| First Author | de Wind N | Year | 1998 |
| Journal | Cancer Res | Volume | 58 |
| Issue | 2 | Pages | 248-55 |
| PubMed ID | 9443401 | Mgi Jnum | J:45433 |
| Mgi Id | MGI:1195422 | Citation | de Wind N, et al. (1998) Mouse models for hereditary nonpolyposis colorectal cancer. Cancer Res 58(2):248-55 |
| abstractText | 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 Ape 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. |
