Reactive Stroma and Tumor Associated Macrophages in Prostate Cancer Progression

描述(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。Pienta博士和Rowley博士之前的联合研究表明，肿瘤相关巨噬细胞(TAM)和反应性间质都促进前列腺癌的进展。Pienta博士展示了CCL2在前列腺癌生长和转移中的重要作用，它通过调节单核/巨噬细胞向肿瘤微环境的渗透，并刺激这些免疫细胞内TAMs的表型变化来促进肿瘤生长。罗利博士已经证明，人类前列腺癌反应性间质是由肌成纤维细胞组成的，这些成纤维细胞在PIN期间启动，并在器官受限的进展过程中与邻近的癌症持续共同进化。这项应用的总体假设是，TAMs和反应性间质相互补充，共同促进原发灶和转移灶的前列腺癌生长。特异靶向1(Pienta)：确定v/hich TAMs促进肌成纤维细胞分化和功能的机制。这一目标将：1)。使用新的转基因小鼠模型，确定TAMS的存在、反应性间质的发展以及前列腺癌原发和转移性发展之间的时间关系。2)。使用人类癌症/间质重组异种移植模型，确定反应性基质/肌成纤维细胞在巨噬细胞募集中的作用。3)。比较和对比TAMs分泌的影响原发癌和转移性前列腺癌部位肌成纤维细胞分化的因素。4)。使用一种新的骨髓内移植方法，评估骨微环境中CCL2/轴的破坏对PCa细胞归巢、骨中生长和骨破坏的影响。特定目标2(Rowley)：确定前列腺癌骨转移中反应性间质的成分。这一目标将：1)。首次确定在原发癌和转移性前列腺癌中，反应性间质的诱导和TAM的诱导之间的关系。2)。将动物模型中的结果与人类疾病进行比较。我们的目标是定义前列腺癌的新生物标记物和治疗靶点。所有这些目标都将使用贝勒大学和密歇根大学孢子组织银行的前列腺癌样本，包括通过快速尸检程序获得的样本，以及前列腺癌在初级前列腺和骨骼中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.