A new conditional Apc-mutant mouse model for colorectal cancer

• Published in: Carcinogenesis (New York) 2010-05, Vol.31 (5), p.946-952
• Main Authors: Robanus-Maandag, Els C., Koelink, Pim J., Breukel, Cor, Salvatori, Daniela C.F., Jagmohan-Changur, Shantie C., Bosch, Cathy A.J., Verspaget, Hein W., Devilee, Peter, Fodde, Riccardo, Smits, Ron
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; CDX2 Transcription Factor; Colorectal Neoplasms - genetics; Disease Models, Animal; Gastroenterology. Liver. Pancreas. Abdomen; Genes, APC; Homeodomain Proteins - genetics; Humans; Integrases - physiology; Medical sciences; Mice; Mice, Inbred C57BL; Mutation; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Transcription Factors - genetics; Tumors
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgq046

Mutations of the adenomatous polyposis coli (APC) gene predispose individuals to familial adenomatous polyposis (FAP), characterized by multiple tumours in the large intestine. Most mouse models heterozygous for truncating mutant Apc alleles mimic FAP, however, the intestinal tumours occur mainly in the small intestine. To model large intestinal tumours, we generated a new conditional Apc-mutant allele, Apc15lox, with exon 15 flanked by loxP sites. Similar survival of Apc1638N/15lox and Apc1638N/+ mice indicated that the normal function of Apc was not impaired by the loxP sites. Deletion of exon 15, encoding nearly all functional Apc domains and containing the polyadenylation signal, resulted in a mutant allele expressing low levels of a 74 kDa truncated Apc protein. Germ line Cre-mediated deletion of exon 15 resulted in ApcΔ15/+ mice, showing a severe ApcMin/+-like phenotype characterized by multiple tumours in the small intestine and early lethality. In contrast, conditional Cre-mediated deletion of exon 15 specifically directed to the epithelia of distal small and large intestine of FabplCre;Apc15lox/+ mice led to longer survival and to tumours that developed predominantly in the large intestine, mimicking human FAP-associated colorectal cancer and sporadic colorectal cancer. We conclude that the FabplCre;Apc15lox/+ mouse should be an attractive model for studies on prevention and treatment of colorectal cancer.