Studies of colon carcinogenesis in animal models are very useful to elucidate mechanisms and provide pointers to potential prevention approaches in the human situation. In the rat colon carcinogenesis model induced by azoxymethane (AOM), we have documented frequent mutations of specific genes. K‐ras mutations at codon 12 were found to be frequent in hyperplastic aberrant crypt foci (ACF) and large adenocarcinomas. In addition, mutations of the β‐catenin gene in its GSK‐3β phosphorylation consensus motif could also be identified in many adenomas and adenocarcinomas, and altered cellular localization of p‐catenin protein was observed in all of the dysplastic ACF, adenomas and adenocarcinomas examined, indicating that activation of Wnt signaling by accumulation of β‐catenin is a major mechanism in the AOM‐induced colon carcinogenesis model. Frequent gene mutations of β‐catenin and altered cellular localization of the protein are also features of AOM‐induced colon tumors in mice. Expression of enzymes associated with inflammation, such as inducible nitric oxide synthase (INOS) and the inducible type of cyclooxyge‐nase (COX), COX‐2, is increased in AOM‐induced rat colon carcinogenesis, and overproduction of nitric oxide (NO) and prostaglandins is considered to be involved in colon tumor development. We have demonstrated that increased expression of INOS is an early and important event occurring in step with β‐catenin alteration in rat colon carcinogenesis. Activation of K‐ras was also found to be involved in up‐regulation of INOS in the presence of inflammatory stimuli. In addition, expression levels of prostaglandin E₂ (PGE₂) receptors may be altered in colon cancers. For example, the EP, and EP₂ subtypes have been shown to be up‐regulated and EP₃ down‐regulated in AOM‐induced colon cancers in rats and mice. EP, and EP₄ appear to be involved in ACF formation, while alteration in EP₂ and EP₃ is considered to contribute to later steps in colon carcinogenesis. Increased expression of some other gene products, such as the targets of Wnt/β‐catenin signaling, have also been reported. The further accumulation of data with this chemically‐induced animal colon carcinogenesis model should provide useful information for understanding colorectal neoplasia in man.

Cyclooxygenase-2 (COX-2) is abundantly expressed in colon cancer cells. It has been reported that inhibition of COX-2 enzyme activity is shown to prevent colon carcinogenesis. Thus, suppression of COX-2 expression may also be an effective chemopreventive strategy. In the present study, we constructed a β-galactosidase reporter gene system in human colon cancer DLD-1 cells, and measured COX-2 promoter-dependent transcriptional activity in the cells. Interferon γ suppressed this COX-2 promoter activity, while 12-O-tetradecanoylphorbol-13-acetate and transforming growth factor α (TGFα) exerted enhancing effects. We then tested the influence of 14 candidate cancer chemopreventive compounds on COX-2 promoter activity. Chemopreventive agents such as quercetin, kaempferol, genistein, resveratrol and resorcinol, all having a common resorcin moiety, were found to effectively suppress the COX-2 promoter activity with and without TGFα-stimulation in DLD-1 cells. Since all these compounds have a resorcin moiety as a common structure, a resorcin-type structure may play an active role in the inhibition of COX-2 expression in colon cancer cells.

Unclear. Recently, we have shown that Syrian golden hamsters feature FI of the pancreas, the severity of which increases along with the progression of carcinogenesis induced by a chemical carcinogen. To translate the results to a clinical setting, we investigated whether FI in the pancreas is associated with pancreatic cancer in a series of patients who had undergone pancreatoduodenectomy. METHODS: In the series, we identified 102 cases with pancreatic ductal adenocarcinoma (PDAC) and 85 controls with cancers except for PDAC. The degree of FI was evaluated histopathologically from the area occupied by adipocytes in pancreas sections, and was compared between the cases and controls. RESULTS: The degree of FI in the pancreas was significantly higher in cases than in controls (median 26 vs. 15%,P<0.001) and positively associated with PDAC, even after adjustment for BMI, prevalence of DM and other confounding factors (odds ratio (OR), 6.1;P<0.001). BMI was identified as the most significantly associated factor with FI in the pancreas. CONCLUSIONS: There is a positive correlation between FI in the pancreas and pancreatic cancer. *Correspondence: Hitoshi Nakagama, MD, DMSc, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: hnakagam@ncc.go.jp Received 1 November 13; revised 6 January 14; accepted 15 January 14 published online 13 March 2014 © 2014 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology...

The mouse model for familial adenomatous polyposis, Apc^Min/+ mouse, contains a truncating mutation in the Apc gene and spontaneously develops numerous adenomas in the small intestine but few in the large bowel. Our study investigated whether dextran sodium sulfate (DSS) treatment promotes the development of colonic neoplasms in Apc^Min/+ mice. Apc^Min/+ and Apc^+/+ mice of both sexes were exposed to 2% dextran sodium sulfate in drinking water for 7 days, followed by no further treatment for 4 weeks. Immunohistochemistry for cyclooxygenase‐2, inducible nitric oxide synthase, β‐catenin, p53, and nitrotyrosine, and mutations of β‐catenin and K‐ras and loss of wild‐type allele of the Apc gene in the colonic lesions were examined. Sequential observation of female Apc^Min/+ mice that received DSS was also performed up to week 5. At week 5, numerous colonic neoplasms developed in male and female Apc^Min/+ mice but did not develop in Apc^+/+ mice. Adenocarcinomas developed in Apc^Min/+ mice that received DSS showed loss of heterozygosity of Apc and no mutations in the β‐catenin and K‐ras genes. The treatment also significantly increased the number of small intestinal polyps. Sequential observation revealed increase in the incidences of colonic neoplasms and dysplastic crypts in female Apc^Min/+ mice given DSS. DSS treatment increased inflammation scores, associated with high intensity staining of β‐catenin, cyclooxygenase‐2, inducible nitric oxide synthase and nitrotyrosine. Interestingly, strong nuclear staining of p53 was specifically observed in colonic lesions of Apc^Min/+ mice treated with DSS. Our results suggest a strong promotion effect of DSS in the intestinal carcinogenesis of Apc^Min/+ mice. The findings also suggest that strong oxidative/nitrosative stress caused by DSS‐induced inflammation may contribute to the colonic neoplasms development.