Coexpression of cyclooxygenases (COX-1, COX-2) and vascular endothelial growth factors (VEGF-A, VEGF-C) in esophageal adenocarcinoma.
Cyclooxygenases (COX), especially COX-2, are considered to be involved in carcinogenesis. Our study was initiated to test whether expression of COX isoforms (COX-1 and COX-2) is linked to expression of potent inducers of angiogenesis [vascular endothelial growth factor (VEGF)-A] and lymphangiogenesis (VEGF-C) in esophageal adenocarcinoma. One hundred twenty-three esophageal adenocarcinomas were investigated by means of quantitative reverse transcription-PCR for expression of COX-1, COX-2, VEGF-A, and VEGF-C. Additionally, COX-2 protein expression was determined using immunohistochemistry. Three esophageal cancer cell lines (OE-33, OSC-1, and OSC-2) were treated with COX-inhibiting substances (diclofenac, rofecoxib, and SC-560) and the effect on expression of the four genes was determined. COX-2 protein expression was found in all carcinomas under analysis. RNA expression levels of COX-1 and COX-2 varied markedly in carcinoma tissues and correlated significantly with each other (P < 0.001, r = 0.726). Furthermore, COX expression correlated with expression of VEGF-A (COX-1: P < 0.001, r = 0.753; COX-2: P < 0.001, r = 0.764) and VEGF-C (COX-1: P < 0.001, r = 0.778; COX-2: P < 0.001; r = 0.613). Exposure of esophageal cancer cell lines OE-33, OSC-1, and OSC-2 with three COX-inhibiting substances (diclofenac, rofecoxib, and SC-560) resulted in significantly reduced expression of VEGF-A and VEGF-C. In conclusion, our data suggest that both COX isoforms may be involved in the pathogenesis of esophageal adenocarcinoma, as they are linked to the expression of important modulators of angiogenesis (VEGF-A) and lymphangiogenesis (VEGF-C).
von Rahden
Burkhard H A
BH
Department of Surgery, Technical University of Munich, Munich, Germany. vrahden@nt1.chir.med.tu-muenchen.de
Stein
Hubert J
HJ
Pühringer
Franziska
F
Koch
Ina
I
Langer
Rupert
R
Piontek
Guido
G
Siewert
J Rüdiger
JR
Höfler
Heinz
H
Sarbia
Mario
M
D000230:Adenocarcinoma / Q000098:blood supply / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D001471:Barrett Esophagus / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004938:Esophageal Neoplasms / Q000098:blood supply / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D008565:Membrane Proteins; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis* / Q000235:genetics; D042561:Vascular Endothelial Growth Factor B / Q000096:biosynthesis* / Q000235:genetics
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D012333:RNA, Messenger; C467484:VEGFA protein, human; C467485:VEGFB protein, human; D042461:Vascular Endothelial Growth Factor A; D042561:Vascular Endothelial Growth Factor B; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases