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

• 批准号: 8396083
• 负责人: Aimalie Lynnette Hardaway
• 金额: $ 3.7万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 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/8396083
• 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 progression

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. ) PUBLIC HEALTH RELEVANCE: The findings of these studies will have a significant impact on current research and available treatments for prostate cancer because: 1) Cathepsin K inhibitors are currently in clinical trials for treatment of osteoporosis. Validating a causal rolefor this enzyme in metastasis of prostate tumors to the bone could be rapidly translated into clinical trials using cathepsin K inhibitors in patients with recurrent prostate cancer; 2) Fat cells have recently been recognized as potential therapeutic targets in obesity-related diseases, a concept that has not yet been applied to prostate cancer. An understanding of the role of marrow adipocytes in prostate cancer progression and metastasis could lead to identification of new therapeutic interventions; and 3) There is clinical evidence for a causative link between inflammation and advanced prostate cancer. The proposed studies will examine the involvement of cathepsin K in bone marrow inflammation and its subsequent effect on prostate tumor biology. This could result in development of new therapies or novel applications of already existing drugs. Ultimately, these studies should lead to identification of novel signaling pathways and molecular mechanisms predisposing prostate cells to metastasize to bone.

描述（由申请人提供）：骨是前列腺癌（PCa）转移的主要部位，大多数晚期前列腺癌患者的骨病变并发症是无法治愈的。尽管前列腺癌研究取得了重要进展，但前列腺癌骨转移的分子机制尚不清楚。新出现的文献证据表明，肥胖和炎症等已知会扰乱骨微环境的内稳态，并导致骨破坏，可能是导致前列腺肿瘤在骨中的定植和生长的因素。半胱氨酸蛋白酶组织蛋白酶K （CTSK）是参与破骨细胞骨吸收的主要胶原酶。在前列腺癌中，与来自同一患者的相应原发肿瘤和软组织相比，骨转移中的CTSK水平更高。此外，CTSK在炎症中发挥重要作用，是一种新兴的肥胖标志物。我们之前的研究表明，CTSK缺陷小鼠骨髓中脂肪细胞成熟严重受损。在缺乏CTSK的情况下，骨骼中前列腺肿瘤的进展延迟，并与影响肿瘤侵袭性和破骨细胞分化的两种促炎因子（即CXCL1和CXCL2）水平的显著降低相关，进一步强调了该蛋白酶在炎症相关的骨骼肿瘤侵袭性中的作用。因此，我们假设骨转移性前列腺癌的生长和侵袭性是由表达ctsk的骨髓脂肪细胞和涉及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是研究骨髓源性脂肪细胞对巨噬细胞炎症的贡献，以及随之而来的前列腺肿瘤细胞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来源的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影响。这些研究将采用体内和体外相结合的方法，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检测，细胞因子阵列，RT PCR和慢病毒敲除技术。肿瘤细胞增殖、侵袭性、细胞外基质降解、细胞因子谱和巨噬细胞表型的变化将被研究，以响应CXCL1和CXCL2，以及潜在的其他脂肪细胞和巨噬细胞衍生因子。这些研究将验证ctsk驱动事件在骨髓炎症中的重要性，并研究CXCL1和CXCL2作为骨转移性疾病治疗干预的新信号因子和潜在靶点。