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

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 β‐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 β‐catenin protein and frequent β‐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.