Co-evolution of the Reactive Microenvironment in Prostate Cancer Progression

前列腺癌进展中反应性微环境的共同进化

• 批准号: 7494164
• 负责人: DAVID R ROWLEY
• 金额: $ 52.98万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-25 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494164
• 关键词: Co; evolution; Reactive; Microenvironment; Prostate

Specific mechanisms of how the reactive microenvironment affects prostate cancer progression are unknown. Previous studies from our group have shown that the reactive microenvironment has properties and gene expression similar to wound repair biology. These include changes in stromal cell phenotype, altered neurogenesis and the involvement of specific T regulatory cells. We have also shown that reactive stroma is tumor promoting. These studies have shown that carcinoma cells and nerves exhibit reciprocal interactions leading to elevated carcinoma oliferation and induced neurogenesis. In addition, the involvement of gamma-sigma T regulatory cells may play an important role in tumor progression. The concurrent recruitment of myofibroblasts to PIN a nd carcinoma foci implicates a coordinated host response in these biologies that promotes tumorigenesis. Importantly, our group has shown that specific biomarkers of this reactive microenvironment are predictive of recurrence of human prostate cancer. The integrated biologies of this response and specific mechanisms are not yet understood at a level where more effective prognostics or novel therapeutics can be developed. Accordingly, the overall objectives of this project are to understand how reactive stroma, neurogenesis, and immunity responses in prostate cancer microenvironment function and interact mechanistically during the initiation and progression of early, organ confined disease. The endpoint of this study is to understand the key components, regulators, and echanisms with a specific focus on early prostate cancer. We have ssembled a team of experts who will focus their efforts on understanding three interrelated biologies in the tumor microenvironment. We propose a Program composed of an Expression Analysis and Pathology Core and three interrelated Projects. Project 1 will address the co-evolution, origin, and specific regulators of reactive stromal cells. Project .2 will address the role of axonogenesis and neurogenesis in regulating early cancer. Project 3 will focus on the role of gamma-sigma T regulatory cells and signaling through Toll-like receptors in prostate cancer progression. Together, these Projects and Core will provide fundamental data regarding the temporal and spatial composition, gene expression profiling, and potential regulators of the microenvironment in human tissues and mouse models. This group of Investigators has worked together for several years and has planned these studies around their pre-established collaborations. The overall goal of this Program is to provide novel pre-clinical data, from which more effective biomarkers and therapeutics can be developed that target the microenvironment of early prostate cancer.

反应性微环境如何影响前列腺癌进展的特定机制尚不清楚。我们小组的先前研究表明，反应性微环境具有类似于伤口修复生物学的特性和基因表达。这些包括基质细胞表型的变化，神经发生的改变以及特定T调节细胞的参与。我们还表明，反应性基质是肿瘤促进。这些研究表明，癌细胞和神经表现出相互相互作用，导致癌变升高和诱导神经发生。另外，γ-智能调节细胞的参与可能在肿瘤进展中起重要作用。同时募集肌纤维细胞固定癌症和癌灶，这意味着在这些生物学中促进肿瘤发生的宿主反应。重要的是，我们的小组表明，这种反应性微环境的特定生物标志物可以预测人类前列腺癌的复发。在可以开发出更有效的预后或新型治疗剂的水平上，尚未了解这种反应和特定机制的综合生物学。因此，该项目的总体目标是了解 前列腺癌微环境功能中的反应性基质，神经发生和免疫反应如何在早期，器官受到的疾病的启动和进展过程中机械地相互作用。这项研究的终点是了解关键组成部分，调节剂和机构，特别关注早期前列腺癌。我们已经组成了一个专家团队，他们将重点放在了解肿瘤微环境中的三个相互关联的生物学上。我们提出了一个由表达分析和病理核心和三个相互关联的项目组成的程序。 项目1将解决反应性基质细胞的共同进化，起源和特定调节剂。 项目.2将解决轴突生成和神经发生在调节早期癌症中的作用。 项目3将重点介绍伽玛 - sigma T调节细胞的作用，并通过前列腺癌进展中的Toll样受体发出信号传导。这些项目和核心将共同提供有关人体组织和小鼠模型中微环境的潜在调节剂的基本数据，基因表达分析以及潜在的调节剂。这组调查人员已经合作了几年，并围绕了他们的预先合作计划了这些研究。该计划的总体目标是提供新颖的临床前数据， 可以从中开发出更有效的生物标志物和治疗剂，以针对早期前列腺癌的微环境。