Functional Role of Bone Marrow Adipocytes in Metastatic Prostate Cancer

骨髓脂肪细胞在转移性前列腺癌中的功能作用

• 批准号: 8789354
• 负责人: Izabela Podgorski
• 金额: $ 31.54万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-06 至 2018-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8789354
• 关键词: Adipocytes; Affect; Age; Agonist; Behavior; Biochemical; Biological Process; Bone Development; Bone Marrow; Bone Marrow Involvement; Bone Resorption; Bone neoplasms; Cancer Detection; Cancer Patient; Cell Culture Techniques; Cell Survival; Cells; Cessation of life; Data; Diet; Disease; Down-Regulation; Exhibits; Exposure to; Fatty Acids; Fatty acid glycerol esters; Future; Genetic; Growth; Health; Human; In Vitro; Incidence; Inflammatory; Interleukin-1; Interleukins; Lead; Lesion; Link; Lipids; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Measurable; Metabolic; Metabolism; Metastatic Lesion; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Modeling; Molecular; Molecular Chaperones; Mus; Neoplasm Metastasis; Obese Mice; Obesity; Outcome; Overweight; PC3 cell line; Patients; Peroxisome Proliferator-Activated Receptors; Prostate; Prostate carcinoma; Radical Prostatectomy; Recurrence; Regulation; Research; Risk Factors; Role; Sampling; Site; Skeleton; Stress; Technology; Testing; Time; Translations; Treatment Protocols; Tumor-Derived; Weight; Work; base; bone; bone metabolism; cell growth; cell type; cytokine; design; genetic manipulation; human FABP4 protein; improved; in vivo; lipid mediator; lipid metabolism; men; mouse model; neoplastic cell; novel; overexpression; prostate cancer cell; protein expression; response; rosiglitazone; skeletal disorder; therapeutic target; tumor; tumor growth; tumor metabolism; tumor progression

DESCRIPTION (provided by applicant): Bone is a primary site of metastasis from prostate cancer (PCa). More than 80% of patients with recurrent PCa suffer from metastatic bone lesions, and there are currently no available treatments that can significantly improve patient outcomes. In order to identify effective therapeutic targets for this devastating and incurable disease, we need to understand the molecular mechanisms that drive tumor cell adaptation, progression and survival in the bone marrow niche. Age and obesity are significant risk factors for development of bone metastatic lesions. In fact, obese and overweight men with PCa are three times more likely to develop metastatic disease compared to normal-weight men with same treatment regimen. The mechanisms behind this association are currently not understood. Both age and obesity greatly increase numbers fat cells (adipocytes) in the bone marrow. Fat cells negatively affect bone metabolism and function, and escalate bone degradation making the bone marrow more supportive of tumor growth. Data from our lab demonstrate that PCa tumors grow larger and progress faster in mice with increased marrow adiposity due to high fat diet. Tumor cells interacting with adipocytes are more invasive and have high expression of protein involved in fat metabolism and transport (i.e., Fatty Acid Binding Protein 4; FABP4) and proinflammatory cytokine IL-1¿. We hypothesize that bone marrow adipocytes promote and support progression of metastatic PCa in bone through the FABP4/IL-1¿-dependent mechanisms. We propose a multi-faceted approach that includes multiple independent mouse models of marrow adiposity, models of intraosseous tumor growth, novel cell culture techniques, pharmacological and genetic manipulation, and lipidomic technology to uncover functional role of bone marrow fat cells in PCa progression in skeleton. We will perform these studies in three Aims. We will: 1) Establish the significance of marrow adipocytes in growth and progression of PCa cells in bone using independent models of marrow adiposity and bone metastasis samples from PCa patients; 2) Elucidate the mechanism of FABP4/IL-1¿ involvement in PCa progression in bone by genetic and biochemical manipulation of fatty acid mobilization and FABP4 expression in vitro and in vivo; and 3) Define the effects of marrow adiposity on fatty acyl lipidome of metastatic tumor cells using lipidomics technology to identify lipid mediators that lead to invasive behavior in tumor cells. Together, our findings will provide functional evidence for involvement of bone marrow fat cells in supporting growth, adaptation and progression of metastatic PCa cells in bone via FABP4/IL-1¿ axis. This work will unravel novel candidate therapeutic targets to provide improvement in patient outcomes. Findings of this work are likely to have high relevance beyond PCa and extend to other bone-trophic cancers.

描述（由申请人提供）：骨骼是前列腺癌（PCa）转移的主要部位。超过80%的复发性PCa患者患有转移性骨病变，目前还没有可以显著改善患者预后的治疗方法。为了确定这种毁灭性和不可治愈的疾病的有效治疗靶点，我们需要了解驱动肿瘤细胞在骨髓小生境中适应，进展和存活的分子机制。 年龄和肥胖是发生骨转移的重要危险因素。事实上，患有PCa的肥胖和超重男性患转移性疾病的可能性是正常体重男性的三倍。这种关联背后的机制目前尚不清楚。年龄和肥胖都大大增加了骨髓中脂肪细胞的数量。 脂肪细胞对骨代谢和功能产生负面影响，并使骨降解加剧，使骨髓更支持肿瘤生长。来自我们实验室的数据表明，PCa肿瘤在由于高脂肪饮食导致骨髓肥胖增加的小鼠中生长得更大，进展更快。与脂肪细胞相互作用的肿瘤细胞更具侵袭性，并且具有参与脂肪代谢和转运的蛋白质的高表达（即，脂肪酸结合蛋白4（FABP 4）和促炎细胞因子IL-1？。我们假设骨髓脂肪细胞通过FABP 4/IL-1？依赖性机制促进和支持骨转移性前列腺癌的进展。 我们提出了一个多方面的方法，包括多个独立的骨髓肥胖小鼠模型，骨内肿瘤生长模型，新的细胞培养技术，药理学和遗传操作，以及脂质组学技术，以揭示骨髓脂肪细胞在骨骼中PCa进展中的功能作用。我们将在三个目标下进行这些研究。我们将：1）使用来自PCa患者的骨髓肥胖和骨转移样品的独立模型，建立骨髓脂肪细胞在骨中PCa细胞生长和进展中的意义; 2）通过体外和体内脂肪酸动员和FABP 4表达的遗传和生化操作，阐明FABP 4/IL-1？参与骨中PCa进展的机制;（3）应用脂质组学技术，明确骨髓肥胖对转移性肿瘤细胞脂肪酰脂质组的影响，以确定导致肿瘤细胞侵袭行为的脂质介质。总之，我们的研究结果将为骨髓脂肪细胞通过FABP 4/IL-1轴参与支持骨中转移性PCa细胞的生长，适应和进展提供功能证据。这项工作将揭示新的候选治疗靶点，以改善患者的预后。这项工作的发现可能具有高度的相关性，超出PCa，并扩展到其他骨营养型癌症。