Roles of proinflammatory chemokines linking obesity and ovarian cancer

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SUMMARY Obesity is increasing rapidly in the population and is a leading preventable cause of morbidity and mortality worldwide. Obesity reduces life expectancy and increases health problems including cardiovascular disease, diabetes and cancer. Particularly, obesity is a big issue of health disparities, revealing the highest rate in African- American (AA) women compared to other ethnic groups. Recently accumulated evidence indicates that obesity is a risk factor for ovarian cancer, leading to poorer quality-of-life outcomes in patients with ovarian cancer. Obese people get more cancer, worse cancer, and die more often from cancer than lean people. Survival of ovarian cancer is worse in AA women compared to white women. Unfortunately, this disparity has widened over time. In spite of an epidemiological link between obesity and low cancer survival rates, little is known about the molecular mechanisms by which obesity affects the progression of ovarian cancer. Recently we identified a proinflammatory chemokine profile linking obesity and ovarian cancer. Because obesity is recognized as a chronic state of inflammation, crosstalk between adipocytes and ovarian cancer cells can drive the inflammatory burden via the elaboration of proinflammatory chemokines that promote cancer progression. This eventually is in part responsible for high mortality rates. This proposal will define the roles of obesity-promoted proinflammatory chemokines on the progression of ovarian cancer. We will clarify the role of this obesity-derived inflammatory burden via proinflammatory chemokines on the progression of ovarian cancer using CXCR2 knockout or obese mice. Based on massive mutation (∼96%) of p53 in a high-grade serous ovarian cancer and a higher link of proinflammatory chemokines between obesity and p53 mutant cells compared to p53 wild-type cells, we will determine the molecular mechanisms by which obesity is involved in producing this higher proinflammatory chemokine burden in p53 mutant ovarian cancer. The findings will provide a deeper understanding of the role of proinflammatory chemokines that link obesity and the progression of ovarian cancer. It is envisaged that these early results will direct therapeutic strategies to improve women cancer survival, particularly for obese cancer patients. Finally, preventing and reducing obesity will provide a firm foundation for long-term survival of ovarian cancer patients and improve their quality of life. !