在小鼠和人类结直肠肿瘤中协调代谢重编程的生物标志物。
Biomarkers of coordinate metabolic reprogramming in colorectal tumors in mice and humans.
机构信息
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
出版信息
Gastroenterology. 2014 May;146(5):1313-24. doi: 10.1053/j.gastro.2014.01.017. Epub 2014 Jan 15.
BACKGROUND & AIMS: There are no robust noninvasive methods for colorectal cancer screening and diagnosis. Metabolomic and gene expression analyses of urine and tissue samples from mice and humans were used to identify markers of colorectal carcinogenesis.
METHODS
Mass spectrometry-based metabolomic analysis of urine and tissues from wild-type C57BL/6J and Apc(Min/+) mice, as well as from mice with azoxymethane-induced tumors, was employed in tandem with gene expression analysis. Metabolic profiling was also performed on colon tumor and adjacent nontumor tissues from 39 patients. The effects of β-catenin activity on metabolic profiles were assessed in mice with colon-specific disruption of Apc.
RESULTS
Thirteen markers were found in urine associated with development of colorectal tumors in Apc(Min/+) mice. Metabolites related to polyamine metabolism, nucleic acid metabolism, and methylation, identified tumor-bearing mice with 100% accuracy, and also accurately identified mice with polyps. Changes in gene expression in tumor samples from mice revealed that derangement of metabolites were a reflection of coordinate metabolic reprogramming in tumor tissue. Similar changes in urinary metabolites were observed in mice with azoxymethane-induced tumors and in mice with colon-specific activation of β-catenin. The metabolic alterations indicated by markers in urine, therefore, appear to occur during early stages of tumorigenesis, when cancer cells are proliferating. In tissues from patients, tumors had stage-dependent increases in 17 metabolites associated with the same metabolic pathways identified in mice. Ten metabolites that were increased in tumor tissues, compared with nontumor tissues (proline, threonine, glutamic acid, arginine, N1-acetylspermidine, xanthine, uracil, betaine, symmetric dimethylarginine, and asymmetric-dimethylarginine), were also increased in urine from tumor-bearing mice.
CONCLUSIONS
Gene expression and metabolomic profiles of urine and tissue samples from mice with colorectal tumors and of colorectal tumor samples from patients revealed pathways associated with derangement of specific metabolic pathways that are indicative of early-stage tumor development. These urine and tissue markers might be used in early detection of colorectal cancer.
背景与目的
目前尚无用于结直肠癌筛查和诊断的可靠无创方法。本研究通过对小鼠尿液和组织样本以及人类尿液和组织样本进行代谢组学和基因表达分析，以鉴定结直肠癌发生的标志物。
方法
采用基于质谱的代谢组学分析方法，对野生型 C57BL/6J 小鼠和 Apc(Min/+)小鼠以及接受氧化偶氮甲烷诱导肿瘤的小鼠的尿液和组织样本进行分析，同时进行基因表达分析。对 39 例结肠癌肿瘤及相邻非肿瘤组织的代谢谱也进行了分析。通过在结肠特异性敲除 Apc 的小鼠中评估β-连环蛋白活性对代谢谱的影响，来检测代谢谱与基因表达之间的关系。
结果
在 Apc(Min/+)小鼠中发现 13 种与结直肠肿瘤发生相关的尿液标志物。与多胺代谢、核酸代谢和甲基化相关的代谢物能够 100%准确地识别出肿瘤小鼠，也能准确识别出带息肉的小鼠。对来自小鼠的肿瘤样本的基因表达变化进行分析发现，代谢物的紊乱反映了肿瘤组织中代谢的协同重编程。在接受氧化偶氮甲烷诱导肿瘤的小鼠和β-连环蛋白在结肠特异性激活的小鼠中，也观察到了尿液代谢物的相似变化。因此，尿液标志物所指示的代谢改变似乎发生在肿瘤发生的早期阶段，此时癌细胞正在增殖。在患者的组织样本中，与在小鼠中相同的代谢途径相关的 17 种代谢物在肿瘤组织中随疾病分期而增加。与非肿瘤组织相比，在肿瘤组织中增加的 10 种代谢物（脯氨酸、苏氨酸、谷氨酸、精氨酸、N1-乙酰亚精胺、黄嘌呤、尿嘧啶、甜菜碱、对称二甲基精氨酸和非对称二甲基精氨酸）也在肿瘤小鼠的尿液中增加。
结论
结直肠肿瘤小鼠的尿液和组织样本以及患者的结直肠肿瘤样本的基因表达和代谢组学分析揭示了与特定代谢途径紊乱相关的途径，这些途径表明了早期肿瘤发展。这些尿液和组织标志物可能用于结直肠癌的早期检测。
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