The Role of Adipocyte-Induced Inflammation in Prostate Tumor Progression

脂肪细胞诱导的炎症在前列腺肿瘤进展中的作用

基本信息

批准号：
8554289
负责人：
Aimalie Lynnette Hardaway
金额：
$ 3.75万
依托单位：
WAYNE STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8554289
关键词：
Adipocytes Affect Animals Biochemical Biological Assay Bone Marrow Bone Resorption Bone neoplasms Bone remodeling CXCL1 gene CXCL2 gene Cancer Detection Cell Maturation Cell Proliferation Cells Clinical Clinical Treatment Clinical Trials Coculture Techniques Cysteine Protease Data Development Diet Disease Drug Industry Environment Enzyme-Linked Immunosorbent Assay Enzymes Event Extracellular Matrix Extracellular Matrix Degradation Fatty acid glycerol esters Future Goals Growth Homeostasis Immunoblotting In Vitro Inflammation Inflammatory Knock-out Lead Lesion Link Literature Malignant Neoplasms Malignant neoplasm of prostate Marrow Metastatic Neoplasm to the Bone Metastatic Prostate Cancer Modeling Molecular Molecular Biology Mus Neoplasm Metastasis Obesity Obesity associated disease Osteoblasts Osteoclasts Osteoporosis Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Phenotype Play Primary Neoplasm Process Production Prostate Prostatic Neoplasms Recurrence Research Research Personnel Research Subjects Role Signal Pathway Signal Transduction Site Skeleton Subfamily lentivirinae System Technology Testing Therapeutic Intervention Training Translating Tumor Biology Work anticancer research base bone bone cell cancer therapy cathepsin K chemokine collagenase cytokine design experience in vivo inhibitor/antagonist innovation macrophage neoplastic cell novel novel therapeutic intervention response soft tissue therapeutic target tumor tumor growth tumor microenvironment tumor progression

项目摘要

DESCRIPTION (provided by applicant): Bone is a primary site of metastasis from prostate cancer (PCa) and most patients with advanced PCa experience complications from the bone lesions that are incurable. Despite important advances that have been made in PCa research, molecular mechanisms behind PCa bone metastases are not well understood. Emerging literature evidence suggests that conditions like obesity and inflammation, known to disturb homeostasis in the bone microenvironment, and contribute to bone destruction, may be contributing factors to colonization and growth of prostate tumors in the bone. The cysteine protease, cathepsin K (CTSK), is a major collagenase involved in osteoclastic bone resorption. In prostate cancer, CTSK levels are higher in bone metastases compared to corresponding primary tumors and soft tissues from the same patients. In addition, CTSK plays important roles in inflammation and is a newly merging marker of adiposity. Our previous studies have shown that adipocyte maturation is severely impaired in bone marrow of CTSK deficient mice. Progression of prostate tumors in the bones in delayed in the absence of CTSK and correlates with significant reduction in levels of two pro-inflammatory factors that affect tumor aggressiveness and osteoclast differentiation (i.e., CXCL1 and CXCL2), further underlining the role of this protease in inflammation-related tumor aggressiveness in the bone. Therefore, we hypothesize that growth and aggressiveness of metastatic prostate cancer in the bone is driven by the CTSK-expressing bone marrow adipocytes and the adipocyte- driven inflammation involving CXCL1 and CXCL2 chemokines. The project is composed of three specific aims. The Aim 1 is to investigate contributions of bone marrow-derived adipocytes to macrophage inflammation and the consequent increase in prostate tumor cell invasiveness and aggressiveness. The Aim 2 is to determine how adipocyte and macrophage-derived CXCL1 and CXCL2 affect tumor cell proliferation, invasion, extracellular matrix degradation and cytokine profiles in vitro, and how the changes in tumor cell aggressiveness ultimately drive macrophage phenotype in the bone tumor microenvironment. The Aim 3 is to assess direct effects of high fat diet on inflammation of the bone marrow and determine the consequences of the resulting pro-inflammatory state on tumor progression in the bone. These studies will utilize combination of in vivo and in vitro approaches including: tumor cell-adipocyte-macrophage co-culture system, in vivo knockout model of bone metastasis, immunoblotting, ELISA assays, cytokine arrays, RT PCR and Lentivirus knockdown technology. Changes in tumor cell proliferation, invasiveness, extracellular matrix degradation, cytokine profiles, and macrophage phenotype will be studied in response to CXCL1 and CXCL2 as well as potentially other adipocyte and macrophage-derived factors. These studies will validate the importance of CTSK-driven events in bone marrow inflammation and investigate CXCL1 and CXCL2 as novel signaling factors and potential targets for therapeutic intervention in bone metastatic disease. )

描述（由申请人提供）：骨是前列腺癌（PCA）转移的主要部位，大多数患有晚期PCA的患者经历了无法治愈的骨骼病变并发症。尽管PCA研究取得了重要的进步，但PCA骨转移背后的分子机制尚不清楚。新兴文献证据表明，肥胖和炎症等疾病（已知会干扰骨微环境中的稳态，并导致骨骼破坏，可能是骨骼中前列腺肿瘤的定殖和生长的因素。半胱氨酸蛋白酶，组织蛋白酶K（CTSK）是参与整骨骨吸收的主要胶原酶。在前列腺癌中，与同一患者的相应原发性肿瘤和软组织相比，骨转移的CTSK水平更高。此外，CTSK在炎症中起着重要作用，并且是肥胖的新标记。我们先前的研究表明，在CTSK缺乏小鼠的骨髓中，脂肪细胞的成熟严重受损。在缺乏CTSK的情况下延迟前列腺肿瘤的进展，并与影响肿瘤侵袭性和破骨细胞分化的两个促炎因子的水平显着降低（即CXCL1和CXCL2），进一步强调了这种蛋白酶在炎症中的作用，进一步强调了这种蛋白酶在肿瘤中的肿瘤侵袭性中的作用。因此，我们假设骨骼转移性前列腺癌的生长和攻击性是由表达CTSK的骨髓脂肪细胞以及涉及CXCL1和CXCL2趋化因子的脂肪细胞驱动的炎症驱动的。该项目由三个具体目标组成。目的1是研究骨髓衍生的脂肪细胞对巨噬细胞炎症的贡献，并导致前列腺肿瘤细胞的侵袭性和侵袭性的增加。目的2是确定脂肪细胞和巨噬细胞衍生的CXCL1和CXCL2如何在体外影响肿瘤细胞的增殖，侵袭，细胞外基质降解和细胞因子谱，以及肿瘤细胞侵袭性的变化最终如何驱动骨肿瘤微环境中的巨噬细胞表型。目的3是评估高脂肪饮食对骨髓炎症的直接影响，并确定由此产生的促炎状态对骨骼肿瘤进展的后果。这些研究将利用体内和体外方法的组合，包括：肿瘤细胞 - 脂肪细胞 - 巨噬细胞共培养系统，骨转移的体内敲除模型，免疫印迹，ELISA分析，细胞因子阵列，RT PCR和Lentivirus敲除技术。肿瘤细胞增殖，侵入性，细胞外基质降解，细胞因子谱和巨噬细胞表型的变化将响应CXCL1和CXCL2以及其他潜在的脂肪细胞和巨噬细胞的因素。这些研究将验证CTSK驱动的事件在骨髓炎症中的重要性，并研究CXCL1和CXCL2作为新的信号传导因素和潜在的骨转移性疾病治疗干预措施的靶标。）