Carcinogenesis Advance Access originally published online on June 5, 2003
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Carcinogenesis, Vol. 24, No. 8, 1407-1413,
August 2003
© 2003 Oxford University Press
CARCINOGENESIS |
Cigarette smoke exposure increases ulcerative colitis-associated colonic adenoma formation in mice
1 Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
2 Department of Pathology, Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
3 Department of Medicine, Faculty of Medicine, The University of Hong Kong, Hong Kong, People's Republic of China
4 Department of Pharmacology, Faculty of Medicine, Zhejiang University, Hangzhou, People's Republic of China
5 To whom correspondence should be addressed Email: chcho{at}hkusua.hku.hk
Both chronic ulcerative colitis and smoking are associated with colorectal cancer in humans. In the present study, we investigated the effects of cigarette smoke (CS) exposure on inflammation-associated tumorigenesis in the mouse colon. Male balb/c mice were allocated into six groups: control, CS (2%), CS (4%), colitis, colitis + CS (2%) and colitis + CS (4%). They were given water or 3% dextran sulfate sodium (DSS) in drinking water for 7 days to induce colitis, with or without 1 h daily exposure to 2 or 4% CS. They were then allowed to drink water for 14 days. The cycle of 7 day DSS ± CS/14 day H2O treatments were repeated twice. Mice were killed immediately or 1 month after the three cycles of treatments. Results indicated colonic adenoma was only found in the colitis group (one out of 11), Colitis + CS (2%) group (seven out of 12) and colitis + CS (4%) group (four out of five) 1 month after three cycles of DSS and/or CS treatment. CS exposure dose-dependently increased adenoma formation in mice with inflamed mucosa. CS exposure plus colitis was strongly associated with a high incidence of dysplasia (P < 0.01) and adenocarcinoma formation (P < 0.01) compared with induction of colitis alone. Colitis induced cell proliferation and apoptosis in colonic tissues. Cigarette smoking significantly attenuated the apoptotic effect by DSS probably via the induction of anti-apoptotic protein bcl-2. The ratio of apoptosis over proliferation was also significantly lower in the colitis + CS groups. Vascular endothelial growth factor and angiogenesis in the colon were also increased by cigarette smoking in animals with colitis. In conclusion, CS promotes inflammation-associated adenoma/adenocarcinoma formation in the mouse colon in a dose-dependent manner. This tumor development is associated with the inhibition of cellular apoptosis and supported by increased angiogenesis.
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