Significance of Microenvironment for Prostate Cancer Initiation and Progression

描述(申请人提供)：最近有证据表明，尽管转化为前列腺的是前列腺上皮细胞 腺癌，前列腺癌的间质成分，强烈影响转化过程和 转化细胞的最终命运。该程序将定义人类前列腺间质的成分 微环境、基质细胞和上皮细胞对微环境的贡献及因素的影响 与前列腺癌的诱发有关，如年龄、氧化应激、炎症产物、间质 组件，以及选定组件的作用机制。此计划产生的产品将 可供研究社区使用的内容包括但不限于：功能阻止人类 抗基质成分的单抗，微阵列和蛋白质组数据库，临床前模型 人体组织基质因子的评价。该方案将包括三个项目，其中包括： 1.老年微环境在癌症发生中的作用：目的1：确定癌症发生的分子变化 与衰老相关的基质的主要细胞和基质成分。目标2：确定 特定年龄相关间质衍生旁分泌因子对肿瘤生长/侵袭的影响 差异化。目标3：确定DNA修复机制的缺陷是否导致脑内分子老化 肿瘤微环境。目的4.评估前列腺间质衰老/衰老假说 增加创伤/应激反应的特性(与Plymate Project共同目标)。 2.旁分泌和辅助分泌调节前列腺癌进展：目的1.使用组织重组 为了模拟癌症的进展，目标2。鉴定和表征细胞间充质调节因子 前列腺发育。目的3.肿瘤和衰老成纤维细胞参与的辅助性他克林信号模型。 3.前列腺癌中层粘连蛋白的异常调节：目的1.明确正常前列腺癌中层粘连蛋白链和整合素亚单位的表达 和恶性前列腺组织。目的2.确定层粘连蛋白在前列腺癌中的功能变化。目标3. 测定AGE对ECM蛋白水解性重塑中层粘连蛋白、信号转导和转录的影响 随着对间充质的侵袭增加。 这项建议的目的是定义前列腺环境对发育和 前列腺癌的进展。此外，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治疗方法。

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.