Roles of proinflammatory chemokines linking obesity and ovarian cancer

促炎趋化因子在肥胖和卵巢癌中的作用

• 批准号: 9211646
• 负责人: DEOK-SOO SON
• 金额: $ 7.28万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9211646
• 关键词: Adipocytes; Affect; African American; Ascites; Automobile Driving; CD-1 Nude Mouse; CRISPR/Cas technology; CXCL1 gene; Cancer Patient; Cardiovascular Diseases; Cause of Death; Cell Proliferation; Cells; Cessation of life; Chronic; Diabetes Mellitus; Diet; Enzyme-Linked Immunosorbent Assay; Epidemiology; Ethnic group; Evaluation; Female; Foundations; Future; Health; Hematoxylin and Eosin Staining Method; Human; IL8RB gene; Immunohistochemistry; In Vitro; Incidence; Inflammation; Inflammatory; Interleukin-8B Receptor; Knock-out; Knockout Mice; Leptin; Life Expectancy; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Modeling; Molecular; Monitor; Morbidity - disease rate; Mutation; Neoplasm Metastasis; Obese Mice; Obesity; Outcome; Patients; Peritoneal; Population; Postmenopause; Preventive; Protocols documentation; Quality of life; Regulation; Risk Factors; Role; Sampling; Serous; Signal Transduction; Staining method; Stains; Survival Rate; System; TP53 gene; The Vanderbilt-Ingram Cancer Center at the Vanderbilt University; Therapeutic; Time; Tumor Burden; Tumor Tissue; Woman; base; bioluminescence imaging; cancer cell; cancer health disparity; cancer survival; cell growth; cell type; chemokine; health disparity; improved; lipid biosynthesis; migration; mortality; mutant; prevent; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenic

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. !

概括 肥胖在人群中正在迅速增加，是发病和死亡率的可预防原因 全世界。肥胖可以降低预期寿命，并增加健康问题，包括心血管疾病， 糖尿病和癌症。特别是，肥胖是健康分配的一个大问题，揭示了非洲的最高比率 与其他种族相比，美国（AA）妇女。最近积累的证据表明肥胖症 是卵巢癌的危险因素，导致卵巢癌患者的生活质量较差。 肥胖者患癌症，癌症更糟，死于癌症的频率要比瘦瘦弱的人多。生存 与白人妇女相比，AA女性的卵巢癌更糟。不幸的是，这种差异已经过去了 时间。尽管肥胖与低癌症存活率之间存在流行病学联系，但对此知之甚少 肥胖会影响卵巢癌进展的分子机制。最近我们确定了一个 促炎性趋化因子谱与肥胖症和卵巢癌联系起来。因为肥胖被认为是 慢性炎症状态，脂肪细胞和卵巢癌细胞之间的串扰可以驱动炎症 通过阐述促进癌症进展的促炎性趋化因子的负担。最终是 部分原因是高死亡率。该提议将定义肥胖促进的角色 关于卵巢癌进展的促炎趋化因子。我们将阐明这种肥胖的作用 使用CXCR2对卵巢癌进展的促炎趋化因子炎症燃烧 敲除或肥胖的老鼠。基于高级浆液卵巢癌中的p53的大量突变（约96％）， 与p53野生型相比 细胞，我们将确定肥胖与产生更高的分子机制 p53突变体卵巢癌中的促炎性趋化因子伯嫩。这些发现将提供更深的 了解将肥胖和卵巢癌进展联系起来的促炎性趋化因子的作用。 可以预见的是，这些早期结果将指导治疗策略以改善女性癌症的生存， 特别是对于肥胖的癌症患者。最后，防止和减少肥胖将为 卵巢癌患者的长期生存并改善其生活质量。 呢