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Increased Expression of Inducible Nitric Oxide Synthase and Cyclooxygenase-2 in Barrett's Esophagus and Associated Adenocarcinomas¹

Department of Medicine, Division of Gastroenterology [K. T. W., S. F., K. S. R., S. J. M.], Greenebaum Cancer Center [K. T. W., S. J. M.], Graduate Program in Molecular and Cell Biology [S. J. M.], and Department of Pathology [S. J. M.], University of Maryland School of Medicine and Baltimore Veterans Affairs Maryland Health Care System, Baltimore, Maryland 21201

Barrett's esophagus is a premalignant condition arising in response to chronic reflux esophagitis. Inducible nitric oxide synthase (iNOS; NOS-2) and cyclooxygenase-2 (COX-2) are mediators of inflammation and regulators of epithelial cell growth. Expression levels of iNOS and COX-2 are high in colorectal adenomas and carcinomas, and COX-2 expression is elevated in gastric cancers. To determine the involvement of iNOS and COX-2 in Barrett's-associated neoplasia, we measured expression of these genes in metaplastic Barrett's and esophageal adenocarcinomas. We detected elevated iNOS and COX-2 mRNA levels in Barrett's mucosa compared with paired gastric control tissues in 16 of 21 (76%) and 17 of 21 (80%) patients, respectively (P < 0.001 for both genes). In esophageal adenocarcinomas, iNOS and COX-2 mRNA levels were increased in four of five and five of five cases, respectively. Furthermore, in 10 of 10 Barrett's patients, immunohistochemical staining for iNOS and COX-2 expression was strongly positive and higher than in matched gastric controls. Increased COX-2 expression was confirmed by Western blotting. These findings support the hypothesis that iNOS and COX-2 are involved early and often in Barrett's-associated neoplastic progression.

¹ Supported by NIH Grants K08-DK02469, R01-CA67497, R01-DK47717, and R01-DK53620; the Robert and Sally D. Funderburg Award in Gastric Cancer Biology; the University of Maryland School of Medicine; and the Office of Medical Research, Department of Veterans Affairs.

² To whom requests for reprints should be addressed, at Baltimore Veterans Affairs Medical Center, Room 5D-151, 10 North Greene Street, Baltimore, MD 21201. Phone: (410) 605-7000, ext. 5211; Fax: (410) 605-7914; E-mail: kwilson@umaryland.edu.

Received 4/ 3/98. Accepted 6/ 1/98.

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