LBPO.CH01 · 化学 · Late-Breaking
阐明上皮性卵巢癌特有的血浆细菌源性及宿主源性代谢物
Elucidating plasma bacterial and host derived metabolites unique to epithelial ovarian cancer
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
本研究的目的是检查上皮性卵巢癌(EOC)女性的血浆代谢物谱，以鉴定与该疾病相关的细菌源性和宿主源性代谢物及通路。EOC若早期发现具有高度可治愈性，但大多数病例在晚期才被诊断，降低了生存率。尽管精准肿瘤学取得了进展，有效的EOC早期疾病筛查检测仍然有限。肿瘤微环境(TME)中的动态代谢串扰已被证明可支持癌症进展。目前的研究表明，细菌代谢物进入体循环并改变TME。因此，了解EOC的血浆代谢组学特征可能为侵入性较小、可实现早期检测的检测提供机会。使用液相色谱-串联质谱，从四个实验组女性的生物库血浆样本生成了全局代谢组学谱，包括EOC(n=10)、良性妇科疾病(n=10)、非EOC实体瘤(n=10)和健康对照(n=10)。血浆样本使用全局发现代谢组学平台进行分析。对经对数转换、中位数标度和最小值填补的数据的统计分析采用单因素方差分析(ANOVA)，以鉴定在实验组之间存在显著差异的生化物质。样本中共鉴定出1,204种已知生化物质。与其他组相比，EOC患者与健康对照相比具有数量最多(335种)的统计学显著(p ≤ 0.05)生化差异(238种上调，97种下调)。EOC患者表现出β-氧化升高、关键磷脂和短/中链脂肪酸水平降低，以及内源性大麻素增加。通过主成分分析，EOC组与对照组的分离程度大于其他组。与健康对照相比，EOC患者中富集程度最高的通路主要由脂质通路组成，但也独特地包括与谷胱甘肽代谢(γ-谷氨酰氨基酸)、维生素A代谢、苯甲酸代谢和嘌呤代谢相关的通路。与健康对照相比，EOC组中包括马尿酸、苯甲酸和3-苯丙酸(氢化肉桂酸)在内的苯甲酸类数量显著(p ≤ 0.05)降低。EOC组的发现提示细胞更新受损，并可能与炎症调控变化相关。苯甲酸相关代谢物水平降低提示肠道细菌可能存在紊乱，进一步将EOC代谢谱与其他组区分开来。比较早期与晚期疾病的更大患者队列可能为哪些通路驱动癌症进展、哪些是结果提供指示。
查看英文原文 English abstract
The purpose of this study was to examine plasma metabolite profiles of women with epithelial ovarian cancer (EOC) to identify bacterial- and host-derived metabolites and pathways associated with this disease. EOC is highly curative if detected early, yet the majority of cases are diagnosed during late stages, decreasing survival rates. Despite advances in precision oncology, effective EOC early disease screening tests remain limited. Dynamic metabolic crosstalk in the tumor microenvironment (TME) is shown to support cancer progression. Current research suggest that bacterial metabolites enter the systemic circulation and alter the TME. Thus, understanding plasma metabolomic characteristics of EOC could present an opportunity for less invasive testing that allows for early detection. Using liquid chromatography-tandem mass spectroscopy, global metabolomic profiles were generated from biobanked plasma samples of women in four experimental groups including EOC (n=10), benign gynecologic diseases (n=10), non-EOC solid tumors (n=10), and healthy controls (n=10). Plasma samples were analyzed using a global discovery metabolomic platform. Statistical analysis of log-transformed, median scaled and minimum imputed data was approached through a one-way ANOVA to identify biochemicals that differed significantly between experimental groups. There were a total of 1,204 known biochemicals identified in the samples. Patients with EOC had the largest number (335) of statistically significant ( p ≤ 0.05) biochemical differences (238 upregulated, 97 downregulated) compared to healthy controls than the other groups. Patients with EOC had elevated beta-oxidation, decreased levels of key phospholipids and short/medium chain fatty acids, and increased endocannabinoids. By principal component analysis, the EOC group exhibited greater separation from the control group than the other groups. Top enriched pathways among patients with EOC compared to healthy controls primarily consisted of lipid pathways but also uniquely included those associated with glutathione metabolism (g-glutamyl amino acids), vitamin A metabolism, benzoate metabolism, and purine metabolism. The number of benzoates including hippurate, benzoate, and 3-phenylpropionate (hydrocinnamate) were significantly ( p ≤ 0.05) lower in the EOC group compared to healthy controls. The EOC group findings are suggestive of impaired cell turnover and potentially relate to inflammation regulation changes. Reduced levels of benzoate-associated metabolites suggest potential disruptions of gut bacteria, further distinguishing the EOC metabolic profile from the other groups. Larger patient cohorts comparing early versus late stage disease may provide indications of which pathways drive cancer progression and which serve as the consequence.
利益披露 Disclosure
D. E. Mahoney, None..
I. Medina-Meza, None.