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Gastrin-Induced Cyclooxygenase-2 Expression in Barrett’s Carcinogenesis

¹ Cancer Cell Unit Hutchison/MRC Research Centre, Cambridge; ² Institute of Cell and Molecular Science, Adult and Paediatric Gastroenterology Department, Barts and the London School of Medicine and Dentistry, London; and ³ Department of Histopathology and ⁴ National Medical Laser Centre Royal Free and University College School of Medicine, University College London, London, United Kingdom

Purpose: Cyclooxygenase (COX)-2 has been causally implicated in carcinogenesis. The evidence for increased COX-2 in the malignant progression of Barrett’s esophagus is contradictory. We hypothesize that COX-2 expression may be causally affected by the gastrin status via the cholecystokinin 2 (CCK₂) receptor.

Experimental Design: COX-2 and prostaglandin E₂ expression were evaluated by Western blotting and enzyme-linked immune assay in samples of squamous esophagus, Barrett’s esophagus with varying degrees of dysplasia to adenocarcinoma, and normal duodenum. Differentiation status was evaluated by histopathology and villin expression. A longitudinal case-control study compared COX-2 in patients who progressed to adenocarcinoma with nonprogressors matched for age and length of follow-up. Messenger RNA levels of gastrin and CCK₂ receptor in biopsies and cell lines were evaluated by reverse transcription-PCR, and in vitro gastrin stimulation was conducted with and without inhibitors for CCK₂ (YM022) and COX-2 (NS-398). Cell proliferation was evaluated using minichromosome maintenance protein 2 (Mcm2) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays.

Results: COX-2 expression is significantly increased in Barrett’s esophagus before dysplasia development. Expression is highly variable within Barrett’s dysplasia and adenocarcinoma samples independent of differentiation status. In a longitudinal case-control study, the expression levels within patients increased over time, regardless of the degree of malignant progression. Biopsies from nondysplastic Barrett’s esophagus expressed increased gastrin mRNA levels compared with other biopsies. Gastrin significantly induced COX-2, prostaglandin E₂, and cell proliferation in biopsies and cell lines. Gastrin-induced proliferation can be inhibited by YM022 and NS-398.

Conclusions: COX-2 is up-regulated early in the Barrett’s metaplasia sequence. During carcinogenesis, gastrin is a significant determinant of COX-2 activity levels via the CCK₂ receptor.

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