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

Abstract

Abstract 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). Citation Format: Chung S. Yang, Jayson Chen, Anna B. Liu, Mao-Jung Lee, Hong Wang, Guangxun Li, Lanjing Zhang, Kenneth Reuhl, Nanjoo Suh. PhIP/DSS-induced colon carcinogenesis in CYP1A-humanized mice and its prevention by tocopherols [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1255. doi:10.1158/1538-7445.AM2017-1255