From the Cover: PhIP/DSS-Induced Colon Carcinogenesis in CYP1A-Humanized Mice and the Possible Role of Lgr5+ Stem Cells.
In the past decades, experimental rodent models developed to study the pathogenesis of human colorectal cancer (CRC) generally employed synthetic chemical carcinogens or genetic manipulation. Our lab, in order to establish a more physiologically relevant CRC model, 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. The resulting colon tumors shared many histologic and molecular features of human colon cancer. In this study, we characterized the early stages of PhIP/DSS-induced colon carcinogenesis. We found that PhIP/DSS treatments caused rapid destruction of the colon 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. Molecular analysis of the early time-points (ie, days 1, 3, 7, 11, 14, and 21 after DSS exposure) indicates Ctnnb1/β-catenin mutations and β-catenin nuclear accumulation in the high-grade dysplastic lesions, but not low-grade dysplastic lesions or adjacent normal tissues. In addition, we investigated the role of Lgr5+ colon stem cells in the PhIP/DSS-induced colon carcinogenesis and found the presence of Lgr5-enhance green fluorescent protein-expressing cells amidst some ulcerated mucosa, high-grade dysplastic lesions and adenocarcinomas, suggesting a possible role of Lgr5+ stem cells in this dietary carcinogen-induced, inflammation-promoted colon carcinogenesis model. Overall, the findings suggest that PhIP/DSS-induced colon carcinogenesis is likely initiated by dominant active Ctnnb1/β-catenin mutation in residual epithelial cells, which when promoted by colitis, developed into high-grade dysplasia and adenocarcinoma.
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.|Joint Graduate Program in Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
Jayson X
JX
Chen
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
Hong
H
Wang
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
Anna
A
Liu
Department of Pathology, University Medical Center of Princeton, Plainsboro, New Jersey.
Lanjing
L
Zhang
Department of Pharmacology and Toxicology, Rutgers, The State University of New Jersey, Piscataway, New Jersey.
Kenneth
K
Reuhl
Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, Piscataway, New Jersey; csyang@pharmacy.rutgers.edu.
Chung S
CS
Yang
D000818:Animals; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000139:chemically induced* / Q000201:enzymology / Q000473:pathology; D016264:Dextran Sulfate / Q000633:toxicity*; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*
D007093:Imidazoles; C116884:LGR5 protein, human; D043562:Receptors, G-Protein-Coupled; D016264:Dextran Sulfate; C049584:2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine
Colon carcinogenesis; DSS; Lgr5+; PhIP; β-catenin
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