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Mouse models for hereditary nonpolyposis colorectal cancer.
Cancer Res. 1998 Jan 15; 58(2):248-55.CR

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.

Authors+Show Affiliations

Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

9443401

Citation

de Wind, N, et al. "Mouse Models for Hereditary Nonpolyposis Colorectal Cancer." Cancer Research, vol. 58, no. 2, 1998, pp. 248-55.
de Wind N, Dekker M, van Rossum A, et al. Mouse models for hereditary nonpolyposis colorectal cancer. Cancer Res. 1998;58(2):248-55.
de Wind, N., Dekker, M., van Rossum, A., van der Valk, M., & te Riele, H. (1998). Mouse models for hereditary nonpolyposis colorectal cancer. Cancer Research, 58(2), 248-55.
de Wind N, et al. Mouse Models for Hereditary Nonpolyposis Colorectal Cancer. Cancer Res. 1998 Jan 15;58(2):248-55. PubMed PMID: 9443401.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mouse models for hereditary nonpolyposis colorectal cancer. AU - de Wind,N, AU - Dekker,M, AU - van Rossum,A, AU - van der Valk,M, AU - te Riele,H, PY - 1998/1/27/pubmed PY - 1998/1/27/medline PY - 1998/1/27/entrez SP - 248 EP - 55 JF - Cancer research JO - Cancer Res VL - 58 IS - 2 N2 - 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. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/9443401/Mouse_models_for_hereditary_nonpolyposis_colorectal_cancer_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=9443401 DB - PRIME DP - Unbound Medicine ER -