Chen Jayson X, Wang Hong, Liu Anna, Zhang Lanjing, Reuhl Kenneth, Yang Chung S
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.
Toxicol Sci. 2017 Jan;155(1):224-233. doi: 10.1093/toxsci/kfw190. Epub 2016 Sep 23.
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.
在过去几十年中，为研究人类结直肠癌（CRC）发病机制而建立的实验性啮齿动物模型通常采用合成化学致癌物或基因操作。我们实验室为了建立一个更具生理相关性的CRC模型，最近开发了一种由肉类衍生的膳食致癌物2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）诱导，并由葡聚糖硫酸钠（DSS）诱导的结肠炎在细胞色素P450 1A人源化（hCYP1A）小鼠中促进的结肠癌发生模型。所产生的结肠肿瘤具有人类结肠癌的许多组织学和分子特征。在本研究中，我们对PhIP/DSS诱导的结肠癌发生的早期阶段进行了特征描述。我们发现，PhIP/DSS处理导致结肠黏膜迅速破坏并伴有严重炎症，随后出现反应性改变和低度发育异常病变，接着出现高度发育异常病变，最终发展为腺癌。对早期时间点（即DSS暴露后第1、3、7、11、14和21天）的分子分析表明，在高度发育异常病变中存在Ctnnb1/β-连环蛋白突变和β-连环蛋白核积累，但在低度发育异常病变或相邻正常组织中未发现。此外，我们研究了Lgr5+结肠干细胞在PhIP/DSS诱导的结肠癌发生中的作用，发现在一些溃疡黏膜、高度发育异常病变和腺癌中存在表达Lgr5-增强绿色荧光蛋白的细胞，这表明Lgr5+干细胞在这种膳食致癌物诱导、炎症促进的结肠癌发生模型中可能发挥作用。总体而言，这些发现表明，PhIP/DSS诱导的结肠癌发生可能由残留上皮细胞中占主导地位的活性Ctnnb1/β-连环蛋白突变引发，在结肠炎的促进下，发展为高度发育异常和腺癌。
