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知之甚少。博士之前的综合研究。 Pienta 和 Rowley 发现肿瘤相关巨噬细胞 (TAM) 和反应性基质都会促进前列腺癌的进展。 Pienta 博士证明了 CCL2 在介导单核细胞/巨噬细胞浸润到肿瘤微环境中以及刺激这些免疫细胞内 TAM 表型变化以促进肿瘤生长方面的调节作用，从而在前列腺肿瘤生长和转移中发挥重要作用。 Rowley 博士证明，人类前列腺癌反应性基质由肌成纤维细胞组成，这些肌成纤维细胞在 PIN 期间启动，并在器官局限性进展期间不断与邻近癌共同进化。该应用的总体假设是，TAM 和反应性基质作为彼此互补的共调节剂，共同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)：定义 TAM 促进肌成纤维细胞分化和功能的机制。该目标将： 1).使用新型转基因小鼠模型定义 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）。使用人类癌症/基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招募中的作用。 3）。使用新型囊泡植入模型比较和对比 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。 4).使用新型骨髓内移植方法评估骨微环境中 CCL2 /TAM 轴破坏对 PCa 细胞归巢、骨生长和骨破坏的影响。具体目标 2 (Rowley)：确定前列腺癌骨转移中反应性基质的组成。该目标将： 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。我们的目标是定义前列腺癌的新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密歇根大学 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以及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。