Quantitative Metabolome Profiling of Colon and Stomach Cancer Microenvironment by Capillary Electrophoresis Time-of-Flight Mass Spectrometry
Quantitative Metabolome Profiling of Colon and Stomach Cancer Microenvironment by Capillary Electrophoresis Time-of-Flight Mass Spectrometry
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DOI：
10.1158/0008-5472.can-08-4806
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发表时间：
2009-06-01
期刊：
影响因子：
11.2
通讯作者：
Soga, Tomoyoshi
中科院分区：
文献类型：
--
作者：
Hirayama, Akiyoshi;Kami, Kenjiro;Soga, Tomoyoshi
大多数癌细胞主要通过糖酵解而不是通过三羧酸（TCA）循环的氧化磷酸化产生能量，即使在存在足够氧气供应的情况下也是如此（瓦尔堡效应）。然而，很少有报道直接测量全球代谢物在临床肿瘤组织。在这里，我们应用毛细管电泳飞行时间质谱，使全面和定量分析带电代谢物，同时测量其水平在肿瘤和大体正常组织从16个结肠癌和12个胃癌患者。对参与糖酵解、磷酸戊糖途径、TCA和尿素循环以及氨基酸和核苷酸代谢的结肠中的94种代谢物和胃中的95种代谢物进行定量，鉴定了几种癌症特异性代谢特征。在结肠和胃肿瘤组织中发现极低的葡萄糖和高的乳酸和糖酵解中间体浓度，这表明糖酵解增强，从而证实了瓦尔堡效应。肿瘤中除谷氨酰胺外的所有氨基酸的显著积累暗示蛋白质的自噬降解和用于能量产生的活性谷氨酰胺分解，即，氨解。此外，显着的器官特异性差异被发现在TCA循环中间体的水平，这反映了每个组织的有氧呼吸的依赖性，根据氧气的可用性。结果发现，在实际肿瘤微环境中，营养条件出乎意料地差，并表明毛细管电泳结合基于质谱的代谢组学，能够量化组织中能量代谢物的水平，可能是开发靶向癌症特异性代谢的新型抗癌药物的有力工具。[Cancer Res 2009;69（11）：4918-25]
Most cancer cells predominantly produce energy by glycolysis rather than oxidative phosphorylation via the tricarboxylic acid (TCA) cycle, even in the presence of an adequate oxygen supply (Warburg effect). However, little has been reported regarding the direct measurements of global metabolites in clinical tumor tissues. Here, we applied capillary electrophoresis time-of-flight mass spectrometry, which enables comprehensive and quantitative analysis of charged metabolites, to simultaneously measure their levels in tumor and grossly normal tissues obtained from 16 colon and 12 stomach cancer patients. Quantification of 94 metabolites in colon and 95 metabolites in stomach involved in glycolysis, the pentose phosphate pathway, the TCA and urea cycles, and amino acid and nucleotide metabolisms resulted in the identification of several cancer-specific metabolic traits. Extremely low glucose and high lactate and glycolytic intermediate concentrations were found in both colon and stomach tumor tissues, which indicated enhanced glycolysis and thus confirmed the Warburg effect. Significant accumulation of all amino acids except glutamine in the tumors implied autophagic degradation of proteins and active glutamine breakdown for energy production, i.e., glutaminolysis. In addition, significant organ-specific differences were found in the levels of TCA cycle intermediates, which reflected the dependency of each tissue on aerobic respiration according to oxygen availability. The results uncovered unexpectedly poor nutritional conditions in the actual tumor microenvironment and showed that capillary electrophoresis coupled to mass spectrometry-based metabolomics, which is capable of quantifying the levels of energy metabolites in tissues, could be a powerful tool for the development of novel anticancer agents that target cancer-specific metabolism. [Cancer Res 2009;69(11):4918-25]