Apoptosis and cell proliferation in the metaplasia-dysplasia-carcinoma-sequence of Barrett's esophagus.
OBJECTIVE
The regulation of apoptosis as a distinctive form of cell death and proliferation in the process of carcinogenesis in Barrett's esophagus is poorly understood. To investigate regulation of apoptosis, proliferation and the participation of the tumor suppressor gene p53, we examined these parameters in Barrett's metaplasia, dysplasia, and adenocarcinoma.


METHODS
Apoptotic cells were identified and quantified in tissue specimens of 45 patients with different stages of Barrett's esophagus and normal fundus epithelium, respectively, using the in situ end-labeling and electron microscopy method in combination with morphological criteria. The tumor suppressor gene p53 was examined by direct sequencing of exon 4-8 as well as immunohistochemically. The proliferative activity was assessed by Ki67 immunostaining.


RESULTS
Apoptotic cell death, identified by the in situ end-labeling and ultrastructural technique was significantly increased in Barrett's epithelium with intestinal metaplasia than in specimens with normal fundic epithelium and Barrett's carcinomas (P < 0.01). The proliferative activity, defined as Ki67 labeling index, was highest in adenocarcinomas (P < 0.01). P53 mutations were found in 8/9 adenocarcinomas and 2/5 specimens with dysplasia. Apoptosis was lower in p53 positive specimens of the metaplasia-dysplasia-carcinoma-sequence than in p53 negative specimens of Barrett's esophagus (P < 0.05).


CONCLUSIONS
The higher levels of both apoptosis and proliferation indicate an increased cell turnover in Barrett's epithelium. Apoptosis seems to maintain tissue homeostasis, which is regulated by p53, and gradually lost in the metaplasia-dysplasia-carcinoma-sequence of Barrett's esophagus.
Halm
U
U
Department of Internal Medicine II, Institute of Pathology, University of Leipzig, Germany. halmu@medizin.uni-leipzig.de
Tannapfel
A
A
Breitung
B
B
Breidert
M
M
Wittekind
C W
CW
Mössner
J
J
D000230:Adenocarcinoma / Q000473:pathology*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis; D001471:Barrett Esophagus / Q000473:pathology*; D004938:Esophageal Neoplasms / Q000473:pathology*; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D019394:Ki-67 Antigen / Q000235:genetics; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D009154:Mutation; D016133:Polymerase Chain Reaction; D011230:Precancerous Conditions / Q000473:pathology*; D012307:Risk Factors; D018709:Statistics, Nonparametric
D019394:Ki-67 Antigen