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 AMPK?1 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.
The proposed research aims to provide a better understanding of the mechanisms by which calorie restriction can impede ovarian cancer progression. Our study will show that calorie restriction can improve anti-tumor immunity by affecting the cellular metabolism of macrophages. This work is directly relevant to public health as the findings of this study will help guide the design of low-cost life-style interventions and precisely targeted therapies for ovarian and other cancers.
