Enhanced colitis‐associated colon carcinogenesis in a novel Apc mutant rat

Abstract

To establish an efficient rat model for colitis-associated colorectal cancer, azoxymethane and dextran sodium sulfate (AOM/DSS)-induced colon carcinogenesis was applied to a novel adenomatous polyposis coli (Apc) mutant, the Kyoto Apc Delta (KAD) rat. The KAD rat was derived from ethylnitrosourea mutagenesis and harbors a nonsense mutation in the Apc gene (S2523X). The truncated APC of the KAD rat was deduced to lack part of the basic domain, an EB1-binding domain, and a PDZ domain, but retained an intact beta-catenin binding region. KAD rats, homozygous for the Apc mutation on a genetic background of the F344 rat, showed no spontaneous tumors in the gastrointestinal tract. At 5 weeks of age, male KAD rats were given a single subcutaneous administration of AOM (20 mg/kg, bodyweight). One week later, they were given DSS (2% in drinking water) for 1 week. At week 15, the incidence and multiplicity of colon tumors developed in the KAD rat were remarkably severe compared with those in the F344 rat: 100 versus 50% in incidence and 10.7 +/- 3.5 versus 0.8 +/- 1.0 in multiplicity. KAD tumors were dominantly distributed in the rectum and distal colon, resembling human colorectal cancer. Accumulation of beta-catenin protein and frequent beta-catenin mutations were prominent features of KAD colon tumors. To our knowledge, AOM/DSS-induced colon carcinogenesis using the KAD rat is the most efficient to induce colon tumors in the rat, and therefore would be available as an excellent model for human colitis-associated CRC.