Metabolomics and metabolic pathway networks from human colorectal cancers, adjacent mucosa, and stool.
Metabolomics and metabolic pathway networks from human colorectal cancers, adjacent mucosa, and stool.
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DOI：
10.1186/s40170-016-0151-y
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发表时间：
2016
影响因子：
5.9
通讯作者：
Ryan EP
中科院分区：
文献类型：
--
作者：
Brown DG;Rao S;Weir TL;O'Malia J;Bazan M;Brown RJ;Ryan EP
结直肠癌(CRC)与细胞氨基酸、核苷酸、戊糖-磷酸途径碳水化合物、糖酵解、糖异生和三羧酸中间产物的紊乱有关。一种非靶向的整体代谢组学方法被用于研究人类结直肠癌、邻近粘膜和粪便。在这项先导性研究中，我们从接受结肠切除术的患者中确定了结直肠癌和邻近粘膜之间的代谢物分布差异。代谢途径分析进一步揭示了复杂的代谢物网络之间的关系。17名结直肠癌患者参与了这项初步研究，他们提供了结直肠癌、肿瘤近端10 cm的邻近粘膜和粪便。用气相色谱-质谱法(GC/MS)和超高效液相色谱-质谱法(UPLC-MS/MS)分析代谢产物。所有的文库标准鉴定都被确认，并通过代谢网络相互作用的MetabLyncTM进一步分析。从结肠组织和大便基质中鉴定出总共728种不同的代谢物。在我们的患者匹配队列中，19种代谢物显著区分了结直肠癌与邻近粘膜。葡萄糖-6-磷酸和果糖-6-磷酸在结直肠癌中的表达分别是粘膜的0.64倍和0.75倍，而异构体：甜菜碱醛、N-甲基二乙醇胺和腺苷琥珀酸脂在结直肠癌中的相对丰度分别高2.68倍和1.88倍。19种代谢物中有11种以前没有报道过与CRC相关。代谢途径分析显示，短链脂肪酸代谢、果糖、甘露糖和半乳糖代谢以及糖酵解、糖异生和丙酮酸代谢显著紊乱。与从人类结直肠癌患者身上发现的500种粪便代谢物相比，只有215种粪便代谢物在组织中也被检测到。这项结直肠癌和粪便代谢组研究发现了可能在结直肠癌发病机制中起关键作用的新的代谢物，证实了先前报道的结直肠癌代谢组研究的结果，并显示了代谢途径异常的网络。此外，我们还发现了CRC和粪便代谢物之间的差异。粪便代谢物谱仅限于与结直肠癌和邻近粘膜直接相关，但代谢途径在两种基质中都是保守的。需要更大规模的患者匹配的结直肠癌、邻近的非癌变结肠粘膜和大便代谢物分析的队列研究，以验证这些小分子差异和代谢途径异常，以便临床应用于结直肠癌的控制、治疗和预防。本文的在线版本(doi：10.1186/s40170-0160151-y)包含补充材料，可供授权用户使用。
Colorectal cancers (CRC) are associated with perturbations in cellular amino acids, nucleotides, pentose-phosphate pathway carbohydrates, and glycolytic, gluconeogenic, and tricarboxylic acid intermediates. A non-targeted global metabolome approach was utilized for exploring human CRC, adjacent mucosa, and stool. In this pilot study, we identified metabolite profile differences between CRC and adjacent mucosa from patients undergoing colonic resection. Metabolic pathway analyses further revealed relationships between complex networks of metabolites. Seventeen CRC patients participated in this pilot study and provided CRC, adjacent mucosa ~10 cm proximal to the tumor, and stool. Metabolomes were analyzed by gas chromatography-mass spectrometry (GC/MS) and ultra-performance liquid chromatography-mass spectrometry (UPLC-MS/MS). All of the library standard identifications were confirmed and further analyzed via MetaboLyncTM for metabolic network interactions. There were a total of 728 distinct metabolites identified from colonic tissue and stool matrices. Nineteen metabolites significantly distinguished CRC from adjacent mucosa in our patient-matched cohort. Glucose-6-phosphate and fructose-6-phosphate demonstrated 0.64-fold and 0.75-fold lower expression in CRC compared to mucosa, respectively, whereas isobar: betaine aldehyde, N-methyldiethanolamine, and adenylosuccinate had 2.68-fold and 1.88-fold higher relative abundance in CRC. Eleven of the 19 metabolites had not previously been reported for CRC relevance. Metabolic pathway analysis revealed significant perturbations of short-chain fatty acid metabolism, fructose, mannose, and galactose metabolism, and glycolytic, gluconeogenic, and pyruvate metabolism. In comparison to the 500 stool metabolites identified from human CRC patients, only 215 of those stool metabolites were also detected in tissue. This CRC and stool metabolome investigation identified novel metabolites that may serve as key small molecules in CRC pathogenesis, confirmed the results from previously reported CRC metabolome studies, and showed networks for metabolic pathway aberrations. In addition, we found differences between the CRC and stool metabolomes. Stool metabolite profiles were limited for direct associations with CRC and adjacent mucosa, yet metabolic pathways were conserved across both matrices. Larger patient-matched CRC, adjacent non-cancerous colonic mucosa, and stool cohort studies for metabolite profiling are needed to validate these small molecule differences and metabolic pathway aberrations for clinical application to CRC control, treatment, and prevention. The online version of this article (doi:10.1186/s40170-016-0151-y) contains supplementary material, which is available to authorized users.