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BIOLOGICAL SCIENCES / MEDICAL SCIENCES
A target-selected Apc-mutant rat kindred enhances the modeling of familial human colon cancer
Departments of Biostatistics and Medical Informatics, Pathology and Laboratory Medicine, ¶Radiology, and Medicine, Section of Gastroenterology and Hepatology, *McArdle Laboratory for Cancer Research, and ||Laboratory of Genetics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53726
Contributed by William F. Dove, January 3, 2007 (received for review December 19, 2006)
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.
chromosome biology | genomic instability | Min mouse | virtual colonoscopy | endoscopy
Author contributions: J.M.A.-L. and L.N.K. contributed equally to this work; J.M.A.-L., L.N.K., J.D.H., M.N.G., and W.F.D. designed research; J.M.A.-L., L.N.K., M.R., J.W., J.D.H., and J.L.W. performed research; J.M.A.-L., L.N.K., C.M.K., J.D.H., and K.-S.C. contributed new reagents/analytic tools; J.M.A.-L., L.N.K., C.M.K., and J.T. analyzed data; and J.M.A.-L., L.N.K., and W.F.D. wrote the paper.
The authors declare no conflict of interest.
Data deposition: The sequence reported in this paper has been deposited in the Rat Genome Database (accession no. 1554322).
This article contains supporting information online at www.pnas.org/cgi/content/full/0611690104/DC1.
**To whom correspondence should be addressed at: McArdle Laboratory for Cancer Research, 1400 University Avenue, Madison, WI 53706. E-mail: dove{at}oncology.wisc.edu
© 2007 by The National Academy of Sciences of the USA
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