Reactive Stroma and Tumor Associated Macrophages in Prostate Cancer Progression

描述（由申请人提供）：微环境如何调节前列腺癌进展的具体机制仍然知之甚少。结合博士之前的研究。Pienta和Rowley发现肿瘤相关巨噬细胞（tumor associated macrophages, tam）和反应性基质都促进前列腺癌的进展。Pienta博士已经证明了CCL2在前列腺肿瘤生长和转移中的主要作用，通过其调节单核细胞/巨噬细胞浸润到肿瘤微环境中的调节作用，并刺激这些免疫细胞内tam的表型变化，以促进肿瘤生长。Rowley博士已经证明，人类前列腺癌反应性基质由肌成纤维细胞组成，在PIN期间启动，并在器官受限进展期间不断与邻近癌共同进化。该应用的总体假设是tam和反应性基质互为补充的共调节因子，共同促进前列腺癌原发和转移部位的生长。特异性目标1 (Pienta)：通过v/ high确定tam促进肌成纤维细胞分化和功能的机制。本目标将：1)。使用新型转基因小鼠模型确定tam的存在、反应性基质的发展以及原发性和转移性前列腺癌的发展之间的时间关系。2）. 利用人类癌症/基质重组异种移植模型确定反应性间质/肌成纤维细胞在巨噬细胞募集中的作用。3)。比较和对比tam分泌的影响原发性和转移性前列腺癌部位肌成纤维细胞分化的因素，使用一种新的小泡植入模型。4)。使用一种新的骨髓内移植方法评估骨微环境中CCL2 /TAM轴的破坏对PCa细胞归巢、骨生长和骨破坏的影响。特异性目的2 (Rowley)：确定前列腺癌骨转移中反应性基质的组成。本目标将：1)。首次确定在原发性和转移性前列腺癌中诱导反应性基质和诱导tam之间的关系。2）. 将动物模型与人类疾病的结果进行比较。我们的目标是为前列腺癌确定新的生物标志物和治疗靶点。所有这些目标都将使用贝勒大学和M大学孢子组织库中的前列腺癌样本，包括通过快速尸检程序获得的样本和来自原发性前列腺癌和骨骼中前列腺癌生长的小鼠模型的样本。

DESCRIPTION (provided by applicant): The specific mechanisms of how the microenvironment regulates prostate cancer progression remain poorly understood. The combined previous studies of Drs. Pienta and Rowley have revealed that tumor associated macrophages (TAMs) and reactive stroma both promote prostate cancer progression. Dr. Pienta has demonstrated a major role for CCL2 in prostate tumor growth and metastasis through its regulatory role in mediating monocyte / macrophage infiltration into the tumor microenvironment and stimulating a phenotypic change to TAMs within these immune cells to promote tumor growth. Dr. Rowley has demonstrated that human prostate cancer reactive stroma is composed of myofibroblasts that initiate during PIN and continually co-evolve with adjacent carcinoma during organ-confined progression. The overall hypothesis of this application is that TAMs and reactive stroma serve as complementary coregulators of each other and together promote prostate cancer growth in primary and metastatic sites. Specific Aim 1 (Pienta): Define the mechanisms by v/hich TAMs promote myofibroblast differentiation and function. This Aim will: 1). Define the temporal relationship between the presence of TAMs, the development of reactive stroma, and the development of primary and metastatic prostate cancers using novel transgenic mouse models. 2). Determine the role of reactive stroma / myofibroblasts in the recruitment of macrophages using a human cancer / stromal recombination xenograft model. 3). Compare and contrast the factors that are secreted by TAMs that affect the differentiation of myofibroblasts in primary and metastatic prostate cancer sites using a novel vossicle implant model. 4). Assess the effects of disruption of the CCL2 /TAM axis in the bone microenvironment on PCa cell homing, growth in bone and bone destruction using a novel intra-marrow transplant approach. Specific Aim 2 (Rowley): Determine the composition of reactive stroma in prostate cancer bone metastases. This Aim will: 1). Determine for the first time the relationship between the induction of reactive stroma and the induction of TAMs in both primary and metastatic prostate cancers. 2). Compare results obtained in animal models with human disease. Our goal is to define new biomarkers and therapeutic targets for prostate cancer. All of these Aims will use the prostate cancer samples in the Baylor University and U of M SPORE Tissue Banks, including samples obtained through the rapid autopsy program and samples from the mouse models of prostate cancer growth in primary prostate and bone.