How adipose tissue influences development and treatment of endometriosis and cancer

背景子宫内膜异位症影响着十分之一的育龄妇女，是慢性盆腔疼痛和不孕症的主要原因[1]。只有在腹腔镜术中才能完全描述疾病的程度，此时功能性子宫内膜样(子宫内膜异位)组织可以显示在子宫内层之外，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平衡，并表达类固醇合成酶，参与疾病的发病机制。矛盾的是，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内脏脂肪的低积累和儿童体重指数的总体下降[2]有关。有氧糖酵解而不是氧化磷酸化是癌细胞优先使用的主要能量来源。这促进了恶性表型，增加了细胞增殖、细胞凋亡逃逸、组织侵袭和转移。在子宫内膜异位症细胞中也发现糖酵解相关基因和代谢物的表达改变，这表明线粒体功能障碍和葡萄糖代谢[4]。然而，氧化还原动态平衡的功能变化还没有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，根据妇科疾病的类型和严重程度，大网膜脂肪组织为子宫内膜异位症和癌细胞提供不同的内分泌支持。目的探讨这种旁分泌关系，并利用细胞代谢来提高治疗效果和患者预后。该项目将涉及一种基于细胞的建模方法，使用来自接受常规腹腔镜手术的同意的妇女的人类子宫内膜和脂肪组织。原代子宫内膜、子宫内膜异位症和癌细胞将单独培养，并与来自配对组织和交叉配对个体的脂肪细胞共同培养。新的治疗药物对细胞代谢、类固醇生成和炎症的影响将使用qRT-PCR、流式细胞仪、免疫分析和最先进的氧化还原系统进行评估。脂质组学还将用于分析细胞、条件培养液和生物液中的二十烷类化合物和其他炎症介质。研究结果将与临床病史和患者报告的症状相关联。潜在的结果/影响这种临床前方法将为导致疾病发病机制、进展和细胞恶性转化的旁分泌途径提供新的见解。这也将表明新的治疗方法对子宫内膜异位症和相关的妇科肿瘤的治疗价值。El-Toukhy(2020)北京奥运会。10.2.Aarestrup等人。(2020)安宏生物。47(2)：173-180。Aarestrup(2017)Int J癌症。140(2)：310-315。4.Young et al.(2017)Hum Reprod更新。23548-559。

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.