Significance of Microenvironment for Prostate Cancer Initiation and Progression

描述（由申请人提供）：最近已经变得明显的是，尽管是前列腺上皮细胞转化为前列腺上皮细胞， 在腺癌中，前列腺的基质成分强烈影响转化过程， 转化细胞的最终命运。该程序将定义人前列腺基质的组成部分， 微环境，基质和上皮细胞对该环境的贡献以及因素的影响 与前列腺癌的诱导相关，例如年龄、氧化应激、炎症产物， 组分和所选组分的作用机制。该计划产生的产品将 可供研究界使用的将包括但不限于：功能性阻断人类 基质成分的单克隆抗体，微阵列和蛋白质组学数据库， 评价基质因子对人体组织的影响。该计划将包括三个项目，其中包括： 1.老年微环境作为致癌作用的贡献者：目的1：确定老年微环境中的分子变化。 与衰老相关的基质的主要细胞和基质成分。目标2：确定 特定年龄相关基质源性旁分泌因子对肿瘤生长/侵袭/ 分化目的3：确定DMA修复机制的缺陷是否有助于分子老化， 肿瘤微环境目标4。评价前列腺基质老化/衰老的假设 增加伤口/应激反应的特征（与Plymate项目共同目标）。 2.旁分泌和旁分泌介导前列腺癌进展：目的1。使用组织重组 对癌症进展进行建模，目标2。间充质调节因子的鉴定和表征 前列腺发育目标3。涉及肿瘤和衰老成纤维细胞的Juxtacrine信号传导模型。 3.层粘连蛋白在前列腺癌中的异常调节：目的1.确定正常前列腺癌中层粘连蛋白链和整合素亚基 和恶性前列腺组织。目标2.层粘连蛋白在前列腺癌中的作用。目标3： 确定年龄诱导的层粘连蛋白、信号传导和转录对ECM蛋白水解重塑的影响 间充质的侵袭增加 该提案的目的是确定前列腺环境对发育的影响， 前列腺癌的发展我们还将确定如何抑制这些微环境因素 可作为前列腺癌预防和进展的潜在疗法。

DESCRIPTION (provided by applicant): Recently it has become evident that although it is the prostate epithelial cell that is transformed into prostate adenocarcinoma, the stromal components of the prostate strongly influence the transformation process and ultimate fate of the transformed cell. This program will define the components of the human prostate stromal microenvironment, the contribution of stromal and epithelial cells to this environment and effects of factors associated with induction of prostate cancer e.g. age, oxidative stress, inflammation product, on the stromal components, and mechanisms of action of selected components. Products arising from this program that will be available to the research community will include but are not limited to: functional blocking human monoclonal antibodies to matrix components, microarray and proteomic databases, preclinical models for evaluation of stromal factors on human tissue. This program will consist of three projects that include: 1. The Aged Microenvironment as a Contributor to Carcinogenesis :Aim 1: Identify molecular changes in the major cellular and matrix constituents of stroma that occur in association with aging. Aim 2: Determine the influence of specific age-associated stromal-derived paracrine factors toward tumor growth/ invasion/ differentiation. Aim 3: Determine if deficiencies in DMA repair mechanisms contribute to molecular aging in the tumor microenvironment. Aim 4. Evaluate hypothesis that aging/senescence of prostate stroma increases characteristics of wound/stress response (co-Aim with Plymate Project). 2. Paracrine and Juxtacrine Mediation of Prostate Cancer Progression : Aim 1. Use of tissue recombination to model cancer progression, Aim 2. Identification and characterization of mesenchymal regulators of prostate development. Aim 3. Juxtacrine signaling models involving tumor and senescent fibroblasts. 3. Laminin Dysregulation in Prostate Cancer: Aim1.Define the laminin chains and integrin subunits in normal and malignant prostate tissue. Aim 2. Determine function of laminin changes in prostate cancer. Aim 3. Determine age-induced changes in laminin, signaling and transcription on proteolytic remodeling of ECM with increased invasion of the mesenchyme. The purpose of this proposal is to define the effects of the prostate environment on development and progression of prostate cancer. Also we will determine how inhibition of these microenvironmental factors can be used as potential therapy for prostate cancer prevention and progression.