Backshall Alexandra, Alferez Denis, Teichert Friederike, Wilson Ian D, Wilkinson Robert W, Goodlad Robert A, Keun Hector C
Department of Biomolecular Medicine, Division of Surgery, Oncology, Reproductive Biology and Anaesthetics, Faculty of Medicine, Imperial College London, Sir Alexander Fleming Building, South Kensington, London, United Kingdom.
J Proteome Res. 2009 Mar;8(3):1423-30. doi: 10.1021/pr800793w.
In this study, we have used metabolic profiling (metabolomics/metabonomics) via high resolution magic angle spinning (HRMAS) and solution state (1)H NMR spectroscopy to characterize small bowel and colon tissue from the Apc(Min/+) mouse model of early gastrointestinal (GI) tumorigenesis. Multivariate analysis indicated the presence of metabolic differences between the morphologically normal/non-tumor tissue from approximately 10 week-old Apc(Min/+) mice and their wild-type litter mates. The metabolic profile of isolated lamina propria and epithelial cells from the same groups could also be discriminated on the basis of genotype. Accounting for systematic variation in individual metabolite levels across different anatomical regions of the lower GI tract, the metabolic phenotype of Apc(Min/+) lamina propria tissue was defined by significant increases in the phosphocholine/glycerophosphocholine ratio (PC/GPC, +21%) and decreases in GPC (-25%) and the gut-microbial cometabolite dimethylamine (DMA, -40%) relative to wild type. In the whole tissue, elevated lactate (+15%) and myo-inositol (+19%) levels were detected. As the metabolic changes occurred in non-tumor tissue from animals of very low tumor burden (<2 polyps/animal), they are likely to represent the specific consequence of reduced Apc function and very early events in tumorigenesis. The observed increase in PC/GPC ratio has been previously reported with immortalisation and malignant transformation of cells and is consistent with the role of Apc as a tumor suppressor. Phospholipase A2, which hydrolyses phosphatidylcholine to Acyl-GPC, is a known modifier gene of the model phenotype (Mom1), and altered expression of choline phospholipid enzymes has been reported in gut tissue from Apc(Min/+) mice. These results indicate the presence of a metabolic phenotype associated with "field cancerization", highlighting potential biomarkers for monitoring disease progression, for early evaluation of response to chemoprevention, and for predicting the severity of the polyposis phenotype in the Apc(Min/+) model.
在本研究中，我们通过高分辨率魔角旋转（HRMAS）和溶液态氢核磁共振波谱（¹H NMR）进行代谢谱分析（代谢组学/代谢物组学），以表征早期胃肠道（GI）肿瘤发生的Apc(Min/+)小鼠模型的小肠和结肠组织。多变量分析表明，约10周龄的Apc(Min/+)小鼠形态学上正常的非肿瘤组织与其野生型同窝小鼠之间存在代谢差异。基于基因型，也可以区分同一组中分离的固有层和上皮细胞的代谢谱。考虑到下消化道不同解剖区域中各个代谢物水平的系统变化，相对于野生型，Apc(Min/+)固有层组织的代谢表型表现为磷酸胆碱/甘油磷酸胆碱比值（PC/GPC，增加21%）显著升高，甘油磷酸胆碱（GPC，降低25%）和肠道微生物共代谢物二甲胺（DMA，降低40%）降低。在整个组织中，检测到乳酸（增加15%）和肌醇（增加19%）水平升高。由于代谢变化发生在肿瘤负荷非常低（<2个息肉/动物）的动物的非肿瘤组织中，它们很可能代表了Apc功能降低的特定后果以及肿瘤发生的非常早期事件。之前已有报道，细胞永生化和恶性转化会出现PC/GPC比值升高，这与Apc作为肿瘤抑制因子的作用一致。磷脂酶A2可将磷脂酰胆碱水解为酰基-GPC，是该模型表型（Mom1）的已知修饰基因，并且已报道Apc(Min/+)小鼠肠道组织中胆碱磷脂酶的表达发生改变。这些结果表明存在与“场癌化”相关的代谢表型，突出了用于监测疾病进展、早期评估化学预防反应以及预测Apc(Min/+)模型中息肉病表型严重程度的潜在生物标志物。
