A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer

被引:119
作者
Amos-Landgraf, James M.
Kwong, Lawrence N.
Kendziorski, Christina M.
Reichelderfer, Mark
Torrealba, Jose
Weichert, Jamey
Haag, Jill D.
Chen, Kai-Shun
Waller, Jordy L.
Gould, Michael N.
Dove, William F.
机构
[1] McArdle Lab Canc Res, Dept Biostat & Med Informat, Madison, WI 53706 USA
[2] McArdle Lab Canc Res, Dept Pathol & Lab Med, Madison, WI 53706 USA
[3] McArdle Lab Canc Res, Dept Radiol, Madison, WI 53706 USA
[4] McArdle Lab Canc Res, Dept Med, Sect Gastroenterol & Hepatol, Madison, WI 53706 USA
[5] Univ Wisconsin, Sch Med & Publ Hlth, Lab Genet, Madison, WI 53726 USA
关键词
chromosome biology; genomic instability; Min mouse; virtual colonoscopy; endoscopy;
D O I
10.1073/pnas.0611690104
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Progress toward the understanding and management of human colon cancer can be significantly advanced if appropriate experimental platforms become available. We have investigated whether a rat model carrying a knockout allele in the gatekeeper gene Adenomatous polyposis coli (Apc) recapitulates familial colon cancer of the human more closely than existing murine models. We have established a mutagen-induced nonsense allele of the rat Apc gene on an inbred F344/NTac (F344) genetic background. Carriers of this mutant allele develop multiple neoplasms with a distribution between the colon and small intestine that closely simulates that found in human familial adenomatous polyposis patients. To distinguish this phenotype from the predominantly small intestinal phenotype found in most Apc-mutant mouse strains, this strain has been designated the polyposis in the rat colon (Pirc) kindred. The Pirc rat kindred provides several unique and favorable features for the study of colon cancer. Tumor-bearing Pirc rats can live at least 17 months, carrying a significant colonic tumor burden. These tumors can be imaged both by micro computed tomography scanning and by classical endoscopy, enabling longitudinal studies of tumor genotype and phenotype as a function of response to chemopreventive and therapeutic regimes. The metacentric character of the rat karyotype, like that of the human and unlike the acrocentric mouse, has enabled us to demonstrate that the loss of the wild-type Apc allele in tumors does not involve chromosome loss. We believe that the Pirc rat kindred can address many of the current gaps in the modeling of human colon cancer.
引用
收藏
页码:4036 / 4041
页数:6
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