Determining the mechanisms by which calorie restriction alters macrophage polarization to promote an anti-tumor environment in epithelial ovarian cancer

确定热量限制改变巨噬细胞极化以促进上皮性卵巢癌抗肿瘤环境的机制

• 批准号: 10133026
• 负责人: Ramandeep Rattan
• 金额: $ 34.43万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10133026
• 关键词: 5' -AMP-activated protein kinase; Address; Affect; Antitumor Response; Ascites; Caloric Restriction; Cancer Biology; Cancer Patient; Cell Respiration; Cells; Cessation of life; Citric Acid Cycle; Cyclic AMP-Dependent Protein Kinases; Data; Development; Dietary Intervention; Energy Metabolism; Environment; Epithelial ovarian cancer; Equilibrium; Exhibits; Fatty acid glycerol esters; Financial Hardship; Glycolysis; Goals; Greater sac of peritoneum; Growth; Immune; Implant; Knockout Mice; Knowledge; Lead; Life Style; Life Style Modification; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Malnutrition; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mus; Neoplasm Metastasis; Operative Surgical Procedures; Outcome; Ovarian; Pathogenesis; Pathway interactions; Patients; Peritoneal; Permeability; Phenotype; Platinum; Population; Process; Production; Prognosis; Public Health; Publishing; Quality of life; Regimen; Research; Resources; Respiration; Survival Rate; Testing; Therapeutic; Transgenic Mice; Translating; Tricarboxylic Acids; Tumor Burden; Tumor Immunity; Tumor-associated macrophages; United States; Work; anti-tumor immune response; base; cancer cell; cancer therapy; cancer type; chemotherapy; cost; design; dietary; dietary approach; dietary restriction; effective therapy; improved; in vivo; lifestyle intervention; macrophage; metabolomics; mouse model; novel; response; side effect; targeted treatment; taxane; translational impact; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenic; western diet

ABSTRACT Epithelial Ovarian Cancer (EOC) is the leading cause of gynecologic cancer death in the United States, and despite the advances made in EOC therapy, the five-year survival rate has been stagnant at approximately 45% for decades. The current standard therapeutic approach is accompanied by toxic side effects, and the high cost of chemotherapy places an enormous financial burden on patients, reducing their quality of life. Thus, there is a critical need to identify low-cost approaches that can both enhance responses to current therapies and improve survival by inhibiting tumor progression. Calorie Restriction has a strong capacity to alter the responses of cancer cells and host cells in the tumor microenvironment, yet the mechanisms of such cross-talk are elusive. Our long- term goal is to identify dietary mechanisms that can be modulated to impede EOC progression and thus be translated into the development of more effective therapies and lifestyle changes for EOC patients. Our studies show that 30% calorie restriction (CR), without malnutrition, in a mouse model of EOC decreases tumor burden, ascites, and metastases. Additionally, our preliminary data strongly suggest that CR inhibits EOC due to a decrease in alternatively-activated pro-tumorigenic (M2-like) macrophages and a corresponding increase in classically-activated anti-tumor macrophages (M1-like), resulting in an increased M1/M2 ratio. This is important as 50% of cells in EOC ascites are pro-tumorigenic macrophages (M2-like) and an increased M1/M2 ratio is an indicator of better prognosis in EOC patients. Macrophage polarization is regulated, in part, through metabolic reprogramming, with M1-like macrophages mainly relying on glycolysis and M2-like macrophages primarily utilizing aerobic respiration. AMPK, a well-known regulator of energy metabolism, controls the balance between glycolysis and mitochondrial respiration and our studies demonstrate that mice fed a CR diet have increased AMPK activity. The overall objective of the proposed research is to determine the mechanism by which a CR diet regulates macrophage polarization in EOC. Our central hypothesis is that the increased activity of AMPK due to a CR diet remodels the glycolysis-tricarboxylic acid (TCA) pathway to promote an M1 (anti-tumor) phenotype, thus leading to a robust anti-tumor immune response and reduction of the tumor. This hypothesis will be tested in two aims: Aim 1 will identify the effects of increased AMPKα1 activity due to CR on the EOC progression, and Aim 2 will determine the mechanisms underlying CR-mediated macrophage polarization in EOC. The proposed study is expected to have a translational impact by elucidating how the simple approach of dietary intervention can cause metabolic regulatory changes responsible for macrophage plasticity during EOC. Ultimately, this process could be exploited to tailor novel complementary therapeutic strategies and life-style modifications to curb progression of EOC and other types of cancer.

摘要 卵巢上皮癌(EOC)是美国妇科癌症死亡的主要原因， 尽管在EOC治疗方面取得了进展，但五年存活率一直停滞不前，约为45% 几十年来。目前的标准治疗方法伴随着毒副作用，而且成本很高 化疗的失败给患者带来了巨大的经济负担，降低了他们的生活质量。因此，有一个 迫切需要确定既能增强对当前疗法的反应又能改进的低成本方法 通过抑制肿瘤进展而存活。限制卡路里摄入有很强的改变癌症反应的能力 细胞和宿主细胞在肿瘤微环境中，然而这种串扰的机制是难以捉摸的。我们的长- 学期目标是确定可以调节以阻碍EoC进展的饮食机制，从而 转化为为EoC患者开发更有效的治疗方法和改变生活方式。我们的研究 显示30%卡路里限制(CR)，在没有营养不良的情况下，在EOC小鼠模型中，降低了肿瘤负担， 腹水和转移瘤。此外，我们的初步数据强烈表明，CR由于一种 交替激活的促肿瘤(M2样)巨噬细胞减少和相应的增加 经典激活的抗肿瘤巨噬细胞(类M1)，导致M1/M2比率增加。这事很重要 由于EOC腹水中50%的细胞是促肿瘤的巨噬细胞(M2样)，并且M1/M2比率的增加是 EoC患者预后较好的指标。巨噬细胞极化在一定程度上是通过代谢调节的。 重编程，类M1巨噬细胞主要依赖糖酵解，类M2巨噬细胞主要依赖糖酵解 利用有氧呼吸。AMPK是一种著名的能量代谢调节剂，它控制着 糖酵解和线粒体呼吸，我们的研究表明，喂食CR饮食的小鼠增加了 AMPK活性。拟议研究的总体目标是确定CR 饮食对EOC中巨噬细胞极化的调节作用我们的中心假设是AMPK活性的增加 由于CR饮食改变了糖酵解-三羧酸(TCA)途径，促进了M1(抗肿瘤) 表型，从而导致强大的抗肿瘤免疫反应和肿瘤的减少。这一假设 将在两个目标中进行测试：目标1将确定由于CR而增加的AMPKα1活性对EoC的影响 Aim 2将确定CR介导的巨噬细胞极化的潜在机制。 平等机会委员会。拟议的研究预计将产生翻译影响，因为它阐明了简单的方法是如何 饮食干预可导致EOC期间巨噬细胞可塑性的代谢调节变化。 最终，这一过程可以被用来定制新的补充治疗策略和生活方式 为抑制EOC和其他类型癌症的进展而进行的修改。