SEX STEROIDS AND GROWTH FACTORS IN PROSTATIC GROWTH

良性前列腺增生和前列腺癌是最常见的 美国男性的增生性和肿瘤性疾病， 两者都在逐年增加。 为了了解细胞和分子基础 在这些疾病中，我们已经开发了小鼠模型， 和啮齿动物体内前列腺肿瘤。 这些模型是根据 观察到非致瘤性间充质细胞可以加速人类 无胸腺小鼠的上皮肿瘤生长。 使用人类前列腺上皮细胞 细胞系LNCaP作为模型，我们观察到前列腺和骨 成纤维细胞在加速LNCaP肿瘤生长方面最有效， 男性宿主 成纤维细胞在肿瘤诱导中的特异性模仿了 人类前列腺癌的自然史，从原发性 有转移到骨头的倾向 我们已经开发出一种新颖 输送浓缩的生长因子（GF）级分的方法， 来自Gelform基质上的体内成纤维细胞条件培养基（CM）， 已经观察到局部血管生成的发生，LNCaP肿瘤生长， 前列腺特异性抗原分泌 在拟议的研究中，我们将继续 以下目标：1）表征存在于 前列腺和骨髓间充质细胞，负责诱导LNCaP 体内肿瘤生长。 我们将定义性类固醇的作用， 参与LNCaP肿瘤的GF和细胞外基质（ECM）途径 生长，使用苏拉明和GF/ECM抗体作为工具。 2)审查 上皮细胞介导的间充质细胞加速机制 体内增殖。 我们将定义和描述性的影响 类固醇、GF和CM在体内和体外对间充质细胞生长影响。 3)到 在无胸腺小鼠中建立BPH和前列腺癌模型， 建立的细胞系（株）或从外科手术中获得的原代细胞系 标本 这些前列腺肿瘤模型对类固醇的敏感性 将检查激动剂和拮抗剂。 4)开发一个三- 三维细胞培养系统，在其中检查的细胞基础， 间质-上皮相互作用。 我们希望这种新的细胞培养 系统将提供一个结构框架，其中上皮细胞 可以表达组织特异性蛋白质，极化分泌功能， 形态发生 这项提案的总体目标是进一步促进我们的 了解间充质细胞的生化和细胞水平， 人BPH和前列腺癌中的上皮相互作用。

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.