Journal
CARCINOGENESIS
Volume 21, Issue 4, Pages 757-768Publisher
OXFORD UNIV PRESS
DOI: 10.1093/carcin/21.4.757
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Animal models of colitis, which develop dysplasia and cancer similar to human ulcerative colitis are needed to further investigate the dysplasia cancer sequence. This study describes the expression of B-catenin and p53 along with the histopathology and inflammation scores as they relate to dysplasia and cancer in the dextran sulfate sodium (DSS) colitis model. swiss Webster mice mere fed with 5% DSS as follows: group A, four cycles of DSS, 84 days total (1 cycle = 7 days DSS + 14 days H2O); group B, four cycles DSS followed by 120 days H2O, 204 days total; group C, 7 days DSS followed by 180 days H2O, 187 days total; group D, 7 days DSS followed by 90 days H2O, 97 days total, The incidences of dysplasia and/or cancer mere 15.8, 37.5, 18.1 and 0% in groups A-D, respectively. Dysplasia and/or cancer occurred as flat lesions or as dysplasia-associated lesion or mass (DALM) as observed in the human, Thirty-three percent of cancers had associated dysplasia, Within group A, inflammation scores were significantly higher in animals with dysplasia and/or cancer compared with those without dysplasia and/or cancer (P < 0.05-P < 0.0001), Inflammation scores were significantly higher in animals with cancers versus those with dysplasia (P < 0.015) and in flat dysplasia and/or cancer versus DALM (P < 0.0042). B-catenin showed translocation from the cell membrane to the cytoplasm and/or nucleus in 100% of DALM and 5.8% of Bat dysplasia and/or cancer. A total of 94.2% of flat dysplasia and/or cancer had exclusive cell membrane expression compared with 0% DALM (P < 0.0001). Only 7.4% of dysplasia and/ or cancer showed nuclear expression of p53, In colitis-associated dysplasia and/or cancer in the DSS model: (1) histology resembles that in the human; (ii) inflammation plays a significant role in the dysplasia cancer sequence and whether dysplasia and/or cancer grows as a Bat lesion or a DALM; (iii) the early molecular pathways are different for Bat dysplasia and/or cancer versus DALM, with nuclear/ cytoplasmic translocation of B-catenin as an early event in DALM but not flat dysplasia and/or cancer; and (iv) p53 has little or no role in dysplasia and/or cancer. This well characterized model provides an excellent vehicle for studying the roles of inflammation, the molecular events and the role of chemopreventive agents in colitis-associated neoplasia.
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