The broad long-term objective of this project is to examine stromal-epithelial interactions in the regulation of differentiation, growth and tumorigenesis of prostatic carcinomas to determine the role of keratinocyte growth factor (KGF), transforming growth factor alpha (TGFalpha) and TGFbetas in these cell-cell interactions. This proposal further develops a recently described model of differentiation therapy in which mesenchyme of the embryonic urogenital sinus (UGM) or neonatal seminal vesicle (SVM) can induce the Dunning prostatic adenocarcinoma to differentiate with a concomitant reduction in growth rate and an apparent loss in tumorigenesis. The long range goals of this project will be achieved by pursuing the following specific aims: (1) In vivo analysis of gene expression and protein production of KGF, TGFalpha and TGFbeta1,2,3 in experimental tissue recombinants composed of UGM or SVM plus normal or neoplastic prostatic epithelium. (2) Analysis of mesenchymal modulation of neoplastic prostatic epithelial differentiation, growth and tumorigenesis in tissue recombinants composed of UGM or SVM plus prostatic tumor cell suspensions grown in vivo. (3) Mechanistic in vitro studies of the role of KGF, TGFalpha and TGFbeta1, 2, 3 in ductal growth and ductal branching morphogenesis in prostatic tumors, normal prostate and tissue recombinants composed of UGM or SVM plus prostatic tumor epithelial cells. (4) Studies on human prostatic adenocarcinomas are proposed to determine whether concepts derived from animal models can be applied to human prostatic carcinomas. The basic experimental design involves examining the expression of KGF, TGFalpha and TGFbeta1,2,3 in experimental tissue recombinants and in normal developing prostates by RIA, RRA, Western blot, PCR and immunocytochemistry. Changes in differentiation and growth rate of prostatic carcinoma cells induced by embryonic UGM or neonatal SVM will be assessed by histology, 3H-thymidine labelling index, and immunocytochemistry for the expression of epithelial androgen receptors. Serum-free cell and organ culture models will be used to examine the roles of KGF, TGFalpha and TGFbeta1,2,3 as paracrine mediators in these cell-cell interactions through the addition of single growth factors to the medium or through use of neutralizing antibodies to growth factors. This project should result in an in-depth characterization of the role of growth factors in the paracrine interactions involved in regulating the growth and differentiation of prostatic carcinoma cells. While most of the studies will use animal models, in the last year of the project we will apply new emerging concepts and techniques to human prostate cancers, which constitute one of the most serious medical problems for the aging male.