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

James M. Amos-Landgraf, Lawrence N. Kwong, Christina M. Kendziorski, Mark Reichelderfer, Jose Torrealba, Jamey Weichert, Jill D. Haag, Kai Shun Chen, Jordy L. Waller, Michael N. Gould, William F. Dove

Research output: Contribution to journalArticlepeer-review

108 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4036-4041
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number10
DOIs
StatePublished - Mar 6 2007

Keywords

  • Chromosome biology
  • Endoscopy
  • Genomic instability
  • Min mouse
  • Virtual colonoscopy

ASJC Scopus subject areas

  • General

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