Metabolomics of ApcMin/+ mice genetically susceptible to intestinal cancer

BMC Systems Biology

Henri Brunengraber¹  Nathan A Berger¹  Stephanie K Doerner³  Yana Sandlers²  Jean-Eudes J Dazard¹ 

[1] Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA;Kennedy Krieger Institute, Baltimore, MA 21205, USA;Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA

关键词: High-throughput mass spectrometry;    Association and correlation analysis;    Tumor development;    Fat diet;    Metabolomics;   

Others  :  864934
DOI  :  10.1186/1752-0509-8-72

 received in 2014-02-25, accepted in 2014-06-10,  发布年份 2014

【 摘 要 】

Background

To determine how diets high in saturated fat could increase polyp formation in the mouse model of intestinal neoplasia, Apc^Min/+, we conducted large-scale metabolome analysis and association study of colon and small intestine polyp formation from plasma and liver samples of Apc^Min/+ vs. wild-type littermates, kept on low vs. high-fat diet. Label-free mass spectrometry was used to quantify untargeted plasma and acyl-CoA liver compounds, respectively. Differences in contrasts of interest were analyzed statistically by unsupervised and supervised modeling approaches, namely Principal Component Analysis and Linear Model of analysis of variance. Correlation between plasma metabolite concentrations and polyp numbers was analyzed with a zero-inflated Generalized Linear Model.

Results

Plasma metabolome in parallel to promotion of tumor development comprises a clearly distinct profile in Apc^Min/+ mice vs. wild type littermates, which is further altered by high-fat diet. Further, functional metabolomics pathway and network analyses in Apc^Min/+ mice on high-fat diet revealed associations between polyp formation and plasma metabolic compounds including those involved in amino-acids metabolism as well as nicotinamide and hippuric acid metabolic pathways. Finally, we also show changes in liver acyl-CoA profiles, which may result from a combination of Apc^Min/+-mediated tumor progression and high fat diet. The biological significance of these findings is discussed in the context of intestinal cancer progression.

Conclusions

These studies show that high-throughput metabolomics combined with appropriate statistical modeling and large scale functional approaches can be used to monitor and infer changes and interactions in the metabolome and genome of the host under controlled experimental conditions. Further these studies demonstrate the impact of diet on metabolic pathways and its relation to intestinal cancer progression. Based on our results, metabolic signatures and metabolic pathways of polyposis and intestinal carcinoma have been identified, which may serve as useful targets for the development of therapeutic interventions.

【 授权许可】

   
2014 Dazard et al.; licensee BioMed Central Ltd.

【 图 表 】

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