Significance of Microenvironment for Prostate Cancer Initiation and Progression

微环境对前列腺癌发生和进展的意义

• 批准号: 7500646
• 负责人: Stephen R. Plymate
• 金额: $ 5.46万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7500646
• 关键词: Age; Aging; Characteristics; Communities; Cytoskeleton; Databases; Development; Environment; Epithelial Cells; Evaluation; Extracellular Matrix; Fibroblasts; Genetic Transcription; Inflammation; Integrins; Laminin; Malignant - descriptor; Malignant neoplasm of prostate; Mediation; Mesenchymal; Mesenchyme; Modeling; Molecular; Oxidative Stress; Pre-Clinical Model; Process; Prostate; Prostate Adenocarcinoma; Proteomics; Purpose; Research; Signal Transduction; Tissue Recombination; Tissues; aged; biological adaptation to stress; carcinogenesis; cell transformation; human monoclonal antibodies; human tissue; paracrine; programs; prostate cancer prevention; repaired; senescence; tumor; tumor growth; tumor progression

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.

最近发现，虽然是前列腺上皮细胞转化为前列腺 腺癌、前列腺的基质成分强烈影响转化过程和 转化细胞的最终命运。该计划将定义人类前列腺基质的成分 微环境、基质细胞和上皮细胞对该环境的贡献以及因素的影响 与前列腺癌的诱发有关，例如年龄、氧化应激、炎症产物、基质上的 成分，以及所选成分的作用机制。该计划产生的产品将 可供研究界使用的内容包括但不限于： 功能性阻断人类 针对基质成分的单克隆抗体、微阵列和蛋白质组数据库、临床前模型 评估人体组织的基质因子。该计划将由三个项目组成，其中包括： 1. 衰老微环境作为致癌因素：目标 1：识别衰老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 特定年龄相关的基质源性旁分泌因子对肿瘤生长/侵袭/的影响 差异化。目标 3：确定 DMA 修复机制的缺陷是否会导致分子老化 肿瘤微环境。目标 4. 评估前列腺基质老化/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. 前列腺癌进展的旁分泌和近分泌介导：目标 1. 组织重组的应用 建立癌症进展模型，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近分泌信号传导模型。 3. 前列腺癌中的层粘连蛋白失调：目的1.定义正常情况下的层粘连蛋白链和整合素亚基 和恶性前列腺组织。目标 2. 确定层粘连蛋白变化在前列腺癌中的功能。目标3。 确定年龄诱导的层粘连蛋白、信号转导和转录对 ECM 蛋白水解重塑的变化 随着间质侵袭的增加。 该提案的目的是确定前列腺环境对发育和发育的影响。 前列腺癌的进展。我们还将确定如何抑制这些微环境因素 可用作前列腺癌预防和进展的潜在疗法。