues. Thus, proliferation of tumor stromal cells is a key process in prostatic carcinogenesis, which is in part regulate by tropic activity of epithelial cells on stroma. In reciprocal fashion, proliferation and differentiation of prostatic carcinoma cells is regulated by stromal cells. The meddiators of these reciprocal cell-cell interactions are proposed to be growth factrors (GF). To achieve these goals the following specific aims will be pursued. (1) Induction of carcinogenesis in non- tumorigenic prostatic epithelial cells (PRE) by human prostatic tumor stroma willbe defined and characterized in terms of epithelial growth, apoptosis, and cytodifferentiation and carcinogenesis. Androgenic regulationof epithelial growth and tumorigenesis in human prostatic epitheluim (huPRE) by tumor stromal cells will be determine. The clear therapeutic implication of this study will be examined by determine whether growth of prostatic carcinomas is dependent upon proliferationof stromal cells. In reciprocal fashion it will be determined whether stromal growth in normal prostate and prostaic tumors is regulated by epithelial cells. (2) Analysis of the growth factor/growth factor receptor profile in epithelial and stromal cells during stromal induction of epithelial carcinogenesis will be pursued by species specific RT-PCR. (3) The role of genetic lesion in the susceptibility of prostatic epithelial cells to the induction of carcinogenesis by tumor stromal cells will be determined using p53 and Rb knockout prostatic epithelium. (4) to dissect molecular pathways involved instromal-epithelial interactions regulating growth and differentiation of prostatic epithelium transgenic knockout mice will be used. In this regard transgenic knockout mice will beused to examine the role of stromal estrogen receptors in prostatic growth and differentiation, the role of growth factors as mediators of epithelial effects on stromal proliferation in the prostate, and the role of growth factor systems as mediators of stromal effects on epithelial proliferation during growth of the prostate. These studies should define critical cellular and molecular pathways in both normal and tumorigenic growth of the prostate, and should provide the biological basis of new therapeutic strategies.
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