Cyclooxygenase-2 upregulates vascular endothelial growth factor expression and angiogenesis in human gastric carcinoma

Int J Oncol. 2003 Nov;23(5):1317-22.

Abstract

Although gastric cancer with cyclooxygenase (COX)-2 overexpression is associated with poor prognosis, the mechanistic pathway remains unknown. We examined the associations between expressions of COX-2 and vascular endothelial growth factor (VEGF) in both gastric cancer cells and in human gastric cancer. The gastric cell line, Kato III, was transiently transfected with cox-2 expressing vector. The levels of COX-2, prostaglandin (PG) E2 and VEGF expression were measured post-transfection. Additionally, expressions of COX-2 and VEGF in human gastric cancer were determined by immunohistochemistry in archive gastrectomy specimens. Tumor angiogenesis was assessed by the microvessel density (MVD), which was determined by anti-CD34 immunostaining. Transient transfection of Kato III with cox-2 was associated with increased COX-2 expression, higher PGE2 production and upregulated VEGF expressions. Treatment with NS398, a specific COX-2 inhibitor, reduced VEGF expression in COX-2 expressing Kato III cells by 25%. Among the 67 gastric cancers examined, COX-2 overexpression was found in 45 (67%) cases whereas increased VEGF expression was detected in 46 (69%) cases. There was a significant association between COX-2 and VEGF expressions in gastric cancer (r=0.25, p=0.041). Additionally, tumor MVD was associated with both COX-2 (r=0.32, p=0.008) and VEGF (r=0.39, p=0.001) expressions. Our results showed that overexpression of COX-2 in both gastric cells and primary gastric cancer is associated with upregulation of VEGF and angiogenesis. Future studies should evaluate the potential anti-angiogenic effect of COX-2 inhibitors on human gastric cancer.

MeSH terms

  • Aged
  • Antigens, CD34 / biosynthesis
  • Blotting, Western
  • Carcinoma / enzymology*
  • Cell Line, Tumor
  • Cyclooxygenase 2
  • Dinoprostone / metabolism
  • Female
  • Genetic Vectors
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Isoenzymes / biosynthesis*
  • Isoenzymes / genetics
  • Male
  • Membrane Proteins
  • Microcirculation
  • Middle Aged
  • Neovascularization, Pathologic*
  • Plasmids / metabolism
  • Prostaglandin-Endoperoxide Synthases / biosynthesis*
  • Prostaglandin-Endoperoxide Synthases / genetics
  • Stomach Neoplasms / enzymology*
  • Transfection
  • Up-Regulation*
  • Vascular Endothelial Growth Factor A / biosynthesis*

Substances

  • Antigens, CD34
  • Isoenzymes
  • Membrane Proteins
  • Vascular Endothelial Growth Factor A
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Prostaglandin-Endoperoxide Synthases
  • Dinoprostone