Bone Marrow Adipocytes Alter the Metabolic Phenotype of Metastatic Prostate Cancer Cells Through the Activation of HIF-1a

骨髓脂肪细胞通过激活 HIF-1a 改变转移性前列腺癌细胞的代谢表型

• 批准号: 9257574
• 负责人: Jonathan Diedrich
• 金额: $ 1.26万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-27 至 2017-07-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9257574
• 关键词: Adipocytes; Affect; Age; B-Cell Neoplasm; Bone Marrow; Cell Communication; Cells; Characteristics; Complement; Disease; Endocrine; Fatty Acids; Fatty acid glycerol esters; Fermentation; Future; Glycerol; Glycolysis; Growth; Hormones; Hypoxia; In Vitro; Lactic acid; Lesion; Lipids; Malignant Neoplasms; Malignant neoplasm of prostate; Marrow; Metabolic; Metastatic Neoplasm to the Bone; Metastatic Prostate Cancer; Molecular; Mus; Neoplasm Metastasis; Obesity; Patients; Phenotype; Prevention; Process; Regulation; Resistance; Risk Factors; Role; Signal Transduction; Site; Technology; Testing; Therapeutic; Therapeutic Intervention; Treatment Efficacy; Work; base; bone; cancer cell; chemotherapeutic agent; cytokine; design; improved; in vivo; in vivo Model; lipid metabolism; metabolic phenotype; neoplastic cell; new therapeutic target; novel; oxidation; paracrine; pressure; prostate cancer cell; release factor; skeletal; stem; therapeutic target; therapy resistant; tumor; tumor growth; tumor metabolism; tumor progression; uptake

PROJECT SUMMARY Bone is a preferential site of metastasis from prostate cancer (PCa). Age and obesity, conditions that increase adipocyte numbers in bone marrow, are risk factors for skeletal metastases from PCa. Marrow adipocytes are responsible for the secretion of a multitude of factors, such as lipids, cytokines, hormones, fatty acids, and glycerol, that have the propensity to influence neighboring cells. Our focus is on the interactions between adipocytes and tumor cells that have infiltrated the bone marrow. Specifically, we are examining how the secretion, transport, and uptake of adipocyte-supplied factors promote metastatic progression in bone. We have shown that PCa cells exposed to adipocytes undergo increased metabolic pressure towards glycolysis and lactic acid fermentation, a characteristic of the Warburg phenotype. We also demonstrated evidence of adipocyte-induced hypoxia signaling in tumor cells. Since it is well-established that both glycolysis and hypoxia can render tumor cells more aggressive and potentially more resistant to therapies, we hypothesize that adipocyte-supplied within the bone microenvironment cause a metabolic switch to glycolysis in PCa cells, leading to increased aggressiveness and survival of the metastatic tumor in the bone marrow niche. We will test this hypothesis through the following two aims: 1) establish the contribution of adipocyte- supplied lipids to metabolic changes in tumor cells; and 2) determine the adipocyte-induced changes in the PCa cell fatty acyl lipidome and identify key lipid metabolites contributing to altered tumor metabolism and hypoxia. We will utilize in vitro and in vivo models of marrow adiposity in combination with lipidomics technology to examine metabolic effects of adipocyte-tumor cell interactions in bone. The main focus of this proposed project is to elucidate novel mechanisms behind chemoresistance and sustained survival of metastatic PCa tumors in bone and to illuminate therapeutic targets for this presently incurable metastatic disease.

项目概要 骨是前列腺癌 (PCa) 的优先转移部位。年龄和肥胖，增加的条件 骨髓中的脂肪细胞数量是 PCa 骨骼转移的危险因素。骨髓脂肪细胞是 负责多种因子的分泌，例如脂质、细胞因子、激素、脂肪酸和 甘油，有影响邻近细胞的倾向。我们的重点是之间的相互作用 已浸润骨髓的脂肪细胞和肿瘤细胞。具体来说，我们正在研究如何 脂肪细胞提供的因子的分泌、运输和摄取促进骨转移进展。我们 研究表明，暴露于脂肪细胞的 PCa 细胞会经历糖酵解代谢压力增加 和乳酸发酵，这是瓦尔堡表型的一个特征。我们还展示了以下证据 脂肪细胞诱导肿瘤细胞缺氧信号传导。因为众所周知，糖酵解和 我们假设，缺氧会使肿瘤细胞更具攻击性，并且可能对治疗更具抵抗力 骨微环境中提供的脂肪细胞导致 PCa 细胞代谢转变为糖酵解， 导致骨髓微环境中转移性肿瘤的侵袭性和存活率增加。 我们将通过以下两个目标来检验这一假设：1）确定脂肪细胞的贡献- 为肿瘤细胞的代谢变化提供脂质； 2）确定脂肪细胞诱导的变化 PCa 细胞脂肪酰脂质组并鉴定导致肿瘤代谢改变的关键脂质代谢物和 缺氧。我们将利用骨髓肥胖的体外和体内模型与脂质组学相结合 检查骨中脂肪细胞-肿瘤细胞相互作用的代谢影响的技术。本次的主要重点 拟议的项目旨在阐明化疗耐药性和持续生存背后的新机制 骨转移性 PCa 肿瘤，并阐明这种目前无法治愈的转移性肿瘤的治疗靶点 疾病。