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。我们小组以前的研究表明，反应性微环境具有与伤口修复生物学相似的特性和基因表达。这些包括基质细胞表型的变化，改变神经发生和特定的T调节细胞的参与。我们还表明，反应性间质是肿瘤促进。这些研究表明，癌细胞和神经表现出相互作用，导致癌细胞数量增加， 并诱导神经发生。此外，γ-σ T调节细胞的参与可能在肿瘤进展中起重要作用。肌成纤维细胞向PIN和癌灶的同时募集暗示了这些生物制剂中促进肿瘤发生的协调宿主应答。重要的是，我们的研究小组已经证明，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。这种反应的综合生物学和具体机制尚未被理解到可以开发更有效的药物或新疗法的水平。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基质、神经发生和免疫反应如何在早期器官局限性疾病的发生和进展过程中发挥作用并相互作用。本研究的终点是了解关键成分，调节因子和机制，特别关注早期前列腺癌。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三种相互关联的生物学。我们提出了一个由表达分析和病理学核心和三个相互关联的项目组成的计划。 项目1将解决反应性基质细胞的共同进化，起源和特异性调节因子。 项目.2将探讨轴突发生和神经发生在调节早期癌症中的作用。 项目3将重点关注gamma-sigma T调节细胞的作用和通过Toll样受体在前列腺癌进展中的信号传导。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时空组成、基因表达谱和潜在调控因子的基本数据。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， 由此可以开发出靶向早期前列腺癌微环境的更有效的生物标志物和治疗剂。

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.