A novel mouse model for colitis-associated colon carcinogenesis induced by 1,2-dimethylhydrazine and dextran sulfate sodium.
OBJECTIVE
To develop an efficient animal colitis-associated carcinogenesis model and to detect the expression of beta-catenin and p53 in this new model.


METHODS
Dysplasia and cancer were investigated in mice pretreated with a single intraperitoneal injection of 20 mg/kg body mass of 1,2-dimethylhydrazine prior to three repetitive oral administrations of 30 g/L dextran sulfate sodium to give conditions similar to the clinically observed active and remission phases. Immunohistochemical staining of beta-catenin and p53 was performed on paraffin-imbedded specimens of animals with cancer and/or dysplasia, those without dysplasia and the normal control animals.


RESULTS
At wk 11, four early-invasive adenocarcinomas and 36 dysplasia were found in 10 (90.9%) of the 11 mice that underwent 1,2-dimethylhydrazine-pretreatment with 3 cycles of 30 g/L dextran sulfate sodium-exposure. Dysplasia and/or cancer occurred as flat lesions or as dysplasia-associated lesion or mass (DALM) as observed in humans. Colorectal carcinogenesis occurred primarily on the distal portion of the large intestine. No dysplasia and/or cancer lesion was observed in the control groups with 1,2-dimethylhydrazine pretreatment or 3 cycles of 30 g/L dextran sulfate sodium exposure alone. Immunohistochemical investigation revealed that beta-catenin was translocated from cell membrane to cytoplasm and/or nucleus in 100% of cases with dysplasia and neoplasm, while normal membrane staining was observed in cases without dysplasia and the normal control animals. Nuclear expression of p53 was not detected in specimens.


CONCLUSIONS
A single dose of procarcinogen followed by induction of chronic ulcerative colitis results in a high incidence of colorectal dysplasia and cancer. Abnormal expression of beta-catenin occurs frequently in dysplasia and cancer. This novel mouse model may provide an excellent vehicle for studying colitis-related colon carcinogenesis.
Wang
Jian-Guo
JG
Department of Gastroenterology, Sir Run Run Shaw Hospital, Hangzhou 310016, Zhejiang Province, China. roshy@163.com
Wang
Dong-Fei
DF
Lv
Bing-Jian
BJ
Si
Jian-Min
JM
D019813:1,2-Dimethylhydrazine / Q000008:administration & dosage; D000230:Adenocarcinoma / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D002273:Carcinogens / Q000008:administration & dosage; D003093:Colitis, Ulcerative / Q000139:chemically induced / Q000150:complications* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000378:metabolism; D016264:Dextran Sulfate / Q000008:administration & dosage; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D015534:Trans-Activators / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051176:beta Catenin
C495267:CTNNB1 protein, mouse; D002273:Carcinogens; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D016264:Dextran Sulfate; D019813:1,2-Dimethylhydrazine