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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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M. Li, R. Lotan, B. Levin, E. Tahara, S. M. Lippman, and X.-C. Xu Aspirin Induction of Apoptosis in Esophageal Cancer: A Potential for Chemoprevention Cancer Epidemiol. Biomarkers Prev., June 1, 2000; 9(6): 545 - 549. [Abstract] [Full Text] |
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A. Shamma, H. Yamamoto, Y. Doki, J. Okami, M. Kondo, Y. Fujiwara, M. Yano, M. Inoue, N. Matsuura, H. Shiozaki, et al. Up-Regulation of Cyclooxygenase-2 in Squamous Carcinogenesis of the Esophagus Clin. Cancer Res., April 1, 2000; 6(4): 1229 - 1238. [Abstract] [Full Text] |
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C. Cahlin, J. Gelin, D. Delbro, C. Lönnroth, C. Doi, and K. Lundholm Effect of Cyclooxygenase and Nitric Oxide Synthase Inhibitors on Tumor Growth in Mouse Tumor Models with and without Cancer Cachexia Related to Prostanoids Cancer Res., March 1, 2000; 60(6): 1742 - 1749. [Abstract] [Full Text] |
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H. Y. Lim, H. J. Joo, J. H. Choi, J. W. Yi, M. S. Yang, D. Y. Cho, H. S. Kim, D. K. Nam, K. B. Lee, and H. C. Kim Increased Expression of Cyclooxygenase-2 Protein in Human Gastric Carcinoma Clin. Cancer Res., February 1, 2000; 6(2): 519 - 525. [Abstract] [Full Text] |
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K. S. Chapple, E. J. Cartwright, G. Hawcroft, A. Tisbury, C. Bonifer, N. Scott, A. C. J. Windsor, P. J. Guillou, A. F. Markham, P. L. Coletta, et al. Localization of Cyclooxygenase-2 in Human Sporadic Colorectal Adenomas Am. J. Pathol., February 1, 2000; 156(2): 545 - 553. [Abstract] [Full Text] [PDF] |
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M. Jaiswal, N. F. LaRusso, L. J. Burgart, and G. J. Gores Inflammatory Cytokines Induce DNA damage and Inhibit DNA repair in Cholangiocarcinoma Cells by a Nitric Oxide-dependent Mechanism Cancer Res., January 1, 2000; 60(1): 184 - 190. [Abstract] [Full Text] |
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K. Uefuji, T. Ichikura, and H. Mochizuki Cyclooxygenase-2 Expression Is Related to Prostaglandin Biosynthesis and Angiogenesis in Human Gastric Cancer Clin. Cancer Res., January 1, 2000; 6(1): 135 - 138. [Abstract] [Full Text] |
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M. Stolina, S. Sharma, Y. Lin, M. Dohadwala, B. Gardner, J. Luo, L. Zhu, M. Kronenberg, P. W. Miller, J. Portanova, et al. Specific Inhibition of Cyclooxygenase 2 Restores Antitumor Reactivity by Altering the Balance of IL-10 and IL-12 Synthesis J. Immunol., January 1, 2000; 164(1): 361 - 370. [Abstract] [Full Text] [PDF] |
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M. Kondo, H. Yamamoto, H. Nagano, J. Okami, Y. Ito, J. Shimizu, H. Eguchi, A. Miyamoto, K. Dono, K. Umeshita, et al. Increased Expression of COX-2 in Nontumor Liver Tissue Is Associated with Shorter Disease-free Survival in Patients with Hepatocellular Carcinoma Clin. Cancer Res., December 1, 1999; 5(12): 4005 - 4012. [Abstract] [Full Text] [PDF] |
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S. Ambs and C. C. Harris RESPONSE: Re: Relationship Between p53 Mutations and Inducible Nitric Oxide Synthase Expression in Human Colorectal Cancer J Natl Cancer Inst, September 1, 1999; 91(17): 1510 - 1511. [Full Text] [PDF] |
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M. A. Molina, M. Sitja-Arnau, M. G. Lemoine, M. L. Frazier, and F. A. Sinicrope Increased Cyclooxygenase-2 Expression in Human Pancreatic Carcinomas and Cell Lines: Growth Inhibition by Nonsteroidal Anti-Inflammatory Drugs Cancer Res., September 1, 1999; 59(17): 4356 - 4362. [Abstract] [Full Text] [PDF] |
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C. Tremblay, M. Dore, P. N. Bochsler, and J. Sirois Induction of Prostaglandin G/H Synthase-2 in a Canine Model of Spontaneous Prostatic Adenocarcinoma J Natl Cancer Inst, August 18, 1999; 91(16): 1398 - 1403. [Abstract] [Full Text] [PDF] |
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J. Okami, H. Yamamoto, Y. Fujiwara, M. Tsujie, M. Kondo, S. Noura, S. Oshima, H. Nagano, K. Dono, K. Umeshita, et al. Overexpression of Cyclooxygenase-2 in Carcinoma of the Pancreas Clin. Cancer Res., August 1, 1999; 5(8): 2018 - 2024. [Abstract] [Full Text] [PDF] |
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P. Michaluart, J. L. Masferrer, A. M. Carothers, K. Subbaramaiah, B. S. Zweifel, C. Koboldt, J. R. Mestre, D. Grunberger, P. G. Sacks, T. Tanabe, et al. Inhibitory Effects of Caffeic Acid Phenethyl Ester on the Activity and Expression of Cyclooxygenase-2 in Human Oral Epithelial Cells and in a Rat Model of Inflammation Cancer Res., May 1, 1999; 59(10): 2347 - 2352. [Abstract] [Full Text] [PDF] |
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J. A. Jankowski, N. A. Wright, S. J. Meltzer, G. Triadafilopoulos, K. Geboes, A. G. Casson, D. Kerr, and L. S. Young Molecular Evolution of the Metaplasia-Dysplasia-Adenocarcinoma Sequence in the Esophagus Am. J. Pathol., April 1, 1999; 154(4): 965 - 973. [Abstract] [Full Text] [PDF] |
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O. N. Tucker, A. J. Dannenberg, E. K. Yang, F. Zhang, L. Teng, J. M. Daly, R. A. Soslow, J. L. Masferrer, B. M. Woerner, A. T. Koki, et al. Cyclooxygenase-2 Expression Is Up-Regulated in Human Pancreatic Cancer Cancer Res., March 1, 1999; 59(5): 987 - 990. [Abstract] [Full Text] [PDF] |
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G. Chan, J. O. Boyle, E. K. Yang, F. Zhang, P. G. Sacks, J. P. Shah, D. Edelstein, R. A. Soslow, A. T. Koki, B. M. Woerner, et al. Cyclooxygenase-2 Expression Is Up-Regulated in Squamous Cell Carcinoma of the Head and Neck Cancer Res., March 1, 1999; 59(5): 991 - 994. [Abstract] [Full Text] [PDF] |
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