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Cf, Yu; Whiteley, Laurence O.; Carryl, O.R.; Basson,

doi:10.1023/a:1010615215528

Cited by 22 publications

(2 citation statements)

References 27 publications

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“…Prevention of colon cancer remains a significant public health issue that is highly associated with genetic and environmental factors such as diet composition [30]. Evidence is emerging that diet and nutrient factors may play an important role in colorectal cancer incidence and progression [31-34].…”

Section: Introductionmentioning

confidence: 99%

Metabolomics of ApcMin/+ mice genetically susceptible to intestinal cancer

et al. 2014

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BackgroundTo 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.ResultsPlasma 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.ConclusionsThese 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.

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Section: Introductionmentioning

confidence: 99%

Metabolomics of ApcMin/+ mice genetically susceptible to intestinal cancer

et al. 2014

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“…Studies have demonstrated that a low-fat diet can prevent colon tumor formation, but the relative risk associated with dietary fat in humans remains unclear. 66 , 67 Our study demonstrates a protective effect of endogenous TSP1 that is sensitive to dietary fat intake. The loss of TSP1 expression that has been documented to result from loss of tumor suppresser genes and activation of oncogenes associated with colon carcinogenesis could contribute to promoting early and late stages of colon tumor formation.…”

Section: Discussionmentioning

confidence: 58%

Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the ApcMin/+ model of colon cancer

et al. 2016

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Thrombospondin 1 is a glycoprotein that regulates cellular phenotype through interactions with its cellular receptors and extracellular matrix-binding partners. Thrombospondin 1 locally regulates angiogenesis and inflammatory responses that contribute to colorectal carcinogenesis in Apc Min/+ mice. The ability of thrombospondin 1 to regulate responses of cells and tissues to a variety of stresses suggested that loss of thrombospondin 1 may also have broader systemic effects on metabolism to modulate carcinogenesis. Apc Min/+ :Thbs1 −/− mice exhibited decreased survival and higher tumor multiplicities in the small and large intestine relative to Apc Min/+ mice when fed a low (5%) fat western diet. However, the protective effect of endogenous thrombospondin 1 was lost when the mice were fed a western diet containing 21% fat. Biochemical profiles of liver tissue identified systemic metabolic changes accompanying the effects of thrombospondin 1 and dietary lipid intake on tumorigenesis. A high-fat western diet differentially regulated elements of amino acid, energy and lipid metabolism in Apc Min/+ :Thbs1 −/− mice relative to Apc Min/+ :Thbs1 +/+ mice. Metabolic changes in ketone body and tricarboxylic acid cycle intermediates indicate functional interactions between Apc and thrombospondin 1 signaling that control mitochondrial function. The cumulative diet-dependent differential changes observed in Apc Min/+ :Thbs1 −/− versus Apc Min/+ mice include altered amino acid and lipid metabolism, mitochondrial dysfunction, eicosanoids and ketone body formation. This metabolic profile suggests that the protective role of thrombospondin 1 to decrease adenoma formation in Apc Min/+ mice results in part from improved mitochondrial function.

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The development of duodenal microadenomas in FAP patients: the human correlate of the Min mouse

Preston

Leedham

Oukrif

et al. 2008

The Journal of Pathology

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The morphological changes associated with the adenoma-carcinoma sequence are well documented in the colorectum. Small intestinal carcinogenesis is thought to progress through a similar adenoma-to-carcinoma pathway, but there is a relative dearth of studies examining the associated morphological changes. The best-known mouse model of intestinal neoplasia, the multiple intestinal neoplasia (Min) mouse, has been criticized as a genetic model of intestinal neoplasia, as the majority of its tumours occur in the small intestine. We examined pancreatico-duodenal resection specimens from seven familial adenomatous polyposis (FAP) patients. Serial sections of these were stained with haematoxylin and eosin for β-catenin and its downstream target CD44, for BMPR1a, lysozyme, carbonic anhydrase II, and with MIB-1. Individual dysplastic crypts were isolated and mutations in the FAP (

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Untitled

Cited by 22 publications

References 27 publications

Metabolomics of ApcMin/+ mice genetically susceptible to intestinal cancer

Metabolomics of ApcMin/+ mice genetically susceptible to intestinal cancer

Dietary fat overcomes the protective activity of thrombospondin-1 signaling in the ApcMin/+ model of colon cancer

The development of duodenal microadenomas in FAP patients: the human correlate of the Min mouse

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