Roles of proinflammatory chemokines linking obesity and ovarian cancer

总结 肥胖症在人口中迅速增加，是发病率和死亡率的主要可预防原因 国际吧肥胖会降低预期寿命，增加健康问题，包括心血管疾病， 糖尿病和癌症特别是，肥胖是健康差距的一个大问题，揭示了非洲最高的比例- 美国（AA）妇女与其他种族群体相比。最近积累的证据表明，肥胖 是卵巢癌的危险因素，导致卵巢癌患者的生活质量较差。 肥胖的人比瘦人更容易得癌症，癌症更严重，死于癌症的几率也更高。生存 与白色女性相比，AA女性的卵巢癌更严重。不幸的是，这种差距已经扩大， 时间尽管肥胖和癌症存活率低之间存在流行病学联系，但人们对肥胖的影响知之甚少。 肥胖影响卵巢癌进展的分子机制。最近我们发现了一个 促炎性趋化因子与肥胖和卵巢癌相关。因为肥胖被认为是 慢性炎症状态下，脂肪细胞和卵巢癌细胞之间的串扰可以驱动炎症 通过制造促进癌症进展的促炎趋化因子来减轻负担。这最终是 部分原因是高死亡率。这项提案将界定肥胖促进的作用， 促炎趋化因子对卵巢癌进展的影响。我们将阐明这种肥胖衍生的作用， 使用CXCR 2通过促炎趋化因子对卵巢癌进展的炎症负荷 敲除或肥胖小鼠。基于高级别浆液性卵巢癌中p53的大量突变（> 96%）， 与p53野生型相比，肥胖和p53突变细胞之间促炎趋化因子的联系更高 细胞，我们将确定肥胖参与产生这种更高的分子机制。 p53突变型卵巢癌中促炎趋化因子负荷这些发现将提供更深入的 了解促炎趋化因子在肥胖和卵巢癌进展之间的作用。 据设想，这些早期结果将指导治疗策略，以提高妇女癌症生存率， 特别是对于肥胖的癌症患者。最后，预防和减少肥胖将为以下方面提供坚实的基础： 卵巢癌患者的长期生存和提高他们的生活质量。 !

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. !