Co-evolution of the Reactive Microenvironment in Prostate Cancer Progression

反应性微环境影响前列腺癌进展的具体机制尚不清楚。本课题组前期研究表明，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改变，神经发生的改变和特异性T调节细胞的参与。我们还发现反应性间质促进肿瘤生长。这些研究表明，癌细胞和神经表现出相互作用，导致癌细胞增殖升高并诱导神经发生。此外，γ -sigma T调节细胞的参与可能在肿瘤进展中发挥重要作用。肌成纤维细胞对PIN和癌灶的同时募集暗示了这些生物学中促进肿瘤发生的协调宿主反应。重要的是，我们的研究小组已经表明，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。这种反应的综合生物学和具体机制尚不清楚，尚不能开发出更有效的预后或新的治疗方法。因此，该项目的总体目标是了解前列腺癌微环境中反应性基质、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发展过程中发挥作用和相互作用。本研究的目的是了解早期前列腺癌的关键成分、调节因子和机制。我们已经组建了一个专家团队，他们将集中精力了解肿瘤微环境中三个相互关联的生物学。我们提出了一个方案

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 proliferation 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 and 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 mechanisms with a specific focus on early prostate cancer. We have assembled 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.