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1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice
C Colussi1, S Fiumicino, A Giuliani
1Laboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanitá, Rome, Italy.
Background:
Defective mismatch repair (MMR) in humans is particularly associated with familial colorectal cancer, but defective repair in mice is generally associated with lymphoma in the absence of experimental exposure to carcinogens. Loss of MMR also confers resistance to the toxic effects of methylating agents. We investigated whether resistance to methylation contributes to increased susceptibility to colorectal cancer in mice by exposing mice with defects in the MMR gene msh2 to a methylating agent.
Methods:
Tumor incidence and time of death in msh2(+/+), msh2(+/-), and msh2(-/-) mice were analyzed after weekly exposure (until tumor appearance) to the methylating agent 1,2-dimethylhydrazine (DMH). Chemically induced and spontaneous tumors were characterized by frequency, type, and location. The tumor incidence in untreated and treated mice of each genotype was compared by a Mann-Whitney U test. Carcinogen-induced apoptosis in histologic sections of small and large intestines was also determined. All statistical tests were two-sided.
Results:
Homozygous inactivation of the msh2 gene statistically significantly accelerated (P<.0001) death due to the development of DMH-induced colorectal tumors and lymphomas. Rates of death from DMH-induced colorectal adenocarcinoma were similar in msh2 heterozygous and wild-type mice, but only msh2 heterozygotes (msh(+/-)) developed additional, noncolorectal malignancies (notably trichofolliculoma [two of 21], angiosarcoma of the kidney capsule [two of 21], and lymphoma [one of 21]), suggesting that heterozygosity for msh2 slightly increases DMH susceptibility. DMH induced apoptosis in small intestinal and colonic epithelial crypts that was dependent on active msh2.
Conclusions:
Inactivation of msh2 allows the proliferation of gastrointestinal tract cells damaged by methylating agents. Furthermore, MMR constitutes a powerful defense against colorectal cancer induced by DNA methylation.
Insights
Defective DNA mismatch repair (MMR) gene msh2 inactivation accelerates colorectal cancer in mice exposed to methylating agents. MMR is crucial for preventing colorectal cancer caused by DNA methylation damage.
Area of Science:
- Genetics and Molecular Biology
- Cancer Research
- Toxicology
Background:
- Defective mismatch repair (MMR) is linked to familial colorectal cancer in humans and lymphoma in mice.
- Loss of MMR confers resistance to methylating agents.
- Investigated if methylation resistance increases colorectal cancer susceptibility in msh2-deficient mice.
Purpose of the Study:
- To determine the role of the msh2 gene in susceptibility to methylating agent-induced colorectal cancer.
- To investigate the relationship between MMR defects, methylation resistance, and cancer development.
Main Methods:
- Mice with varying msh2 gene status (msh2(+/+), msh2(+/-), msh2(-/-)) were exposed to the methylating agent 1,2-dimethylhydrazine (DMH).
- Tumor incidence, type, and location were analyzed.
- Carcinogen-induced apoptosis in the gastrointestinal tract was assessed.
Main Results:
- Homozygous msh2 inactivation significantly accelerated death from DMH-induced colorectal tumors and lymphomas.
- Mice heterozygous for msh2 showed increased susceptibility to non-colorectal malignancies.
- DMH-induced apoptosis in intestinal crypts was dependent on active msh2.
Conclusions:
- msh2 gene inactivation permits proliferation of methylating agent-damaged gastrointestinal cells.
- MMR is a critical defense mechanism against DNA methylation-induced colorectal cancer.