Transgenic Mouse Models That Explore the Multistep Hypothesis of Intestinal Neoplasia

• Published in: The Journal of cell biology Vol. 123; no. 4; pp. 877 - 893
• Main Authors: Kim, Steve H., Roth, Kevin A., Moser, Amy R., Gordon, Jeffrey I.
• Format: Journal Article
• Language: English
• Published: New York, NY Rockefeller University Press 01.11.1993; The Rockefeller University Press
• Subjects: Analysis of Variance; Animal tumors. Experimental tumors; Animals; Antigens, Polyomavirus Transforming - genetics; Antigens, Polyomavirus Transforming - metabolism; Base Sequence; Biological and medical sciences; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell cycle; Cell Differentiation; Cell Division; Cell lines; Cellular biology; Crypts; Digestive system; Disease Models, Animal; DNA; Enterocytes; Epithelial cells; Epithelium; Experimental digestive system and abdominal tumors; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Genes, ras; Intestinal Mucosa - metabolism; Intestinal Neoplasms - genetics; Intestines - cytology; Medical sciences; Messenger RNA; Mice; Mice, Transgenic; Molecular Sequence Data; Neoplasm Proteins; Nerve Tissue Proteins; Oncogenes; Phenotype; Restriction Mapping; Rodents; Stem Cells - metabolism; Transgenes; Transgenic animals; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; Cell proliferation; Animal model; Polyomavirus; Rodentia; Gut; Transgenic animal; Papovaviridae; Recombinant DNA; Cell differentiation; Epithelium; Carcinogenesis; Virus; Vertebrata; Mammalia; Histopathology; Mouse; Digestive diseases; Tumor; Enterocyte; Onc gene; SV40 virus
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.123.4.877

SV-40 T antigen (TAg), human K-rasVal12, and a dominant negative mutant of human p53 (p53Ala143) have been expressed singly and in all possible combinations in postmitotic enterocytes distributed throughout the duodenal-colonic axis of 1-12-mo-old FVB/N transgenic mice to assess the susceptibility of this lineage to gene products implicated in the pathogenesis of human gut neoplasia. SV-40 TAg produces re-entry into the cell cycle. Transgenic pedigrees that produce K-rasVal12 alone, p53Ala143 alone, or K-rasVal12 and p53Ala143 have no detectable phenotypic abnormalities. However, K-rasVal12 cooperates with SV-40 TAg to generate marked proliferative and dysplastic changes in the intestinal epithelium. These abnormalities do not progress to form adenomas or adenocarcinomas over a 9-12-mo period despite sustained expression of the transgenes. Addition of p53Ala143 to enterocytes that synthesize SV-40 TAg and K-rasVal12 does not produce any further changes in proliferation or differentiation. Mice that carry one, two, or three of these transgenes were crossed to animals that carry Min, a fully penetrant, dominant mutation of the Apc gene associated with the development of multiple small intestinal and colonic adenomas. A modest (2-5-fold) increase in tumor number was noted in animals which express SV-40 TAg alone, SV-40 TAg and K-rasVal12, or SV-40 TAg, K-rasVal12 and p53Ala143. However, the histopathologic features of the adenomas were not altered and the gut epithelium located between tumors appeared similar to the epithelium of their single transgenic, bi-transgenic, or tri-transgenic parents without Min. These results suggest that (a) the failure of the dysplastic gut epithelium of SV-40 TAg X K-rasVal12 mice to undergo further progression to adenomas or adenocarcinomas is due to the remarkable protective effect of a continuously and rapidly renewing epithelium, (b) initiation of tumorigenesis in Min mice typically occurs in crypts rather than in villus-associated epithelial cell populations, and (c) transgenic mouse models of neoplasia involving members of the enterocytic lineage may require that gene products implicated in tumorigenesis be directed to crypt stem cells or their immediate descendants. Nonetheless, directing K-rasVal12 production to proliferating and nonproliferating cells in the lower and upper half of small intestinal and colonic crypts does not result in any detectable abnormalities.