SMOOTH MUSCLE-EPITHELIAL INTERACTIONS IN PROSTATE CANCER

使用动物和人类模型，该项目的主要目标是 研究平滑肌（SM）细胞和分子机制- 调节生长和分化的上皮相互作用 正常和恶性前列腺上皮（PRE）。前提是 SM在前列腺中分化为相互SM的结果<-> 上皮细胞之间的相互作用， 成人前列腺的结构和功能前列腺癌发生过程中 SM上皮信号传导的进行性扰动<->导致 从去分化的SM细胞发展肿瘤基质， 积极促进或允许前列腺癌发生。追求 该前列腺肿瘤模型，以下具体目标将是 （1）分析PRE对SM细胞与肿瘤细胞的反应， 基质。(2)正常PRE与 前列腺癌细胞对SM细胞分化的影响。（三） 调节PRE的旁分泌因子的鉴定和表征 生长和SM分化。(4)促雄激素机制的研究进展 SM分化。(5)基质调节和可逆性分析 上皮细胞B型钙粘蛋白(6)E-钙粘蛋白系统的表征 和上皮粘附在体外生长的PRE细胞中， 与正常或肿瘤间质细胞，以确定是否影响 在PRE中，基质细胞对E-钙粘蛋白系统的作用是通过直接介导的， 细胞接触或旁分泌作用分子。(7)抑制 通过药理学试剂降低PRE粘附。的具体目标 这项研究将通过分析组织重组体进行检查， 体内，转基因小鼠的使用，细胞培养，免疫细胞化学，以及 各种生物化学和分子方法（RT-PCR，RNA酶保护， 蛋白质印迹、蛋白质纯化和凝胶电泳）。青蛙 预计这项工作将确定新的 可用于区分攻击性与 缓慢生长的前列腺肿瘤此外，有可能这 研究将确定一种或多种调控生长的策略， 前列腺癌细胞的分化和侵袭行为。

Using both animal and human models, the main goal of this project is to investigate cellular and molecular mechanisms of smooth muscle (SM)- epithelial interactions which regulate growth and differentiation of normal and malignant prostatic epithelium (PRE). The hypothesis is that SM differentiates in the prostate as a result of reciprocal SM <-> epithelial interactions that play a homeostatic role in maintaining adult prostatic structure and function. During prostatic carcinogenesis progressive perturbation of SM <-> epithelial signaling leads to development of a tumor stroma from dedifferentiated SM cells which either actively promote or permit prostatic carcinogenesis. To pursue this model of prostatic neoplasia, the following specific aims will be pursued: (l) Analysis of response of PRE to SM cells versus tumor stroma. (2) Analysis of differential effects of normal PRE versus prostatic carcinoma cells on differentiation of SM cells. (3) Identification and characterization of paracrine factors regulating PRE growth and SM differentiation. (4) Analysis of androgenic mechanisms of SM differentiation. (5) Analysis of stromal regulation and reversibility of epithelial B-cadherin. (6) Characterization of the E-cadherin system and epithelial adhesion in PRE cells growing in vitro in association with normal or tumor stromal cells to determination whether effects of stromal cells on the E-cadherin system in PRE is mediated via direct cell contact or paracrine acting molecules. (7) Reversal or inhibition of reduced PRE adhesion by pharmacologic agents. The specific aims of this study will be examined through analysis of tissue recombinants in vivo, use of transgenic mice, cell culture, immunocytochemistry, and a variety of biochemical and molecular methods (RT-PCR, RNase protection, Western blot, protein purification, and gel electrophoresis). Frog the proposed studies it is anticipated that the work will identify new diagnostic markers useful for discriminating between aggressive versus slow growing prostatic tumors. In addition, it is possible that this study will identify one or more strategies for regulating the growth, differentiation and)'or invasive behavior of prostatic carcinoma cells.