Hinoi Takao, Akyol Aytekin, Theisen Brian K, Ferguson David O, Greenson Joel K, Williams Bart O, Cho Kathleen R, Fearon Eric R
Department of Internal Medicine, The Cancer Center, University of Michigan School of Medicine, Ann Arbor, Michigan 48109-2200, USA.
Cancer Res. 2007 Oct 15;67(20):9721-30. doi: 10.1158/0008-5472.CAN-07-2735.
Mutations in the adenomatous polyposis coli (APC) gene are pivotal in colorectal tumorigenesis. Existing mouse intestinal tumor models display mainly small intestinal lesions and carcinomas are rare. We defined human CDX2 sequences conferring colon epithelium-preferential transgene expression in the adult mouse. Mice carrying a CDX2P-NLS Cre recombinase transgene and a loxP-targeted Apc allele developed mainly colorectal tumors, with carcinomas seen in 6 of 36 (17%) of mice followed for 300 days. Like human colorectal lesions, the mouse tumors showed biallelic Apc inactivation, beta-catenin dysregulation, global DNA hypomethylation, and aneuploidy. The predominantly distal colon and rectal distribution of tumors seen in mice where one Apc allele was inactivated in epithelial cells from distal ileum to rectum suggests that regional differences in the intestinal tract in the frequency and nature of secondary genetic and epigenetic events associated with adenoma outgrowth have a contributing role in determining where adenomas develop. The presence of large numbers of small intestine tumors seemed to inhibit colorectal tumor development in the mouse, and gender-specific effects on tumor multiplicity in the distal mouse colon and rectum mimic the situation in humans where males have a larger number of advanced adenomas and carcinomas in the distal colon and rectum than females. The mouse model of colon-preferential gene targeting described here should facilitate efforts to define novel factors and mechanisms contributing to human colon tumor pathogenesis, as well as work on tumor-promoting environmental factors and agents and strategies for cancer prevention and treatment.
腺瘤性结肠息肉病（APC）基因的突变在结直肠癌发生过程中起关键作用。现有的小鼠肠道肿瘤模型主要表现为小肠病变，很少出现癌。我们确定了在成年小鼠中赋予结肠上皮优先转基因表达的人CDX2序列。携带CDX2P-NLS Cre重组酶转基因和loxP靶向Apc等位基因的小鼠主要发生结直肠癌，在随访300天的36只小鼠中有6只（17%）出现癌。与人类结直肠病变一样，小鼠肿瘤表现为Apc双等位基因失活、β-连环蛋白失调、全基因组DNA低甲基化和非整倍体。在远端回肠至直肠的上皮细胞中一个Apc等位基因失活的小鼠中，肿瘤主要分布在远端结肠和直肠，这表明肠道中与腺瘤生长相关的继发性遗传和表观遗传事件的频率和性质的区域差异在决定腺瘤发生部位方面起作用。大量小肠肿瘤的存在似乎抑制了小鼠结直肠癌的发生，并且对小鼠远端结肠和直肠肿瘤 multiplicity 的性别特异性影响类似于人类的情况，即男性在远端结肠和直肠中的晚期腺瘤和癌比女性多。这里描述的结肠优先基因靶向小鼠模型应有助于确定导致人类结肠肿瘤发病机制的新因素和机制，以及研究肿瘤促进环境因素和药物以及癌症预防和治疗策略。
