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。Pienta博士和罗利博士先前的研究表明，肿瘤相关巨噬细胞（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CCL 2在前列腺肿瘤生长和转移中的重要作用，通过其调节作用介导单核细胞/巨噬细胞浸润到肿瘤微环境中，并刺激这些免疫细胞内TAM的表型变化以促进肿瘤生长。罗利博士已经证明，人前列腺癌反应性基质由肌成纤维细胞组成，肌成纤维细胞在PIN期间启动，并在器官局限性进展期间与相邻癌持续共同进化。本申请的总体假设是TAM和反应性基质充当彼此的互补共调节剂，并且一起促进前列腺癌在原发部位和转移部位的生长。具体目标1（Pienta）：通过TAM促进肌成纤维细胞分化和功能来定义机制。这一目标将：1）。使用新型转基因小鼠模型，确定TAM的存在、反应性间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）。使用人类癌症/间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子，使用新的vossicle植入模型。4）。使用新型骨髓内移植方法评估骨微环境中CCL 2/TAM轴的破坏对PCa细胞归巢、骨生长和骨破坏的影响。具体目标2（罗利）：确定前列腺癌骨转移中反应性基质的组成。这一目标将：1）。首次确定原发性和转移性前列腺癌中反应性基质的诱导与TAM的诱导之间的关系。2）。将动物模型中获得的结果与人类疾病进行比较。我们的目标是为前列腺癌定义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U of M SPORE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.