Vascular Endothelial Growth Factor and not Cyclooxygenase 2 Promotes Endothelial Cell Viability in the Pancreatic Tumor Microenvironment

Abstract

Cyclooxygenase 2 (COX-2) and vascular endothelial growth factor (VEGF), often coexpressed in cancer, are associated with poor prognosis. However, results from pancreatic cancer trials of their inhibitors were disappointing. This study delineated the role of COX-2 and nonsteroidal anti-inflammatory drugs in angiogenesis and VEGF regulation. AsPC-1 and BxPC-3 pancreatic cancer cells were cocultured with human umbilical vein endothelial cells (HUVECs). NS398 or VEGF-neutralizing antibody was added, and HUVEC viability assayed. Prostaglandin E2 and VEGF were quantified. Tumor cells were treated with NS398 or celecoxib, and VEGF quantified. In cocultures, HUVEC viability in AsPC-1 was 60% that of BxPC-3 controls (P < 0.05). Prostaglandin E2 and VEGF from BxPC-3 were double that of AsPC-1 (P < 0.05). NS398 reduced prostaglandin E2 to undetectable levels (P < 0.05) but had no effect on HUVEC viability. Vascular endothelial growth factor-neutralizing antibody reduced HUVEC viability in BxPC-3 wells to that of AsPC-1 (P < 0.05). NS398 had no effect on VEGF. Celecoxib increased VEGF in a concentration-dependent manner in each cell line up to 4-fold (P < 0.05). Cyclooxygenase 2 does not regulate VEGF in pancreatic cancer, and celecoxib upregulates VEGF in pancreatic cancer. It is VEGF, and not COX-2, inhibitors that reduce tumor-stimulated endothelial cell viability. Future pancreatic cancer trials should consider lower-dose nonsteroidal anti-inflammatory drugs in combination with VEGF inhibitors.