Abstract 1255: PhIP/DSS-induced colon carcinogenesis in CYP1A-humanized mice and its prevention by tocopherols

• Published in: Cancer research (Chicago, Ill.) Ill.), 2017-07, Vol.77 (13_Supplement), p.1255-1255
• Main Authors: Yang, Chung S., Chen, Jayson, Liu, Anna B., Lee, Mao-Jung, Wang, Hong, Li, Guangxun, Zhang, Lanjing, Reuhl, Kenneth, Suh, Nanjoo
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2017-1255

In order to establish a more physiologically relevant colorectal cancer model, we recently developed a colon-carcinogenesis model induced by the meat-derived dietary carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP), and promoted by dextran sodium sulfate (DSS)-induced colitis in the cytochrome P450 1A-humanized (hCYP1A) mice. PhIP/DSS treatments caused rapid destruction of the colonic mucosa with severe inflammation, followed by the presence of reactive changes and low-grade dysplastic lesions, and then manifestation of high-grade dysplastic lesions and finally adenocarcinomas in the middle to distal colon of the hCYP1A mice after 10 weeks. Molecular analysis of the high-grade dysplastic lesions present at early time-points indicates Ctnnb1/β-catenin mutations and β-catenin nuclear accumulation in high-grade dysplastic lesions, but not in low-grade dysplastic lesions or adjacent normal tissues. Using hCYP1A/Lgr5-EGFP mouse, which harbors EGFP-tagged Lgr5 allele, we also investigated the role of Lgr5+ colon stem cells in the PhIP/DSS-induced colon carcinogenesis and found the presence of Lgr5-EGFP-expressing cells amidst ulcerated mucosa, high-grade dysplastic lesions and adenocarcinomas, suggesting a possible role of Lgr5+ stem cells in this colon-carcinogenesis model. In addition, our study demonstrated strong cancer preventive effects of tocopherols (T), the major forms of vitamin E, in PhIP/DSS-induced colon carcinogenesis. Dietary supplementation with δ-T and γ-T significantly reduced colon tumor formation and suppressed the expression of markers of oxidative and nitrosative stress as well as pro-inflammatory mediators in tumors and adjacent tissues. By administering δ-T at different time points, we found that the inhibitory effect of δ-T against colon carcinogenesis was mainly due to protection against early cellular and DNA damages caused by PhIP. α-T was found to be ineffective in inhibiting colon tumorigenesis and less effective in attenuating the molecular changes. Altogether, PhIP/DSS-induced colon carcinogenesis is likely initiated from residual epithelial cells (possibly Lgr5+ colon stem cells) and promoted by colitis, and subsequently developed into high-grade dysplasia and adenocarcinoma. These events are effectively inhibited by δ-T and γ-T, but not α-T. (This work was supported by the US NIH grants RO1 CA133021, RO1 AT007036, and F31 CA168333 as well as shared facilities funded by center grant P30 CA72720 and P30 ES005022)