Apoptosis and cell proliferation in the metaplasia-dysplasia-carcinoma-sequence of Barrett's esophagus

Background/Aims: The regulation of apoptosis as a distinctive form of cell death and proliferation in the process of carcinogenesis in Barrett's esoph agus is poorly understood. To investigate regulation of apoptosis, prolifer ation and the participation of the tumor suppressor gene p53, we examined t hese parameters in Barrett's metaplasia, dysplasia, and adenocarcinoma. Methodology: Apoptotic cells were identified and quantified in tissue speci mens of 45 patients with different stages of Barrett's esophagus and normal fundus epithelium, respectively, using the in situ end-labeling and electr on microscopy method in combination with morphological criteria. The tumor suppressor gene p53 was examined by direct sequencing of exon 4-8 as well a s immunohistochemically. The proliferative activity was assessed by Ki67 im munostaining. Results: Apoptotic cell death, identified by the in situ end-labeling and u ltrastructural technique was significantly increased in Barrett's epitheliu m with intestinal metaplasia than in specimens with normal fundic epitheliu m and Barrett's carcinomas (P<0.01). The proliferative activity, defined as Ki67 labeling index, was highest in adenocarcinomas (P<0.01). P53 mutation s were found in 8/9 adeno carcinomas and 2/5 specimens with dysplasia. Apop tosis was lower in p53 positive specimens of the metaplasia-dysplasia-carci noma-sequence than in p53 negative specimens of Bal rett's esophagus (P<0.0 5). Conclusions: The higher levels of both apoptosis and proliferation indicate an increased cell turnover in Barrett's epithelium. Apoptosis seems to mai ntain tissue homeostasis, which is regulated by p53, and gradually lost in the metaplasia-dysplasia-carcinoma-sequence of Barrett's esophagus.