糖代谢异常促进肥胖型卵巢癌发生发展的机制研究及靶向治疗探讨

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer and also one of the most poorly understood. Recent study showed that abnormal glucose metabolism is an essential contributor to tumor progression.LKB1/AMPK and PI3K/Akt/mTOR pathways are critical for the regulation of cell proliferation and metabolism and are often hyper-activated in obesity patients of EOC. We posit that the metabolic effects of obesity play a role in the pathogenesis of EOC and lead to biologically kinds of cancers,possibly through aberrant activation of mTOR kinase as well as mTOR-associated metabolic pathways. Thus, obese OC patients may benefit from targeting agents that inhibit these pathways, such as mTOR inhibitors or metformin. This proposal will address these gaps in knowledge by investigating the impact of obesity on the proliferative and metabolic effects of the mTOR inhibitor, everolimus, the dual PI3K/mTOR inhibitor,NVP-BEZ235,and the AMPK activator, metformin, in three complementary model systems: in vitro using human OC cell lines; in vivo using a novel serous ovarian tumor mouse model; and ex vivo using OC tumors from consenting women undergoing surgical debulking. The role of obesity in OC initiation and promotion will be evaluated through comprehensive cross-species genomic and metabolomic analyses with the goal of identifying common genetic or metabolic biomarkers associated with obesity-related tumor promotion and response to target treatment.

最新的研究证据表明，肥胖与糖代谢异常能促进某些恶性肿瘤的发生发展。我们初期的实验结果显示高糖状态在体外能促进卵巢癌细胞的增殖、在体内可加快该肿瘤的进展，LKB1/AMPK和PI3K/AKT/mTOR信号通路在肥胖型卵巢癌发生发展过程中发挥重要作用。本课题拟运用卵巢癌细胞株、卵巢上皮癌小鼠模型和卵巢癌患者新鲜标本的原代培养细胞三种实验平台，研究糖代谢异常对肥胖型卵巢上皮癌发生发展的作用。应用基因组学、代谢组学和生物统计等技术，分析肥胖、非肥胖卵巢癌小鼠模型及肥胖、非肥胖卵巢癌患者中肿瘤组织和血清中基因表达和代谢的差异，以期筛选出与肥胖型卵巢癌相关的基因和生物标记物。通过观察mTOR抑制剂依维莫司、AKT/mTOR双重抑制剂NVP-BEZ和AMPK激动剂二甲双胍在体外对卵巢癌细胞生长代谢的影响及在体内对肥胖型小鼠卵巢癌模型肿瘤的干预效果，探索靶向治疗提高肥胖型卵巢癌疗效的可行性。

肥胖与糖代谢异常能促进某些恶性肿瘤的发生发展。我们初期的实验结果显示高糖状态在体外能促进卵巢癌细胞的增殖、在体内可加快该肿瘤的进展，LKB1/AMPK和 PI3K/AKT/mTOR 信号通路在肥胖型卵巢癌发生发展过程中发挥重要作用。本课题运用卵巢癌细胞株、卵巢上皮癌小鼠模型和卵巢癌患者新鲜标本的原代培养细胞三种实验平台，研究糖代谢异常对肥胖型卵巢上皮癌发生发展的作用。应用基因组学、代谢组学和生物统计等技术，分析肥胖、非肥胖卵巢癌小鼠模型及肥胖、非肥胖卵巢癌患者中肿瘤组织和血清中基因表达和代谢的差异，筛选出了与肥胖型卵巢癌相关的基因和生物标记物。通过观察mTOR抑制剂依维莫司和AMPK激动剂二甲双胍在体外对卵巢癌细胞生长代谢的影响及在体内对肥胖型小鼠卵巢癌模型肿瘤的干预效果，验证了靶向治疗提高肥胖型卵巢癌疗效的可行性。