Most human colorectal carcinomas (CRCs) generally arise from adenomatous precursors, and mutations in the adenomatous polyposis coli (APC) gene are pivotal in colorectal tumorigenesis. Mouse intestinal tumor models have shown mainly small intestinal lesions; carcinomas are rare. Hinoi and colleagues defined sequences from the human CDX2 gene conferring colon epithelium–preferential transgene expression in the adult mouse, as indicated by the preferential activation of β-galactosidase expression following CDX2P-NLS Cre recombinase–mediated excision of a transcriptional stop element (top right panel; distal esophagus at top right, followed by stomach, small intestine, cecum, colon, and anus at bottom left). CPC;Apc mice carrying a CDX2P-NLS Cre recombinase transgene and a loxP-targeted Apc allele developed mainly colorectal tumors. The excised gastrointestinal tract from a 10-month-old CPC;Apc mouse is shown (top left panel). The location, size, and invasive potential of tumors arising in 18 male and 18 female CPC;Apc mice were defined (bottom right). On average, 5–8 tumors were found in the distal colon of a CPC;Apc mouse, along with 1 cecal and 3 distal small intestinal tumors. Male CPC;Apc mice had roughly 50% more distal lesions than female mice. Invasive carcinomas, similar to the muscularis propria–invasive, β-catenin nuclearpositive staining lesion shown (bottom left panel), were seen in 6 of 36 (17%) mice followed for 300 days. Like human colorectal lesions, the mouse tumors showed biallelic Apc inactivation, β-catenin dysregulation, global DNA hypomethylation, and aneuploidy. The mouse model should facilitate efforts to define novel factors and mechanisms contributing to human CRCs, as well as work on tumor-promoting environmental factors and agents, and strategies for cancer prevention or treatment. For details, see the article by Hinoi and colleagues on page 9721 of this issue.

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