Benign prostatic hyperplasia (BPH) and prostate cancer are the most common hyperplastic and neoplastic diseases in U.S. males, and the incidence of both is increasing yearly. To understand the cellular and molecular basis of these diseases, we have developed mouse models for growing both human and rodent prostate tumors in vivo. These models were developed based on an observation that nontumorigenic mesenchymal cells can accelerate human epithelial tumor growth in athymic mice. Using a human prostate epithelial cell line, LNCaP, as a model, we have observed that prostate and bone fibroblasts are most effective in accelerating LNCaP tumor growth in the male hosts. The fibroblast specificity in tumor induction mimicked the natural history of human prostate cancer, which progresses from its primary with a propensity to metastasize to the bone. We have developed a novel method of delivering concentrated growth factor (GF) fractions obtained from fibroblast-conditioned medium (CM) in vivo on a Gelform matrix and have observed the occurrence of local angiogenesis, LNCaP tumor growth, and prostate specific antigen secretion. In the proposed study, we will pursue the following objectives: 1) To characterize the factor(s) present in prostate and bone mesenchymal cells that is responsible for inducing LNCaP tumor growth in vivo. We will define the role of sex steroids and examine the GF and extracellular matrix (ECM) pathways involved in LNCaP tumor growth, using suramin and GF/ECM antibodies as tools. 2) To examine the mechanism for epithelial cell-mediated acceleration of mesenchymal cell proliferation in vivo. We will define and characterize the effects of sex steroid, GF, and CM on mesenchymal cell growth in vivo and in vitro. 3) To establish both BPH and prostate cancer models in athymic mice, using either established cell lines (strains) or primary lines obtained from surgical specimens. The sensitivity of these prostate tumor models toward steroid agonists and antagonists will be examined. 4) To develop a three- dimensional cell culture system in which to examine the cellular basis of mesenchymal-epithelial interaction. We hope that this new cell culture system will provide a structural frame work in which the epithelial cells can express tissue-specific proteins, polarized secretory functions, and morphogenesis. The overall goal of this proposal is to further our understanding at the biochemical and cellular levels of the mesenchymal- epithelial interaction in human BPH and prostate cancer.
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