An Msh2 Conditional Knockout Mouse for Studying Intestinal Cancer and Testing Anticancer Agents

Melanie H. Kucherlapati, Kyeryoung Lee, Andrew A. Nguyen, Alan B. Clark, Harry Hou, Andrew Rosulek, Hua Li, Kan Yang, Kunhua Fan, Martin Lipkin, Roderick T. Bronson, Linda Jelicks, Thomas A. Kunkel, Raju Kucherlapati, Winfried Edelmann

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44 Scopus citations

Abstract

Background & Aims: Mutations in the DNA mismatch repair (MMR) gene MSH2 cause Lynch syndromes I and II and sporadic colorectal cancers. Msh2null mice predominantly develop lymphoma and do not accurately recapitulate the colorectal cancer phenotype. Methods: We generated and examined mice with a conditional Msh2 disruption (Msh2LoxP), permitting tissue-specific gene inactivation. ECMsh2LoxP/LoxP mice carried an EIIa-Cre transgene, and VCMsh2LoxP/LoxP mice carried a Villin-Cre transgene. We combined the VCMsh2LoxP allele with either Msh2Δ7null (VCMsh2LoxP/null) or Msh2G674D mutations (VCMsh2LoxP/G674D) to create allelic phase mutants. These mice were given cisplatin or 5-fluorouracil/leucovorin and oxaliplatin (FOLFOX), and their tumors were measured by magnetic resonance imaging. Results: Embryonic fibroblasts from ECMsh2LoxP/LoxP mice do not express MSH2 and are MMR deficient. Reverse transcription, polymerase chain reaction, and immunohistochemistry from VCMsh2LoxP/LoxP mice demonstrated specific loss of Msh2 messenger RNA and protein from epithelial cells of the intestinal tract. Microsatellite instability was observed in all VCMsh2 strains and limited to the intestinal mucosa. Resulting adenomas and adenocarcinomas had somatic truncation mutations to the adenomatous polyposis coli (Apc) gene. VCMsh2LoxP/LoxP mice did not develop lymphoma. Comparison of allelic phase tumors revealed significant differences in multiplicity and size. When treated with cisplatin or FOLFOX, tumor size was reduced in VCMsh2LoxP/G674D but not VCMsh2LoxP/null tumors. The apoptotic response to FOLFOX was partially sustained in the intestinal mucosa of VCMsh2LoxP/G674D animals. Conclusions: Msh2LoxP/LoxP mice in combination with appropriate Cre recombinase transgenes have excellent potential for preclinical modeling of Lynch syndrome, MMR-deficient tumors of other tissue types, and use in drug development.

Original languageEnglish (US)
Pages (from-to)993-1002.e1
JournalGastroenterology
Volume138
Issue number3
DOIs
StatePublished - Mar 2010

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Keywords

  • Chemotherapy
  • Mismatch Repair
  • Msh2
  • Tumorigenesis

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

Cite this

Kucherlapati, M. H., Lee, K., Nguyen, A. A., Clark, A. B., Hou, H., Rosulek, A., Li, H., Yang, K., Fan, K., Lipkin, M., Bronson, R. T., Jelicks, L., Kunkel, T. A., Kucherlapati, R., & Edelmann, W. (2010). An Msh2 Conditional Knockout Mouse for Studying Intestinal Cancer and Testing Anticancer Agents. Gastroenterology, 138(3), 993-1002.e1. https://doi.org/10.1053/j.gastro.2009.11.009