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Genetic analysis of APC, p53 and K‐ras in novel rat models of colitis‐associated dysplasia
Author(s) -
Santiago Cariluz,
Pagan Beatriz,
Isidro Angel A,
Appleyard Caroline B
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a219-a
Subject(s) - dysplasia , colitis , colorectal cancer , ulcerative colitis , medicine , gastroenterology , inflammation , carcinogenesis , cancer , disease
Colorectal cancer can arise spontaneously, by inheritance, or from dysplasia in ulcerative colitis. We have recently created colitis‐associated dysplasia models in rats to mimic the human progression from chronic inflammation to cancer. Aim To further characterize these models and search for changes in commonly mutated genes (APC, p53, and K‐ras). Methods The following groups of rats were used: Reactivated‐DMH : a single dose of trinitrobenzene sulfonic acid (TNBS ic) was followed six weeks later by reactivation with TNBS (iv) for three days, then 1,2‐dimethylhydrazine (DMH sc) once a week. Prolonged Reactivation : inflammation was induced with TNBS, and chronic colitis was maintained by administration of TNBS twice a week. Normal : no treatment. Rats were sacrificed at 5, 10 and 15 weeks. Colon samples were analyzed macroscopically then divided for histological and molecular analysis. PCR was performed using DNA extracted from colon tissue. PCR products were analyzed for mutations in the WAVE® (denaturing HPLC) system. Results Both reactivated‐DMH and prolonged reactivation presented inflammatory changes and colon shortening, with significantly less weight gain in the latter group. These changes were most pronounced in the distal colon. The incidence of dysplasia at 15 weeks was 60% in prolonged reactivation and 100% in reactivated‐DMH . No tumors or gene mutations have been found at the time points studied so far. Conclusion Both prolonged reactivation and reactivated‐DMH groups resemble the chronic human condition and confirm that the presence of long term colitis increases the risk of developing cancer. SO6GM08239, RR03050 & F31 GM073539.