1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice.
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.
Colussi
C
C
Laboratory of Comparative Toxicology and Ecotoxicology, Istituto Superiore di Sanitá, Rome, Italy.
Fiumicino
S
S
Giuliani
A
A
Rosini
S
S
Musiani
P
P
Macrí
C
C
Potten
C S
CS
Crescenzi
M
M
Bignami
M
M
D019813:1,2-Dimethylhydrazine / Q000633:toxicity*; D000230:Adenocarcinoma / Q000139:chemically induced / Q000235:genetics*; D000477:Alkylating Agents / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D020137:Base Pair Mismatch; D002273:Carcinogens / Q000633:toxicity*; D002455:Cell Division / Q000187:drug effects; D003106:Colon / Q000187:drug effects / Q000473:pathology; D003110:Colonic Neoplasms / Q000139:chemically induced / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D004268:DNA-Binding Proteins; D004351:Drug Resistance; D005838:Genotype; D006201:Hair Diseases / Q000139:chemically induced / Q000235:genetics; D018859:Hair Follicle; D006394:Hemangiosarcoma / Q000139:chemically induced / Q000235:genetics; D007413:Intestinal Mucosa / Q000187:drug effects / Q000473:pathology; D007421:Intestine, Small / Q000187:drug effects / Q000473:pathology; D007680:Kidney Neoplasms / Q000139:chemically induced / Q000235:genetics; D008228:Lymphoma, Non-Hodgkin / Q000139:chemically induced / Q000235:genetics*; D008745:Methylation; D051379:Mice; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein; D018295:Neoplasms, Basal Cell / Q000139:chemically induced / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D000477:Alkylating Agents; D002273:Carcinogens; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein; D019813:1,2-Dimethylhydrazine