How adipose tissue influences development and treatment of endometriosis and cancer

脂肪组织如何影响子宫内膜异位症和癌症的发展和治疗

• 批准号: 2627163
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2627163
• 关键词: How; adipose; tissue; influences; development

BackgroundEndometriosis affects 1 in 10 women of reproductive age and is the leading cause of chronic pelvic pain and infertility [1]. The extent of disease is only fully characterised at laparoscopy when functional endometrial-like (endometriotic) tissue can be visualised beyond the lining of the uterus, primarily around the ovaries and on peritoneal surfaces. Adipocytes from the surrounding fat regulate energy homeostasis as well as express steroidogenic enzymes for disease pathogenesis. Paradoxically, endometriosis has been associated with low visceral fat accumulation at lesion sites and an overall decrease in childhood body mass index [2] in contrast to women with related neoplastic disease [3]. Aerobic glycolysis rather than oxidative phosphorylation is used preferentially as a main energy source by cancer cells. This promotes a malignant phenotype, increasing cell proliferation, apoptotic escape, tissue invasion and metastasis. Altered expression of glycolysis-related genes and metabolites has also been identified in endometriotic cells, which suggest mitochondrial dysfunction and glucose metabolism [4]. However, the functional changes in redox homeostasis have not been investigated according to stage of menstrual cycle, severity of illness or medical treatment. We hypothesise that omental adipose tissue provides differential endocrine support to endometriotic and cancer cells according to gynaecological disease type and severity. Objectives Our main aim is to investigate this paracrine relationship and exploit cell metabolism to improve therapeutic efficacy and patient outcome. MethodsThe project will involve a cell-based modelling approach using human endometrial and adipose tissues from consenting women undergoing routine laparoscopic surgery. Primary endometrial, endometriotic and cancer cells will be cultured alone and in co-culture with adipocytes from paired tissues and cross-matched individuals. The effect of novel therapeutic agents on cell metabolism, steroidogenesis and inflammation will be assessed using qRT-PCR, flow cytometry, immunoassay and a state-of-the-art redox system. Lipidomics will also be used to profile eicosanoids and other inflammatory mediators in cells, conditioned medium and biological fluids. Findings will be correlated with clinical history and patient-reported symptoms.Potential outcomes/ impactThis preclinical approach will provide new insights into the paracrine pathways leading to disease pathogenesis, progression and the malignant transformation of cells. It will also indicate the therapeutic value of new treatment moieties for endometriosis and related gynaecological cancers.References1. El-Toukhy (2020) BJOG. 10 . 2. Aarestrup et al. (2020) Ann Hum Biol. 47(2):173-180. Aarestrup (2017) Int J Cancer. 140(2): 310-315. 4. Young et al. (2017) Hum Reprod Update. 23, 548-559.

背景子宫内膜异位症影响1/10的育龄妇女，是慢性盆腔疼痛和不孕的主要原因[1]。只有在腹腔镜检查中，当功能性子宫样组织（子宫内膜）可见时，疾病的程度才能得到充分的表征，主要是卵巢周围和腹膜表面。来自周围脂肪的脂肪细胞调节能量稳态以及表达用于疾病发病机制的类固醇生成酶。奇怪的是，与患有相关肿瘤疾病的女性相比，子宫内膜异位症与病变部位的内脏脂肪堆积低和儿童体重指数总体下降相关[2][3]。有氧糖酵解而不是氧化磷酸化优先用作癌细胞的主要能量来源。这促进恶性表型，增加细胞增殖、凋亡逃逸、组织侵袭和转移。糖酵解相关基因和代谢物的表达改变也已在线粒体细胞中鉴定，这表明线粒体功能障碍和葡萄糖代谢[4]。然而，氧化还原稳态的功能变化尚未根据月经周期的阶段，疾病的严重程度或药物治疗进行研究。我们假设网膜脂肪组织根据妇科疾病的类型和严重程度，为卵巢癌和癌细胞提供不同的内分泌支持。目的我们的主要目的是调查这种旁分泌的关系，并利用细胞代谢，以提高治疗效果和病人的结果。MethodsThe项目将涉及一个基于细胞的建模方法，使用同意接受常规腹腔镜手术的妇女的人类子宫内膜和脂肪组织。原代子宫内膜、子宫内膜异位和癌细胞将单独培养，并与来自配对组织和交叉匹配个体的脂肪细胞共培养。将使用qRT-PCR、流式细胞术、免疫测定和最先进的氧化还原系统评估新型治疗剂对细胞代谢、类固醇生成和炎症的影响。脂质组学还将用于分析细胞、条件培养基和生物液体中的类花生酸和其他炎症介质。结果将与临床病史和患者报告的symptoms.Potential outcomes/ impactThis临床前方法将提供新的见解旁分泌途径导致疾病的发病机制，进展和细胞的恶性转化。它也将表明新的治疗部分子宫内膜异位症和相关的妇科癌症的治疗价值。El-Toukhy（2020）BJOG. 10 . 2. Aarestrup等人（2020）Ann Biol.47（2）：173-180. Aarestrup（2017）Int J Cancer. 140（2）：310-315。4. Young et al.（2017）Reprod Update. 23，548-559。