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An Msh2 conditional knockout mouse for studying intestinal cancer and testing anticancer agents

Melanie H Kucherlapati1, Kyeryoung Lee, Andrew A Nguyen

  • 1Department of Medicine/Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA. mkucherlapati@partners.org

Gastroenterology
|November 26, 2009
PubMed
Abstract

Insights

Conditional Msh2 disruption in mice models Lynch syndrome and colorectal cancer. These models accurately show microsatellite instability and response to chemotherapy, aiding drug development for MMR-deficient tumors.

Area of Science:

  • Genetics and Molecular Biology
  • Cancer Research
  • Animal Models

Background:

  • Mutations in the DNA mismatch repair (MMR) gene MSH2 are linked to Lynch syndromes and sporadic colorectal cancers.
  • Msh2-deficient mice typically develop lymphoma, not accurately modeling colorectal cancer phenotypes.

Purpose of the Study:

  • To create and examine mice with tissue-specific Msh2 gene inactivation for improved colorectal cancer modeling.
  • To evaluate the efficacy of chemotherapy in these novel mouse models.

Main Methods:

  • Generated conditional Msh2 knockout mice (Msh2(LoxP)) with tissue-specific Cre recombinase expression (EIIa-Cre and Villin-Cre).
  • Created allelic phase mutants by combining Msh2(LoxP) with null or specific mutation alleles.
  • Treated mice with cisplatin or FOLFOX chemotherapy and monitored tumor growth using MRI.

Main Results:

  • Villin-Cre mediated Msh2 deletion specifically in intestinal epithelial cells, leading to MMR deficiency and microsatellite instability.
  • Tumors in these mice exhibited somatic mutations in the Apc gene, characteristic of colorectal cancer.
  • Msh2(LoxP/G674D) mice showed reduced tumor size and sustained apoptosis in response to FOLFOX, unlike Msh2(LoxP/null) mice.

Conclusions:

  • Msh2(LoxP/LoxP) mice with specific Cre transgenes serve as effective preclinical models for Lynch syndrome and MMR-deficient colorectal cancers.
  • These models are valuable for evaluating drug efficacy in MMR-deficient tumor contexts.
  • The study highlights the potential for developing targeted therapies for MSH2-associated cancers.

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