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

摘要 上皮性卵巢癌（EOC）是美国妇科癌症死亡的主要原因， 尽管EOC治疗取得了进展，但5年生存率一直停滞在约45% 几十年目前的标准治疗方法伴随着毒副作用，并且成本高 化疗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 迫切需要确定低成本的方法，既可以提高对目前疗法的反应， 通过抑制肿瘤进展来存活。热量限制有很强的能力来改变癌症的反应 细胞和宿主细胞在肿瘤微环境中的相互作用，但这种相互作用的机制是难以捉摸的。我们长久以来- 长期目标是确定可以调节以阻止EOC进展的饮食机制， 转化为EOC患者更有效的治疗方法和生活方式的改变。我们的研究 显示在EOC小鼠模型中30%卡路里限制（CR），无营养不良，降低肿瘤负荷， 腹水和转移。此外，我们的初步数据强烈表明，CR抑制EOC是由于 交替激活的促肿瘤发生（M2样）巨噬细胞减少， 经典活化的抗肿瘤巨噬细胞（M1样），导致M1/M2比值增加。这很重要 因为EOC腹水中50%的细胞是促肿瘤发生的巨噬细胞（M2样），并且增加的M1/M2比率是一个重要因素。 EOC患者预后较好的指标。巨噬细胞极化部分通过代谢调节， 重编程，M1样巨噬细胞主要依赖于糖酵解，M2样巨噬细胞主要依赖于糖酵解。 利用有氧呼吸。AMPK是一种众所周知的能量代谢调节剂，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 饮食调节EOC中的巨噬细胞极化。我们的中心假设是AMPK活性的增加 由于CR饮食重塑了糖酵解-三羧酸（TCA）途径，以促进M1（抗肿瘤） 表型，从而导致稳健的抗肿瘤免疫应答和肿瘤的减少。这一假设 将在两个目标中进行测试：目标1将确定CR引起的AMPKα1活性增加对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通过阐明如何使用简单的方法来产生翻译影响， 饮食干预可引起代谢调节变化，这是EOC期间巨噬细胞可塑性的原因。 最终，这一过程可以用来调整新的补充治疗策略和生活方式。 修改以遏制EOC和其他类型癌症的进展。

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.