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Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR.

ABSTRACT: Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D2) caused more adenomas in Apc(Min/+) mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D2 (PGD2) binds to the prostaglandin D2 receptor known as PTGDR (or DP1). PGD2 metabolites bind to peroxisome proliferator-activated receptor ? (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors take part in tumor suppression by PGD2. To assess, we produced Apc(Min/+) mice with and without Ptgdr knockouts (147 mice). In separate experiments, we produced Apc(Min/+) mice expressing transgenic lipocalin-type prostaglandin D synthase (PTGDS), with and without heterozygous Pparg knockouts (104 mice). Homozygous Ptgdr knockouts raised total numbers of tumors by 30-40% at 6 and 14 weeks. Colon tumors were not affected. Heterozygous Pparg knockouts alone did not affect tumor numbers in Apc(Min/+) mice. As mentioned above, our Pparg knockout assessment also included mice with highly expressed PTGDS transgenes. Apc(Min/+) mice with transgenic PTGDS had fewer large adenomas (63% of control) and lower levels of v-myc avian myelocytomatosis viral oncogene homolog (MYC) mRNA in the colon. Heterozygous Pparg knockouts appeared to blunt the tumor-suppressing effect of transgenic PTGDS. However, tumor suppression by PGD2 was more clearly mediated by receptor PTGDR in our experiments. The suppression mechanism did not appear to involve changes in microvessel density or slower proliferation of tumor cells. The data support a role for PGD2 signals acting through PTGDR in suppression of intestinal tumors.

SUBMITTER: Tippin BL

PROVIDER: S-EPMC4303173 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR.

Tippin Brigette L BL Kwong Alan M AM Inadomi Michael J MJ Lee Oliver J OJ Park Jae Man JM Materi Alicia M AM Buslon Virgilio S VS Lin Amy M AM Kudo Lili C LC Karsten Stanislav L SL French Samuel W SW Narumiya Shuh S Urade Yoshihiro Y Salido Eduardo E Lin Henry J HJ

Cancer medicine 20140412 4

Our earlier work showed that knockout of hematopoietic prostaglandin D synthase (HPGDS, an enzyme that produces prostaglandin D2) caused more adenomas in Apc(Min/+) mice. Conversely, highly expressed transgenic HPGDS allowed fewer tumors. Prostaglandin D2 (PGD2) binds to the prostaglandin D2 receptor known as PTGDR (or DP1). PGD2 metabolites bind to peroxisome proliferator-activated receptor γ (PPARG). We hypothesized that Ptgdr or Pparg knockouts may raise numbers of tumors, if these receptors ...[more]

PMID: 24729479

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Project description:BACKGROUND:To determine how diets high in saturated fat could increase polyp formation in the mouse model of intestinal neoplasia, ApcMin/+, we conducted large-scale metabolome analysis and association study of colon and small intestine polyp formation from plasma and liver samples of ApcMin/+ 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 ApcMin/+ mice vs. wild type littermates, which is further altered by high-fat diet. Further, functional metabolomics pathway and network analyses in ApcMin/+ 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 ApcMin/+-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.

Dataset Information

Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR.

Publications

Intestinal tumor suppression in ApcMin/+ mice by prostaglandin D2 receptor PTGDR.

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