Reactive Stroma and Tumor Associated Macrophages in Prostate Cancer Progression

前列腺癌进展中的反应性基质和肿瘤相关巨噬细胞

• 批准号: 7978318
• 负责人: KENNETH J. PIENTA
• 金额: $ 57.39万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-07 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7978318
• 关键词: Affect; Animal Model; Antibodies; Autopsy; Biological Markers; Biology; Bone Marrow; CCL2 gene; Carcinoma; Cells; Data; Development; Elements; Enzymes; Evolution; Funding; Genetic Recombination; Goals; Growth; Growth Factor; Health; Homing; Human; Immune; Implant; Infiltration; Knowledge; Lesion; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Matrix Metalloproteinases; Mediating; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Michigan; Modeling; Monocyte Chemoattractant Protein-1; Myofibroblast; Neoplasm Metastasis; Organ; Osteoclasts; Patients; Principal Investigator; Production; Prostate; Prostatic Neoplasms; Reproduction spores; Role; Sampling; Signal Transduction Pathway; Site; Testing; Time; Tissue Banking; Tissue Banks; Tissues; Transgenic Mice; Transplantation; Universities; Vacuum; Work; Wound Healing; Xenograft Model; bone; cancer cell; cancer site; effective therapy; human disease; insight; macrophage; monocyte; mouse model; novel; programs; response; therapeutic target; tumor; tumor growth; tumor progression; tumorigenesis

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.

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很少了解。先前对DRS的总合并研究。 Pienta和Rowley表明肿瘤相关的巨噬细胞（TAM）和反应性基质都促进了前列腺癌的进展。 Pienta博士通过调节在将单核细胞 /巨噬细胞浸润到肿瘤微环境中介导单核细胞 /巨噬细胞中的调节作用，在前列腺肿瘤生长和转移中表现出了主要作用，并刺激了这些免疫细胞中TAM的表型变化，以促进肿瘤的生长。 Rowley博士表明，人类前列腺癌反应性基质由在PIN期间启动的肌纤维细胞组成，并在器官构造的进展过程中与相邻癌不断共同进化。该应用的总体假设是TAM和反应性基质是彼此的互补分析剂，并共同促进了原发性和转移性部位的前列腺癌的生长。特定目标1（Pienta）：通过V/HICH TAM定义机制促进肌纤维细胞的分化和功能。这个目标将：1）。定义TAM的存在，反应性基质的发展以及使用新型转基因小鼠模型的原代和转移性前列腺癌的发展之间的时间关系。 2）。使用人类癌 /基质重组异种移植模型来确定反应性基质 /肌纤维细胞在募集巨噬细胞中的作用。 3）。比较和对比使用新型伏击植入物模型，TAM分泌的TAM分泌的因素会影响原发性和转移性前列腺癌部位的分化。 4）。评估CCL2 /TAM轴破坏骨微环境对PCA细胞寄养，使用新型的果内移植方法的影响。特定目标2（Rowley）：确定前列腺癌骨转移中反应性基质的组成。这个目标将：1）。首次确定反应性基质的诱导与原代和转移性前列腺癌中TAM的诱导之间的关系。 2）。比较在患有人类疾病的动物模型中获得的结果。我们的目标是为前列腺癌定义新的生物标志物和治疗靶标。所有这些目标都将在贝勒大学和M孢子组织库中使用前列腺癌样品，包括通过快速尸检程序获得的样品以及从原发性前列腺和骨骼中前列腺癌生长的小鼠模型中获得的样品。