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: 10012771
• 负责人: DEOK-SOO SON
• 金额: $ 8.15万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-26 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012771
• 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; Histologic; 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; Quantitative Reverse Transcriptase PCR; Regulation; Risk Factors; Role; Sampling; Serous; Signal Transduction; Stains; Survival Rate; System; TP53 gene; The Vanderbilt-Ingram Cancer Center at the Vanderbilt University; Therapeutic; Thinness; Time; Tumor Burden; Tumor Tissue; Wild Type Mouse; Woman; base; bioluminescence imaging; cancer cell; cancer health disparity; cancer survival; cell growth; cell type; chemokine; gamma-Chemokines; health disparity; improved; lipid biosynthesis; migration; mortality; mutant; prevent; 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. !

摘要 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 全世界。肥胖会减少预期寿命，增加包括心血管疾病在内的健康问题， 糖尿病和癌症。特别是，肥胖是健康差距的一个大问题，揭示了非洲最高的肥胖率-- 美国(AA)女性与其他种族的比较。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。 肥胖的人比瘦的人得更多的癌症，更严重的癌症，死于癌症的几率更高。幸存的 与白人女性相比，AA女性的卵巢癌更严重。不幸的是，这种差距已经扩大。 时间到了。尽管肥胖与低癌症存活率之间存在流行病学联系，但人们对肥胖与癌症低存活率之间的关系知之甚少。 肥胖影响卵巢癌进展的分子机制。最近我们发现了一种 促炎症性趋化因子与肥胖和卵巢癌的关系。因为肥胖被认为是一种 慢性炎症状态，脂肪细胞和卵巢癌细胞之间的串扰可以推动炎症 通过阐述促进癌症进展的促炎趋化因子来增加负担。这最终会是 这在一定程度上导致了高死亡率。这项提案将定义促进肥胖的作用 促炎症趋化因子在卵巢癌进展中的作用。我们将阐明这种由肥胖引发的 应用CXCR2研究促炎症趋化因子在卵巢癌进展中的炎症负担 基因敲除或肥胖的老鼠。基于高级别浆液性卵巢癌中P53的大量突变(∼96%)和 与野生型P53相比，肥胖与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水平的分子机制 促炎症性趋化因子在突变型卵巢癌中的作用。这些发现将提供更深层次的 了解促炎性趋化因子在肥胖和卵巢癌进展中的作用。 预计这些早期结果将指导提高女性癌症存活率的治疗策略， 尤其是对肥胖的癌症患者。最后，预防和减少肥胖将为 提高卵巢癌患者的长期生存和生活质量。 好了！