Co-evolution of the Reactive Microenvironment in Prostate Cancer Progression

反应性微环境如何影响前列腺癌进展的具体机制尚不清楚。本课题组以前的研究表明，反应性微环境具有类似于创伤修复生物学的性质和基因表达。这些包括基质细胞表型的改变，神经发生的改变和特定T调节细胞的参与。我们还表明，反应性间质是肿瘤的促进剂。这些研究表明，癌细胞和神经表现出相互作用，导致肿瘤的增殖和诱导神经发生。此外，伽玛-西格玛T调节细胞的参与可能在肿瘤进展中发挥重要作用。肌成纤维细胞同时募集到PIN和癌灶中，意味着在这些生物学中有协调的宿主反应，促进了肿瘤的发生。重要的是，我们的团队已经证明，这种反应性微环境的特定生物标记物可以预测人类前列腺癌的复发。这种反应的综合生物学机制和具体机制尚不清楚，可以开发出更有效的预后或新的治疗方法。因此，本项目的总体目标是了解 前列腺癌微环境中的反应性间质、神经发生和免疫反应如何在早期器官受限疾病的发生和发展过程中发挥作用和相互作用。这项研究的目的是了解前列腺癌的关键成分、调节因子和机制，尤其是早期前列腺癌。我们已经组建了一个专家团队，他们将专注于了解肿瘤微环境中相互关联的三种生物学。我们提出了一个由一个表情分析和病理学核心以及三个相互关联的项目组成的项目。 项目1将讨论反应性基质细胞的共同进化、起源和特定的调节因子。 项目2将解决轴突发生和神经发生在调节早期癌症中的作用。 项目3将侧重于伽马-西格玛T调节细胞和通过Toll样受体的信号在前列腺癌进展中的作用。总之，这些项目和Core将提供有关人类组织和小鼠模型中的时间和空间组成、基因表达谱以及潜在的微环境调节器的基本数据。这组研究人员已经合作了几年，并围绕他们预先建立的合作计划了这些研究。该计划的总体目标是提供新的临床前数据， 由此可以开发出针对早期前列腺癌微环境的更有效的生物标记物和治疗药物。

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.