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Mouse models for hereditary nonpolyposis colorectal cancer
N de Wind1, M Dekker, A van Rossum
1Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam.
Cancer Research
|January 27, 1998
Summary
Defects in mismatch repair (MMR) genes cause hereditary nonpolyposis colorectal cancer (HNPCC). Mouse models show HNPCC tumors arise from mutagen exposure, not tissue specificity or immune evasion, with potential clone collaboration in intestinal cancers.
Area of Science:
- Genetics
- Cancer Biology
- Immunology
Background:
- Germ-line defects in mismatch repair (MMR) genes are the basis of hereditary nonpolyposis colorectal cancer (HNPCC).
- Loss of the wild-type allele in MMR genes leads to a mutator phenotype, accelerating tumor development.
- The tissue specificity of tumorigenesis in HNPCC, particularly in the gastrointestinal and genitourinary tracts, remains poorly understood.
Purpose of the Study:
- To investigate the etiology and tissue distribution of tumors in HNPCC using mouse models with Msh2 deficiency.
- To elucidate the roles of exogenous mutagens, tissue-specific allele loss, and immune surveillance in HNPCC tumorigenesis.
- To develop a mouse model for intestinal tumorigenesis in HNPCC by incorporating the Apc Min allele.
Main Methods:
- Development of mouse models with complete or hemizygous Msh2 deficiency.
- Administration of ethylnitrosourea to assess lymphomagenesis enhancement.
- Generation of Apc+/Min;Msh2+/- mice to model intestinal tumorigenesis and analyze Msh2 allele loss in tumors.
Main Results:
- Completely Msh2-deficient mice predominantly developed lymphomas, with synergistic enhancement by ethylnitrosourea.
- Immunocompromised Tap1-/-;Msh2-/- mice, lacking lymphomas, developed HNPCC-like tumors, suggesting immune surveillance does not determine the tumor spectrum.
- Apc+/Min;Msh2+/- mice exhibited loss of the wild-type Msh2 allele in a significant fraction of intestinal tumors, with evidence of apparent biclonality suggesting potential tumor clone collaboration.
Conclusions:
- The HNPCC tumor spectrum is likely determined by the exposure of mismatch repair-deficient cells to exogenous mutagens, rather than tissue-specific allele loss or immune surveillance.
- The findings suggest that immune surveillance does not dictate the tissue distribution of HNPCC-associated tumors.
- Evidence of biclonality in intestinal tumors of Apc+/Min;Msh2+/- mice indicates a potential requirement for collaboration between independent tumor clones during intestinal tumorigenesis.