Professorial Surgical Unit, University of Dublin, Trinity College, Dublin, Ireland.
Pancreas. 2010 Jul;39(5):595-603. doi: 10.1097/MPA.0b013e3181c6575d.
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.
环氧化酶 2（COX-2）和血管内皮生长因子（VEGF）在癌症中常共同表达，与预后不良相关。然而，其抑制剂在胰腺癌试验中的结果令人失望。本研究阐明了 COX-2 和非甾体抗炎药在血管生成和 VEGF 调节中的作用。
将人胰腺癌细胞株 AsPC-1 和 BxPC-3 与脐静脉内皮细胞（HUVEC）共培养。加入 NS398 或 VEGF 中和抗体，检测 HUVEC 活力。定量检测前列腺素 E2 和 VEGF。用 NS398 或塞来昔布处理肿瘤细胞，定量检测 VEGF。
在共培养中，AsPC-1 中 HUVEC 的活力为 BxPC-3 对照组的 60%（P<0.05）。BxPC-3 中的前列腺素 E2 和 VEGF 是 AsPC-1 的两倍（P<0.05）。NS398 将前列腺素 E2 降低至无法检测的水平（P<0.05），但对 HUVEC 活力没有影响。VEGF 中和抗体将 BxPC-3 孔中的 HUVEC 活力降低至与 AsPC-1 相同的水平（P<0.05）。NS398 对 VEGF 没有影响。塞来昔布以浓度依赖的方式增加两种细胞系中的 VEGF，最高可达 4 倍（P<0.05）。
COX-2 不能调节胰腺癌中的 VEGF，塞来昔布可上调胰腺癌中的 VEGF。是 VEGF 而不是 COX-2 抑制剂降低了肿瘤刺激的内皮细胞活力。未来的胰腺癌试验应考虑低剂量非甾体抗炎药与 VEGF 抑制剂联合使用。
