Expression of cyclin D1 and p53 and its correlation with proliferative activity in the spectrum of esophageal carcinomas induced after duodenal content reflux and 2,6-dimethylnitrosomorpholine administration in rats

Alterations in expression of the p53 and cyclin DI genes have been implicat ed in the development of esophageal carcinomas in both humans and animal mo dels. We hypothesize that altered expression of cyclin D1 and p53 may be in volved in the sequential development of esophageal carcinomas with glandula r differentiation induced by the carcinogen, 2,6-dimethylnitrosomorpholine (DMNM) in rats with duodenal content reflux esophagitis, In the present stu dy Sprague-Dawley rats were given DMNM 15 days after performing an esophago -jejunostomy in order to induce chronic duodenal content reflux esophagitis , Expression and localization of p53, cyclin D1 and Ki-67 were examined by immunohistochemical analyses. Twenty of 24 animals developed different type s of esophageal carcinomas, including pure squamous carcinoma, adenosquamou s carcinoma and pure adenocarcinoma, Undifferentiated basaloid areas mere f requently observed in these tumors. Cyclin Df. overexpression was observed in hyperplastic lesions and increased through dysplasia and in undifferenti ated areas of infiltrating carcinoma. Cyclin D1 expression coincided with i ncreased Ki-67 expression and decreased along with cell differentiation. Th e p53 immunohistochemical pattern was parallel to that of cyclin DI, althou gh the percentage of positive cells was usually smaller in all lesions and increased p53 expression started at the dysplastic stage. These findings su ggest that overexpression of cyclin D1 may be an early event in DMNM-induce d rat esophageal tumorigenesis, causing increased proliferation of esophage al stem cells, Abnormal p53 expression may then be required to promote the development of neoplastic transformation from dysplastic epithelium through invasive phenotype, being more evident in cancer cells with squamous diffe rentiation.