Research Project-Obesity in Cancer: The role of obesity in NF-kB-induced cancer stem cell-like phenotype and its implication in ovarian cancer tumorigenesis and chemoresistance

研究项目-癌症中的肥胖-项目摘要 这项研究的总体目标是确定肥胖在激活卵巢中的NF-κB途径中的作用 肿瘤启动细胞(TICs)促进肿瘤生长和化疗耐药。卵巢癌是最常见的 美国致命的妇科恶性肿瘤，尽管大多数患者最初对铂类药物有反应- 在基础化疗的基础上，70%以上的晚期肿瘤复发，导致高发病率和死亡率。一 卵巢癌发生的危险因素是肥胖，这是一种与疾病进展和 经过初步治疗后结果不佳。研究表明，高脂饮食和肥胖激活了NF-κB信号 引发炎症的途径。核因子-κB是一种普遍存在的信号通路，其靶基因编码蛋白质 调节免疫反应、细胞存活、增殖、黏附以及与微环境的相互作用。 核因子-κB在卵巢癌中异常激活并促进化疗所必需的TIC表型 抵抗。目前尚不清楚是什么因素(S)激活了卵巢癌细胞中的NF-κB。这项建议 研究脂肪细胞(组成脂肪组织的脂肪细胞)分泌激活因子的假说 卵巢癌细胞中的核因子-κB通路驱动肿瘤生长和化疗耐药。 目标1将测试肥胖是否通过分泌脂肪因子来丰富卵巢癌患者的症状。这将是 通过卵巢癌细胞与患者来源脂肪细胞共培养实验进行测量 脂肪因子的分泌、基因表达的变化、具有TIC特征的癌细胞的丰富以及肿瘤的生长 在活体内。目的2将确定炎症刺激如何导致卵巢癌细胞中不同的NF-κB活性。 在暴露于炎性细胞因子和脂肪因子后，将检测到NF-κB信号级联反应 在卵巢肿瘤的微环境中。核因子-κB报告活性、dna结合、转录因子激活和 药物抑制将用于研究对炎症诱导信号至关重要的核因子-κB蛋白 和肿瘤的形成。目标3将发现为什么卵巢癌细胞的化疗耐药性在 肥胖的环境。化疗敏感性和已知的介导耐药途径的变化(NF- KB、AKT、STAT3)将在与脂肪细胞共同培养的卵巢癌细胞中进行评估。一种新的治疗方法 针对肥胖、抑制核因子-κB并有效消除TICS的体外实验将在体内测试其预防 在肥胖的卵巢癌小鼠模型中，化疗抵抗和引发肿瘤消退。 这项提议的结果将通过提供机制上的洞察力来促进卵巢癌领域的发展 肥胖与疾病进展和化疗抵抗有关。提案目标的完成将提供新颖的 关于卵巢癌生物学以及脂肪细胞和核因子-κB在促进抽动的作用的信息。知识 从这些研究中获得的成果将导致对癌症采取更有效的预防和治疗策略 肥胖是一个危险因素。

RESEARCH PROJECT-OBESITY IN CANCER – Project Summary The overall objective of this study is to define the role of obesity in activating the NF-κB pathway in ovarian cancer tumor-initiating cells (TICs) to facilitate tumor growth and chemoresistance. Ovarian cancer is the most lethal gynecological malignancy in the United States and although most patients initially respond to platinum- based chemotherapy, over 70% of advanced stage tumors relapse leading to high morbidity and mortality. One risk factor for the development of ovarian cancer is obesity, a condition associated with disease progression and poor outcomes after initial treatment. Studies show that a high fat diet and obesity activate the NF-κB signaling pathway to trigger inflammation. NF-κB is a ubiquitous signaling pathway whose target genes encode proteins that regulate immune response, cell survival, proliferation, adhesion, and interaction with the microenvironment. NF-κB is aberrantly activated in ovarian cancer and promotes a TIC phenotype necessary for chemotherapy resistance. It is unknown what factor(s) trigger NF-κB activation in ovarian cancer cells. This proposal investigates the hypothesis that adipocytes (fat cells that comprise adipose tissue) secrete factors that activate NF-κB pathways in ovarian cancer cells to drive tumor growth and chemotherapy resistance. Aim 1 will test whether obesity enriches for ovarian cancer TICs through the secretion of adipokines. This will be investigated through co-culture experiments of ovarian cancer cells with patient-derived adipocytes to measure adipokine secretion, gene expression changes, enrichment of cancer cells with TIC features, and tumor growth in vivo. Aim 2 will determine how inflammatory stimuli lead to differential NF-κB activation in ovarian cancer cells. NF-κB signaling cascades will be examined after exposure to inflammatory cytokines and adipokines prominent in the ovarian tumor microenvironment. NF-κB reporter activity, DNA binding, transcription factor activation, and pharmacological inhibition will be used to investigate NF-κB proteins critical for inflammation-induced signaling and tumor formation. Aim 3 will discover why chemotherapy resistance of ovarian cancer cells is enhanced in the obese setting. Chemotherapy sensitivity and changes in pathways known to mediate drug resistance (NF- kB, AKT, STAT3) will be evaluated in ovarian cancer cells cultured with adipocytes. A novel therapeutic that targets obesity, inhibits NF-κB, and effectively eliminates TICs in vitro will be tested in vivo for its ability to prevent chemotherapy resistance and trigger tumor regression in an obese mouse model of ovarian cancer. Results of this proposal will advance the ovarian cancer field by providing mechanistic insight into the role of obesity in disease progression and chemotherapy resistance. Completion of the proposal aims will provide novel information about ovarian cancer biology and the role of adipocytes and NF-κB in promoting TICs. Knowledge gained from these studies will lead to more effective preventive and therapeutic strategies for cancers in which obesity is a risk factor.