Dataset Information

ApcMin/+ tumours and normal mouse small intestines show linear metabolite concentration and DNA cytosine hydroxymethylation gradients from pylorus to colon.

ABSTRACT: Topographical variations of metabolite concentrations have been reported in the duodenum, jejunum and ileum of the small intestine, and in human intestinal tumours from those regions, but there are no published metabolite concentrations measurements correlated with linear position in the mouse small intestine or intestinal tumours. Since DNA methylation dynamics are influenced by metabolite concentrations, they too could show linear anatomical variation. We measured metabolites by HR-MAS 1H NMR spectroscopy and DNA cytosine modifications by LC/MS, in normal small intestines of C57BL/6J wild-type mice, and in normal and tumour samples from ApcMin/+ mice. Wild-type mouse intestines showed approximately linear, negative concentration gradations from the pylorus (i.e. the junction with the stomach) of alanine, choline compounds, creatine, leucine and valine. ApcMin/+ mouse tumours showed negative choline and valine gradients, but a positive glycine gradient. 5-Hydroxymethylcytosine showed a positive gradient in the tumours. The linear gradients we found along the length of the mouse small intestine and in tumours contrast with previous reports of discrete concentration changes in the duodenum, jejunum and ileum. To our knowledge, this is also the first report of a systematic measurement of global levels of DNA cytosine modification in wild-type and ApcMin/+ mouse small intestine.

SUBMITTER: Madhu B

PROVIDER: S-EPMC7423954 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Apc<sup>Min/+</sup> tumours and normal mouse small intestines show linear metabolite concentration and DNA cytosine hydroxymethylation gradients from pylorus to colon.

Madhu Basetti B Uribe-Lewis Santiago S Bachman Martin M Murrell Adele A Griffiths John R JR

Scientific reports 20200812 1

Topographical variations of metabolite concentrations have been reported in the duodenum, jejunum and ileum of the small intestine, and in human intestinal tumours from those regions, but there are no published metabolite concentrations measurements correlated with linear position in the mouse small intestine or intestinal tumours. Since DNA methylation dynamics are influenced by metabolite concentrations, they too could show linear anatomical variation. We measured metabolites by HR-MAS <sup>1< ...[more]

PMID: 32788746

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Project description:A mouse model of human Familial Adenomatous Polyposis responds favorably to pharmacological inhibition of 5'-methylthioadenosine phosphorylase (MTAP). Methylthio-DADMe-Immucillin-A (MTDIA) is an orally available, transition state analogue inhibitor of MTAP. 5'-Methylthioadenosine (MTA), the substrate for MTAP, is formed in polyamine synthesis and is recycled by MTAP to S-adenosyl-L-methionine (SAM) via salvage pathways. MTDIA treatment causes accumulation of MTA, which inhibits growth of human head and neck (FaDu) and lung (H359, A549) cancers in immunocompromised mouse models. We investigated the efficacy of oral MTDIA as an anti-cancer therapeutic for intestinal adenomas in immunocompetent APCMin/+ mice, a murine model of human Familial Adenomatous Polyposis. Tumors in APCMin/+ mice were decreased in size by MTDIA treatment, resulting in markedly improved anemia and doubling of mouse lifespan. Metabolomic analysis of treated mice showed no changes in polyamine, methionine, SAM or ATP levels when compared with control mice but indicated an increase in MTA, the MTAP substrate. Generation of an MTDIA-resistant cell line in culture showed a four-fold amplification of the methionine adenosyl transferase (MAT2A) locus and expression of this enzyme. MAT2A is downstream of MTAP action and catalyzes synthesis of the SAM necessary for methylation reactions. Immunohistochemical analysis of treated mouse intestinal tissue demonstrated a decrease in symmetric dimethylarginine, a PRMT5-catalyzed modification. The anti-cancer effects of MTDIA indicate that increased cellular MTA inhibits PRMT5-mediated methylations resulting in attenuated tumor growth. Oral dosing of MTDIA as monotherapy has potential for delaying the onset and progression of colorectal cancers in Familial Adenomatous Polyposis (FAP) as well as residual duodenal tumors in FAP patients following colectomy. MTDIA causes a physiologic inactivation of MTAP and may also have efficacy in combination with inhibitors of MAT2A or PRMT5, known synthetic-lethal interactions in MTAP-/- cancer cell lines.

Project description:PurposeExposure to ionizing radiation increases risk of breast cancer. Although proton radiation is encountered in outer space and in medicine, we do not fully understand breast cancer risks from protons owing to limited in vivo data. The purpose of this study was to comparatively assess the effects of γ-rays and protons on mammary tumorigenesis in APCMin/+ mice.Methods and materialsFemale APCMin/+ mice were exposed to 1 GeV protons (1.88 or 4.71 Gy) and 137Cs γ-rays (2 or 5 Gy). Mice were euthanized 100 to 110 days after irradiation, at which point mammary tumors were scored, tumor grades were assessed, and relative biological effectiveness was calculated. Molecular phenotypes were determined by assessing estrogen receptor α (ERα) and human epidermal growth factor receptor 2 (HER2) status. ERα downstream signaling was assessed by immunohistochemistry.ResultsExposure to proton radiation led to increased mammary tumor frequency at both proton radiation doses compared with γ-rays. The calculated relative biological effectiveness for proton radiation-induced mammary tumorigenesis was 3.11 for all tumors and >5 for malignant tumors relative to γ-rays. Tumor frequency per unit of radiation was higher at the lower dose, suggesting a saturation effect at the higher dose. Protons induced more adenocarcinomas relative to γ-rays, and proton-induced tumors show greater ERα and HER2 positivity and higher activation of the ERα downstream PI3K/Akt and cyclin D1 pathways relative to γ-rays.ConclusionsOur data demonstrate that protons pose a higher risk of mammary tumorigenesis relative to γ-rays. We also show that proton radiation-induced tumors in APCMin/+ mice are ERα- and HER2-positive, which is consistent with our previous data on radiation-induced estrogenic response in wild-type mice. Although this study establishes APCMin/+ as a model with adequate signal-to-noise ratio for space radiation-induced mammary tumorigenesis, further studies will be required to address the uncertainties in space radiation-induced breast cancer risk estimation.

Dataset Information

ApcMin/+ tumours and normal mouse small intestines show linear metabolite concentration and DNA cytosine hydroxymethylation gradients from pylorus to colon.

Publications

Apc<sup>Min/+</sup> tumours and normal mouse small intestines show linear metabolite concentration and DNA cytosine hydroxymethylation gradients from pylorus to colon.

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