title: 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.
authors.affiliation: Institute of Laboratory Animals, Graduate School of Medicine, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Yoshimi
authors.forename: Takuji
authors.initials: T
authors.lastname: Tanaka
authors.forename: Akiko
authors.initials: A
authors.lastname: Takizawa
authors.forename: Megumi
authors.initials: M
authors.lastname: Kato
authors.forename: Masumi
authors.initials: M
authors.lastname: Hirabayashi
authors.forename: Tomoji
authors.initials: T
authors.lastname: Mashimo
authors.forename: Tadao
authors.initials: T
authors.lastname: Serikawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Kuramoto
mesh_terms: 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
chemical_list: D018389:Codon, Nonsense; C495268:Ctnnb1 protein, rat; C528430:Kras protein, rat; D051176:beta Catenin; D016283:Proto-Oncogene Proteins p21(ras); D005038:Ethylnitrosourea
references.citation: Int J Cancer. 2006 Jan 1;118(1):25-34
references.pmid: 16049979
references.citation: Science. 1997 Mar 21;275(5307):1787-90
references.pmid: 9065402
references.citation: Science. 1996 May 17;272(5264):1020-3
references.pmid: 8638125
references.citation: Cancer Res. 1995 Jul 15;55(14):2972-7
references.pmid: 7606712
references.citation: Cancer Res. 2007 Nov 15;67(22):10766-73
references.pmid: 18006820
references.citation: Physiol Genomics. 2006 Feb 14;24(3):198-206
references.pmid: 16368876
references.citation: Clin Genet. 2000 Mar;57(3):205-12
references.pmid: 10782927
references.citation: Cancer Sci. 2003 Nov;94(11):965-73
references.pmid: 14611673
references.citation: Immunol Rev. 2005 Aug;206:260-76
references.pmid: 16048554
references.citation: Eur Surg Res. 1999;31(3):272-80
references.pmid: 10352356
references.citation: J Cell Sci. 2007 Oct 1;120(Pt 19):3327-35
references.pmid: 17881494
references.citation: Gastroenterology. 2004 Feb;126(2):451-9
references.pmid: 14762782
references.citation: Curr Opin Cell Biol. 2008 Apr;20(2):186-93
references.pmid: 18359618
references.citation: Cancer Res. 2005 Jan 1;65(1):121-9
references.pmid: 15665287
references.citation: Nat Genet. 2008 May;40(5):514-5
references.pmid: 18443587
references.citation: Cancer Lett. 2003 Aug 20;198(2):145-52
references.pmid: 12957352
references.citation: Cancer Sci. 2004 Jun;95(6):475-80
references.pmid: 15182426
references.citation: Cancer Sci. 2005 Feb;96(2):69-76
references.pmid: 15723650
references.citation: Dis Colon Rectum. 2000 May;43(5):720-1
references.pmid: 10826438
references.citation: Cancer Res. 1994 Jul 15;54(14):3676-81
references.pmid: 8033083
references.citation: Chem Biol Interact. 2009 Jan 27;177(2):128-36
references.pmid: 19028472
references.citation: Am J Physiol Gastrointest Liver Physiol. 2004 Jul;287(1):G7-17
references.pmid: 15194558
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 6;104(10):4036-41
references.pmid: 17360473
references.citation: J Leukoc Biol. 2000 Mar;67(3):267-78
references.pmid: 10733087
references.citation: Cancer Lett. 2002 Sep 8;183(1):31-41
references.pmid: 12049812
references.citation: Gastroenterology. 1990 Mar;98(3):694-702
references.pmid: 1688816
references.citation: Nat Med. 2009 Jan;15(1):104-9
references.pmid: 19029979
references.citation: Science. 1990 Jan 19;247(4940):322-4
references.pmid: 2296722
references.citation: Cancer Res. 1998 Jan 1;58(1):42-6
references.pmid: 9426055
references.citation: Neurosci Res. 2007 Dec;59(4):413-25
references.pmid: 17889953
references.citation: Carcinogenesis. 2005 Jan;26(1):229-38
references.pmid: 15459021
references.citation: Science. 1991 Aug 9;253(5020):661-5
references.pmid: 1651562
references.citation: Gene. 2005 Nov 21;361:1-12
references.pmid: 16185824