Prostate neoplasia in the form of cancer and benign prostatic hyperplasia have assumed a prominent role in the morbidity and mortality of the aging adult male, and is projected to further increase in incidence over the next several decades as the modal male population in North America progressively ages. Hence, the mechanisms which regulate growth of the prostate are of particular relevance to the management and treatment of prostate neoplasia. In this context, paracrine interactions between stromal cells and epithelial of the prostate are thought to play a fundamental role in the regulation of prostate growth. Over the last few years this laboratory has identified a novel nerve growth factor-like protein (neurotrophin) secreted by stromal cells and a corresponding receptor system on the adjacent epithelial cells that mediates paracrine growth of the human prostate. Both low affinity p75 NGF receptors and a member of the high affinity trk tyrosine kinase family of NGF receptors occur in the human prostate. Recently, this laboratory reported that the p75 NGF receptor is progressively lost during neoplastic progression of the human prostate, so that it is completely absent in metastatic prostate tumor cell lines. Since in other cell systems, the p75 receptor is thought to modulate the activity of the trk receptors, we propose to test the hypothesis that during neoplastic progression of the human prostate a defect in p75 expression eliminates modulation of the trk tyrosine kinase receptor, leading to uncontrolled growth of the prostatic epithelial cells. In order to fully investigate the role of NGF receptors in prostate neoplasia it is proposed to examine the immuno- localization of the trk receptor in epithelial cells of the normal, benign and malignant human prostate. As a follow up to these studies the autophosphorylation of the epithelial trk receptor in response to neurotrophin stimulation will be examined by immunoprecipitation of the trk receptor and probing with an antiphosphotyrosine antibody. Subsequently, the effect of growth factors not related to the neurotrophins on NGF receptor expression is to be examined. Finally, we will directly test the hypothesis that loss of the p75 receptor eliminates modulation of the trk receptor leading to uncontrolled growth of the epithelial cells by transfecting the p75 gene back into prostatic tumor cells which we have previously demonstrated lack p75 expression. We will then test the p75 transfectants for reduced trk auto- phosphorylation and reduced growth rate. These studies should provide definitive evidence for the paracrine role of neurotrophin mediated NGF receptor signalling in the growth of the human prostate.
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