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 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.
Yoshimi
Kazuto
K
Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto, Japan.
Tanaka
Takuji
T
Takizawa
Akiko
A
Kato
Megumi
M
Hirabayashi
Masumi
M
Mashimo
Tomoji
T
Serikawa
Tadao
T
Kuramoto
Takashi
T
D000818:Animals; D018389:Codon, Nonsense; D003092:Colitis / Q000150:complications*; D003110:Colonic Neoplasms / Q000209:etiology* / Q000473:pathology; D005038:Ethylnitrosourea; D005260:Female; D017491:Genes, APC; D008297:Male; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D051176:beta Catenin / Q000235:genetics
D018389:Codon, Nonsense; C495268:Ctnnb1 protein, rat; C528430:Kras protein, rat; D051176:beta Catenin; D016283:Proto-Oncogene Proteins p21(ras); D005038:Ethylnitrosourea
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