Jiménez Beatriz, Abellona U Mei Ran, Drymousis Panagiotis, Kyriakides Michael, Clift Ashley K, Liu Daniel S K, Rees Eleanor, Holmes Elaine, Nicholson Jeremy K, Kinross James M, Frilling Andrea
Department of Surgery and Cancer, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
Department of Metabolism, Nutrition and Reproduction, Imperial College London, Exhibition Road, London SW7 2AZ, UK.
Cancers (Basel). 2021 Jan 20;13(3):374. doi: 10.3390/cancers13030374.
The incidence of neuroendocrine neoplasms (NEN) is increasing, but established biomarkers have poor diagnostic and prognostic accuracy. Here, we aim to define the systemic metabolic consequences of NEN and to establish the diagnostic utility of proton nuclear magnetic resonance spectroscopy (H-NMR) for NEN in a prospective cohort of patients through a single-centre, prospective controlled observational study. Urine samples of 34 treatment-naïve NEN patients (median age: 59.3 years, range: 36-85): 18 had pancreatic (Pan) NEN, of which seven were functioning; 16 had small bowel (SB) NEN; 20 age- and sex-matched healthy control individuals were analysed using a 600 MHz Bruker H-NMR spectrometer. Orthogonal partial-least-squares-discriminant analysis models were able to discriminate both PanNEN and SBNEN patients from healthy control (Healthy vs. PanNEN: AUC = 0.90, Healthy vs. SBNEN: AUC = 0.90). Secondary metabolites of tryptophan, such as trigonelline and a niacin-related metabolite were also identified to be universally decreased in NEN patients, while upstream metabolites, such as kynurenine, were elevated in SBNEN. Hippurate, a gut-derived metabolite, was reduced in all patients, whereas other gut microbial co-metabolites, trimethylamine--oxide, 4-hydroxyphenylacetate and phenylacetylglutamine, were elevated in those with SBNEN. These findings suggest the existence of a new systems-based neuroendocrine circuit, regulated in part by cancer metabolism, neuroendocrine signalling molecules and gut microbial co-metabolism. Metabonomic profiling of NEN has diagnostic potential and could be used for discovering biomarkers for these tumours. These preliminary data require confirmation in a larger cohort.
神经内分泌肿瘤(NEN)的发病率正在上升,但现有的生物标志物在诊断和预后方面的准确性较差。在此,我们旨在确定NEN的全身代谢后果,并通过一项单中心、前瞻性对照观察性研究,在一个前瞻性队列患者中确立质子核磁共振波谱(H-NMR)对NEN的诊断效用。对34例未经治疗的NEN患者(中位年龄:59.3岁,范围:36 - 85岁)的尿液样本进行分析:其中18例患有胰腺(Pan)NEN,其中7例具有功能性;16例患有小肠(SB)NEN;使用600 MHz布鲁克H-NMR光谱仪对20名年龄和性别匹配的健康对照个体进行了分析。正交偏最小二乘判别分析模型能够将PanNEN和SBNEN患者与健康对照区分开来(健康对照与PanNEN:AUC = 0.90,健康对照与SBNEN:AUC = 0.90)。还发现色氨酸的次级代谢产物,如胡芦巴碱和一种与烟酸相关的代谢产物在NEN患者中普遍降低,而上游代谢产物,如犬尿氨酸,在SBNEN中升高。马尿酸盐是一种源自肠道的代谢产物,在所有患者中均减少,而其他肠道微生物共代谢产物,三甲胺 - 氧化物、4 - 羟基苯乙酸和苯乙酰谷氨酰胺,在SBNEN患者中升高。这些发现表明存在一种新的基于系统的神经内分泌回路,部分受癌症代谢、神经内分泌信号分子和肠道微生物共代谢的调节。NEN的代谢组学分析具有诊断潜力,可用于发现这些肿瘤的生物标志物。这些初步数据需要在更大的队列中得到证实。