INVOLVEMENT OF BCL-2 ONCOPROTEIN IN THE DEVELOPMENT OF ENTEROCHROMAFFIN-LIKE CELL GASTRIC CARCINOIDS

To evaluate the involvement of the apoptosis-suppressing protein BCL-2 in the gastrin-dependent mechanism of induction of gastric enterochro maffin-like (ECL) cell carcinoids, the endocrine cells of the oxyntic mucosa were immunohistochemically investigated in (a) 10 normogastrine mic subjects with histologically normal gastric mucosa; (b) 22 patient s with endocrine cell hyperplasia and affected by hypergastrinemic con ditions with different risk of gastric carcinoid development, such as sporadic Zollinger-Ellison syndrome (sZES; n = 9), ZES associated with multiple endocrine neoplasia-1 (MEN-1;n = 4), and atrophic fundal gas tritis (AFG; n = 9); (c) 14 patients with ECL cell gastric carcinoids accounting for a total of 31 tumors investigated. In the normal oxynti c mucosa, BCL-2 was consistently expressed by a subset of endocrine ce lls accounting for 50.0% (median; range, 24.6-74.0%) of the total numb er of endocrine cells immunostained for chromogranin A (CgA) in consec utive sections. BCL-2-immunoreactive cells were located mostly in the middle mucosal layer, suggesting a role for the protein during downwar d migration of maturing endocrine cells. No BCL-2 immunoreactivity was found in other specialized gastric epithelial cells. Expression of BC L-2 by hyperplastic oxyntic endocrine cells (mostly ECL cells) varied in parallel with the risk of carcinoid development. In fact, the ratio of BCL-2- to CgA-immunoreactive cells was reduced (median, 4.6%; p < 0.0001; range, 0.9-42.0%) in sZES, a condition showing virtually no ri sk, unchanged (median, 55.6%; range, 29.4-83.8%) in cases of MEN-1/ZES with intermediate risk, and increased (median, 87.6%; p < 0.014; rang e, 48.8-199.4%) in cases of AFG, a condition at the highest risk of ca rcinoid. In ECL cell carcinoids, BCL-2 expression varied markedly from one tumor to another even in the same patient and was low or absent i n most cases. In both hyperplastic and neoplastic ECL cells, an invers e relation between BCL-2 expression and CgA immunoreactivity, that is, the cell granule content, was found. These results suggest that BCL-2 expression by hyperplastic ECL cells is independent of the influence of serum gastrin and may contribute to the development of ECL cell car cinoid tumors by extending cell exposure to oncogenic factors. Once a carcinoid tumor is established, BCL-2 expression becomes inconsistent.