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Mechanisms linking obesity to altered metabolism in mice colon carcinogenesis.

ABSTRACT: There are an increasing number of reports on obesity being a key risk factor for the development of colon cancer. Our goal in this study was to explore the metabolic networks and molecular signaling pathways linking obesity, adipose tissue and colon cancer. Using in-vivo experiments, we found that mice fed a high-fat diet (HFD) and injected with MC38 colon cancer cells develop significantly larger tumors than their counterparts fed a control diet. In ex-vivo experiments, MC38 and CT26 colon cancer cells exposed to conditioned media (CM) from the adipose tissue of HFD-fed mice demonstrated significantly lower oxygen consumption rate as well as lower maximal oxygen consumption rate after carbonyl cyanide-4-trifluoromethoxy-phenylhydrazone treatment. In addition, in-vitro assays showed downregulated expression of mitochondrial genes in colon cancer cells exposed to CM prepared from the visceral fat of HFD-fed mice or to leptin. Interestingly, leptin levels detected in the media of adipose tissue explants co-cultured with MC38 cancer cells were higher than in adipose tissue explants cultures, indicating cross talk between the adipose tissue and the cancer cells. Salient findings of the present study demonstrate that this crosstalk is mediated at least partially by the JNK/STAT3-signaling pathway.

SUBMITTER: Nimri L

PROVIDER: S-EPMC4741993 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Low dietary folate intake is associated with an increased risk for colon cancer; however, relevant genetic animal models are lacking. We therefore investigated the effect of targeted ablation of two folate transport genes, folate binding protein 1 (Folbp1) and reduced folate carrier 1 (RFC1), on folate homeostasis to elucidate the molecular mechanisms of folate action on colonocyte cell proliferation, gene expression, and colon carcinogenesis. Targeted deletion of Folbp1 (Folbp1(+/-) and Folbp1(-/-)) significantly reduced (P < 0.05) colonic Folbp1 mRNA, colonic mucosa, and plasma folate concentration. In contrast, subtle changes in folate homeostasis resulted from targeted deletion of RFC1 (RFC1(+/-)). These animals had reduced (P < 0.05) colonic RFC1 mRNA and exhibited a 2-fold reduction in the plasma S-adenosylmethionine/S-adenosylhomocysteine. Folbp1(+/-) and Folbp1(-/-) mice had larger crypts expressed as greater (P < 0.05) numbers of cells per crypt column relative to Folbp1(+/+) mice. Colonic cell proliferation was increased in RFC1(+/-) mice relative to RFC1(+/+) mice. Microarray analysis of colonic mucosa showed distinct changes in gene expression specific to Folbp1 or RFC1 ablation. The effect of folate transporter gene ablation on colon carcinogenesis was evaluated 8 and 38 weeks post-azoxymethane injection in wild-type and heterozygous mice. Relative to RFC1(+/+) mice, RFC1(+/-) mice developed increased (P < 0.05) numbers of aberrant crypt foci at 8 weeks. At 38 weeks, RFC1(+/-) mice developed local inflammatory lesions with or without epithelial dysplasia as well as adenocarcinomas, which were larger relative to RFC1(+/+) mice. In contrast, Folbp1(+/-) mice developed 4-fold (P < 0.05) more lesions relative to Folbp1(+/+) mice. In conclusion, Folbp1 and RFC1 genetically modified mice exhibit distinct changes in colonocyte phenotype and therefore have utility as models to examine the role of folate homeostasis in colon cancer development.

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Mechanisms linking obesity to altered metabolism in mice colon carcinogenesis.

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