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-肥胖与癌症：肥胖在NF-kB诱导的癌症干细胞样表型中的作用及其在卵巢癌肿瘤发生和化疗耐药中的意义

• 批准号: 10403543
• 负责人: Carrie Danielle House
• 金额: $ 27.21万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-11 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403543
• 关键词: Adhesions; Adipocytes; Adipose tissue; Biological Assay; C-reactive protein; Cancer Biology; Cancer Relapse; Carboplatin; Cell Cycle; Cell Survival; Cells; Chemoresistance; Clinical; Co-Immunoprecipitations; Coculture Techniques; County; DNA Binding; Data; Development; Disease; Disease Progression; Disease Resistance; Drug Targeting; Drug resistance; Exposure to; Fibrinogen; Flow Cytometry; Gene Expression; Genes; Goals; Health Disparities Research; High Fat Diet; Hispanic Populations; IL8 gene; Immune response; In Vitro; Inflammation; Inflammatory; Influentials; Interleukin-1 beta; Interleukin-6; Knowledge; Lead; Leptin; Link; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Monitor; Morbidity - disease rate; NF-kappa B; Obese Mice; Obesity; Outcome; Ovarian; Pathway interactions; Patients; Peritoneal; Pharmacology; Phenotype; Platinum; Play; Population; Poverty; Premalignant Cell; Preventive; Process; Proteins; Proto-Oncogene Proteins c-akt; Recurrence; Recurrent disease; Relapse; Reporter; Research; Research Project Grants; Resected; Residual Tumors; Resistance; Risk Factors; Role; STAT3 gene; Signal Pathway; Signal Transduction; Stimulus; TNF gene; Testing; Therapeutic; Transforming Growth Factor beta; Tumor stage; United States; Work; Xenograft Model; adipokines; base; cancer cell; cancer drug resistance; cancer stem cell; cell growth; cellular engineering; chemotherapy; cytokine; experimental study; in vivo; in vivo evaluation; inflammatory marker; insight; mortality; mouse model; new therapeutic target; novel; novel therapeutics; ovarian neoplasm; prevent; small hairpin RNA; stem-like cell; therapeutically effective; transcription factor; transcriptome sequencing; treatment strategy; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis

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.

研究计划-肥胖与癌症-计划摘要 本研究的总体目标是确定肥胖在卵巢癌细胞NF-κB通路激活中的作用。 癌症肿瘤起始细胞（TIC）以促进肿瘤生长和化学抗性。卵巢癌是最常见的 致命的妇科恶性肿瘤在美国，虽然大多数患者最初响应铂- 在化疗基础上，超过70%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相关的疾病， 初步治疗后效果不佳。研究表明高脂饮食和肥胖激活NF-κB信号通路 引发炎症的途径。NF-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、粘附以及与微环境的相互作用。 NF-κB在卵巢癌中异常激活并促进化疗所必需的TIC表型 阻力目前尚不清楚是什么因子触发了卵巢癌细胞中NF-κB的激活。这项建议 研究假设脂肪细胞（脂肪细胞组成的脂肪组织）分泌因子，激活 卵巢癌细胞中的NF-κB通路驱动肿瘤生长和化疗耐药性。 目的1将测试肥胖是否通过脂肪因子的分泌来富集卵巢癌TIC。这将是 通过卵巢癌细胞与患者来源的脂肪细胞的共培养实验来研究， 脂肪因子分泌、基因表达变化、具有TIC特征的癌细胞富集和肿瘤生长 in vivo.目的2将确定炎症刺激如何导致卵巢癌细胞中NF-κB的不同活化。 NF-κB信号级联将在暴露于炎性细胞因子和脂肪因子后进行检查， 在卵巢肿瘤微环境中。NF-κB报告基因活性、DNA结合、转录因子激活和 药理学抑制将用于研究炎症诱导信号传导的关键NF-κB蛋白 和肿瘤形成。目的3将发现为什么卵巢癌细胞的化疗耐药性增强， 肥胖的环境。化疗敏感性和已知介导耐药性（NF-κ B）的途径的变化 kB、AKT、STAT 3）将在与脂肪细胞一起培养的卵巢癌细胞中进行评价。一种新的治疗方法， 靶向肥胖，抑制NF-κB，并在体外有效消除TIC，将在体内测试其预防肥胖的能力。 在卵巢癌的肥胖小鼠模型中，化疗耐药性和触发肿瘤消退。 该提案的结果将通过提供对以下作用的机制性见解来推进卵巢癌领域： 肥胖与疾病进展和化疗耐药性的关系。完成提案的目的将提供新颖的 关于卵巢癌生物学的信息以及脂肪细胞和NF-κB在促进TIC中的作用。知识 从这些研究中获得的信息将导致更有效的癌症预防和治疗策略， 肥胖是一个危险因素。