PMID:9443401

Citation	de Wind, N, Dekker, M, van Rossum, A, van der Valk, M and te Riele, H (1998) Mouse models for hereditary nonpolyposis colorectal cancer. Cancer Res. 58:248-55
Abstract	Hemizygous germ-line defects in mismatch repair (MMR) genes underlie hereditary nonpolyposis colorectal cancer (HNPCC). Loss of the wild-type allele results in a mutator phenotype, accelerating tumorigenesis. Tumorigenesis specifically occurs in the gastrointestinal and genitourinary tracts; the cause of this tissue specificity is elusive. To understand the etiology and tissue distribution of tumors in HNPCC, we have developed mouse models carrying a deficiency in the MMR gene Msh2. Most of the completely Msh2-deficient mice succumbed to lymphomas at an early age; lymphomagenesis was synergistically enhanced by exposure to ethylnitrosourea. Lymphomas were absent in immunocompromised Tap1-/-;Msh2-/- mice; these mice generally succumbed to HNPCC-like tumors. Together, these data suggest that the HNPCC tumor spectrum is determined by exposure of MMR-deficient cells to exogenous mutagens, rather than by tissue-specific loss of the wild-type MMR allele or by immune surveillance. Msh2 hemizygous mice had an elevated tumor incidence that, surprisingly, was rarely correlated with loss of the Msh2+ allele. To develop a model for intestinal tumorigenesis in HNPCC, we introduced the Min allele of the Apc tumor suppressor gene. We observed loss of the wild-type Msh2 allele in a significant fraction of intestinal tumors in Apc+/Min;Msh2+/- mice. In some of the latter tumors, one area of the tumor displayed loss of the Msh2+ allele, but not of the Apc+ allele, whereas another area displayed the inverse genotype. This apparent biclonality might indicate a requirement for collaboration between independent tumor clones during intestinal tumorigenesis.
Links	PubMed
Keywords	Adenomatous Polyposis Coli Protein; Animals; Clone Cells; Colorectal Neoplasms, Hereditary Nonpolyposis/etiology; Colorectal Neoplasms, Hereditary Nonpolyposis/genetics; Colorectal Neoplasms, Hereditary Nonpolyposis/pathology; Cytoskeletal Proteins/genetics; DNA-Binding Proteins/genetics; Disease Models, Animal; Ethylnitrosourea/pharmacology; Female; Gene Deletion; Immunocompromised Host; Loss of Heterozygosity; Lymphoma/genetics; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Mice, Mutant Strains; MutS Homolog 2 Protein; Proto-Oncogene Proteins/genetics; Survival Rate
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