![]() Grossly, most colonic tumors were peduncular, whereas adenomas in the small intestine had a flat appearance. The histopathology and morphology of the tumors closely resembled that of human tumors, with adenomatous changes evident, including dysplasia, nuclear enlargement, an increased mitotic rate, and the expansion of crypts showing loss of the normal columnar architecture ( Fig. Neoplasms in Heterozygotes and Embryonic Lethality of Homozygotes for the Apc am1137 Allele. The color bar below indicates the genotype–phenotype correlation of sites of protein truncation to disease severity. Arrows indicate orthologous locations of mouse model and Pirc truncating mutations and the two most common FAP mutation sites. ( B) Sequence trace of the founder rat showing heterozygosity for the A→T transversion at nucleotide 3409 of Apc ( Upper) compared with a wild-type littermate ( Lower). Screening of 1,360 F1 progeny yielded a single yeast plate with half-red and half-white colonies, which is the expected ratio for a heterozygous mutant. The amplicon was then gap-repaired into the universal vector and transformed into ADE2-deficient yeast. Two thousand five hundred and thirty bases of Apc exon 15 spanning codons 757–1,600 were amplified with primers chimeric for Apc sequence and homology to a “universal vector” that accepts any such chimeric amplicon ( 11). ( A) Scheme for the colorimetric yeast assay. Isolation and identification of the Pirc line of rats. We believe that the Pirc rat kindred can address many of the current gaps in the modeling of human colon cancer.įig. 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. 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. Tumor-bearing Pirc rats can live at least 17 months, carrying a significant colonic tumor burden. ![]() The Pirc rat kindred provides several unique and favorable features for the study of colon cancer. 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. 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. We have established a mutagen-induced nonsense allele of the rat Apc gene on an inbred F344/NTac (F344) genetic background. 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. ![]() Progress toward the understanding and management of human colon cancer can be significantly advanced if appropriate experimental platforms become available.
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