Gastroenterology

Gastroenterology

Volume 118, Issue 3, March 2000, Pages 487-496
Gastroenterology

Alimentary Tract
Cyclooxygenase 2 expression in Barrett's esophagus and adenocarcinoma: Ex vivo induction by bile salts and acid exposure,☆☆

https://doi.org/10.1016/S0016-5085(00)70254-XGet rights and content

Abstract

Background & Aims: Barrett's esophagus (BE) results from chronic, severe gastroesophageal reflux and predisposes to esophageal adenocarcinoma. Cyclooxygenase (COX)-2 is involved in chronic inflammation and epithelial cell growth. We investigated COX-2 expression in BE and esophageal adenocarcinoma to explore a potential relation between COX-2 expression and metaplasia or carcinogenesis. Methods: Endoscopic mucosal biopsy specimens of Barrett's intestinal metaplasia (n = 30), Barrett's dysplasia (n = 11), and esophageal adenocarcinoma (n = 5) were compared with normal esophagus (n = 46) and duodenum (n = 46) and analyzed by Western blotting and immunohistochemistry. Results: Immunoblots revealed constitutive expression of COX-2 in normal esophagus and duodenum. COX-2 protein expression was significantly higher in patients with Barrett's metaplasia, dysplasia, and adenocarcinoma compared with normal squamous esophageal or columnar duodenal epithelia and was heterogenous in different regions of the BE surface. Immunohistochemistry revealed prominent staining in the glands of BE, dysplasia, and adenocarcinoma and faint staining in the basal layers of squamous esophagus and the surface of the duodenum. In response to pulses of acid or bile salts in an ex vivo organ culture system, COX-2 expression increased significantly in BE tissues, and this effect was attenuated by the selective COX-2 inhibitor NS-398. Conclusions: The results show COX-2 expression in normal esophagus, which increases significantly in BE and esophageal adenocarcinoma. COX-2 is regulated ex vivo by exposure to acid or bile salts.

GASTROENTEROLOGY 2000;118:487-496

Section snippets

Patient population

We studied endoscopic (mucosal) biopsy specimens obtained from 46 patients with BE or esophageal adenocarcinoma who underwent upper endoscopy and biopsies as part of routine dysplasia surveillance or evaluation of upper gastrointestinal symptoms. The study was conducted at the Palo Alto Veterans Affairs Health Care System and Stanford University Hospital under a protocol that was approved by the Medical Committee for the Protection of Human Subjects. All patients had originally been referred

Clinical data

The study included the following groups of patients: (1) 30 patients, 28 men and 2 women aged 38–83 years (mean age, 63), who were found on endoscopy to have BE, all of the intestinal metaplasia type without dysplasia; (2) 11 patients, all men aged 45–79 years (mean age, 65), who were found to have BE with dysplasia; and (3) 5 patients, all men aged 50–76 years (mean age, 58), who were found on endoscopy to have esophageal adenocarcinoma involving the distal esophagus without endoscopically

Discussion

Our study evaluates the role of COX-2 in various stages of Barrett's esophageal metaplasia and shows a progressive increase in expression of this enzyme with disease progression from Barrett's metaplasia to dysplasia and adenocarcinoma. Our data indicate that COX-2 is constitutively expressed in normal esophageal and duodenal epithelia and is overexpressed as an early event in the esophageal neoplastic transformation process of Barrett's columnar metaplasia (i.e., in the absence of dysplasia).

Acknowledgements

The authors thank the Gastroenterology staff, fellows, and nurses at the Palo Alto VA Health Care System for their assistance in the collection of tissue samples, and Kris Morrow for figure preparation.

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    Supported in part by the Stanford Cancer Council (to G.T.), Cancer Research Foundation of America (to B.S.K.), Veterans Administration Career Development and Merit Awards (to M.B.O.), and Digestive Disease Center grant DK 38707.

    ☆☆

    Address requests for reprints to: George Triadafilopoulos, M.D., Gastroenterology Section, Palo Alto VA Health Care System (111-GI), 3801 Miranda Avenue, Palo Alto, California 94304. e-mail: [email protected]; fax: (650) 856-8024.

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