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

基本信息

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
项目类别：
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

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

展开

项目摘要

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.

项目摘要骨是前列腺癌（PCA）转移的优先部位。年龄和肥胖，状况增加骨髓中的脂肪细胞数是PCA骨骼转移的危险因素。骨髓脂肪细胞是负责分泌多种因素，例如脂质，细胞因子，激素，脂肪酸和甘油，具有影响相邻细胞的倾向。我们的重点是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供应因子的分泌，运输和摄取可促进骨骼转移性进展。我们已经表明，暴露于脂肪细胞的PCA细胞经历了代谢压力增加的糖酵解和乳酸发酵，这是Warburg表型的特征。我们还证明了肿瘤细胞中脂肪细胞诱导的缺氧信号传导。由于糖酵解和缺氧可以使肿瘤细胞更具侵略性，并且可能对疗法具有更大的抵抗力，我们假设骨微环境中脂肪细胞供应的脂肪细胞会导致代谢转换为PCA细胞中的糖酵解，导致骨髓小裂中转移性肿瘤的攻击性和存活率提高。我们将通过以下两个目的来检验这一假设：1）确定脂肪细胞的贡献为肿瘤细胞的代谢变化提供了脂质。 2）确定脂肪细胞引起的变化 PCA细胞脂肪酰基脂肪组，并鉴定关键的脂质代谢产物，导致肿瘤代谢改变和缺氧。我们将利用体外和体内骨髓肥胖模型与脂质组学结合研究骨骼中脂肪细胞肿瘤细胞相互作用的代谢作用的技术。主要重点拟议的项目是阐明化学耐药性背后的新型机制和持续的生存骨骼中的转移性PCA肿瘤并为此目前无法治愈的转移性照明治疗靶标疾病。