title: Growth stimulation of COX-2-negative pancreatic cancer by a selective COX-2 inhibitor.
abstract: Cyclooxygenase 2 (COX-2) inhibitors are promising antiangiogenic agents in several preclinical models. The aim of the present study was to evaluate the effect of selective COX-2 inhibitors on vascular endothelial growth factor (VEGF) production in vitro and angiogenesis and growth of pancreatic cancer in vivo, focusing on putative differences between COX-2-negative and COX-2-positive tumors. VEGF production and angiogenesis in vitro were determined by ELISA and endothelial cell migration assay. To determine whether the effect of COX-2 inhibitors was mediated by peroxisome proliferator-activated receptor gamma (PPAR-gamma), we used a dominant-negative PPAR-gamma and a pharmacologic inhibitor. In vitro findings were validated in a pancreatic cancer animal model. Microvessel density was assessed by CD31 immunostaining. Intratumoral prostaglandin and VEGF levels were measured by mass spectroscopy and ELISA. Selective COX-2 inhibitors had a concentration-dependent effect on VEGF production in vitro. Higher concentrations increased VEGF levels and stimulated angiogenesis by activating PPAR-gamma. In vivo, nimesulide increased VEGF production by cancer cells in COX-2-positive and COX-2-negative pancreatic tumors. In COX-2-negative pancreatic cancer, this effect was associated with an increase in angiogenesis and growth. In COX-2-positive pancreatic cancer, the nimesulide-induced increase of VEGF production by the cancer cells was offset by a decrease in VEGF production by the nonmalignant cell types leading to reduced tumor angiogenesis and growth. Selective COX-2 inhibitors had opposite effects on growth and angiogenesis in pancreatic cancer depending on COX-2 expression. These findings imply that assessing the COX-2 profile of the pancreatic tumor is mandatory before initiating therapy with a selective COX-2 inhibitor.
authors.affiliation: Section of Gastrointestinal Surgery, David Geffen School of Medicine at University of California-Los Angeles, 10833 LeConte Avenue, Los Angeles, CA 90095-6904, USA. Geibl@mednet.ucla.edu
authors.forename: Guido
authors.initials: G
authors.lastname: Eibl
authors.forename: Yasunori
authors.initials: Y
authors.lastname: Takata
authors.forename: Laszlo G
authors.initials: LG
authors.lastname: Boros
authors.forename: Joey
authors.initials: J
authors.lastname: Liu
authors.forename: Yuji
authors.initials: Y
authors.lastname: Okada
authors.forename: Howard A
authors.initials: HA
authors.lastname: Reber
authors.forename: Oscar J
authors.initials: OJ
authors.lastname: Hines
mesh_terms: D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D041681:NIH 3T3 Cells; D009389:Neovascularization, Pathologic / Q000473:pathology; D047495:PPAR gamma / Q000502:physiology; D010190:Pancreatic Neoplasms / Q000098:blood supply / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency*; D013449:Sulfonamides / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D008565:Membrane Proteins; D047495:PPAR gamma; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone; C012655:nimesulide