Cellular kinetics in Barrett's epithelium carcinogenic sequence: roles of apoptosis, bcl-2 protein, and cellular proliferation.

To gain insight into the neoplastic progression of Barrett's epithelium (BE), we assessed the expression of Ki-67 antigen and bcl-2 protein and the occurrence of apoptosis in metaplastic epithelium with and without regenerative atypia (RA), low-grade dysplasia, and high-grade dysplasia (HGD). To refine our understanding of the epithelial kinetics during the carcinogenic sequence, we performed separate analyses of four different mucosal regions, i.e., surface epithelium, upper and lower crypts, and glands. Expansion of the proliferative zone was noted in dysplasia and to a mild degree in epithelium with RA but not in BE. Expression of bcl-2 protein was seen in the proliferative zone in BE and showed a significant increase in RA but was essentially absent in HGD. Numerous apoptotic nuclei were seen in HGD, decreasing along the cellular gradient from gland to surface. We noted a positive correlation between Ki-67 and bcl-2 in the proliferative zone of BE and RA, whereas a negative correlation was present on the surface of RA. Ki-67 was positively correlated with apoptosis in the lower crypts of HGD. bcl-2 expression was negatively correlated with apoptosis in all regions except the proliferative zone of dysplastic areas. Our findings suggest that overexpression of bcl-2 protein is not an important step in the carcinogenesis of BE. We confirm the upward shift of cellular proliferation in dysplastic epithelia. Apoptosis that is increased in dysplasia might play a significant role in carcinogenesis by restraining increased cellular proliferation.