Potential involvement of the cyclooxygenase-2 pathway in the regulation of tumor-associated angiogenesis and growth in pancreatic cancer.
Angiogenesis plays a crucial role in tumor development and growth. The present investigation was undertaken to test the potential involvement of the cyclooxygenase-2 (COX-2) pathway in the regulation of angiogenesis and growth in pancreatic cancer. We compared the angiogenic characteristics of a COX-2-positive human pancreatic tumor cell line, BxPC-3, with those of a COX-2-negative pancreatic tumor cell line, AsPC-1. Cultured BxPC-3 cells promoted a marked increase of endothelial cell migration in comparison with migration that occurred in the absence of cancer cells. Furthermore, BxPC-3 cell culture supernatants induced endothelial cell capillary morphogenesis in vitro and neovascularization in vivo. In contrast, cultured AsPC-1 cells elicited a modest effect on endothelial cell migration and neovascularization in vivo. Pretreatment of BxPC-3 cells with the selective COX-2 inhibitor NS-398 (50 micro M) dramatically decreased angiogenic responses of endothelial cells. NS-398 (25-100 micro M) caused inhibition of BxPC-3 cell proliferation but had no effect on AsPC-1 cell growth. SC-560, a selective COX-1 inhibitor, had no effect on growth of either cell lines. These results suggest an involvement of COX-2 in the control of tumor-dependent angiogenesis and growth in certain pancreatic cancers and provide the rational for inhibition of the COX pathway as an effective therapeutic approach for pancreatic tumors.
Chu
Jingsong
J
Signal Transduction Laboratory, Methodist Research Institute, Indianapolis, Indiana 46202, USA.
Lloyd
Frank L
FL
Trifan
Ovidiu C
OC
Knapp
Brian
B
Rizzo
Maria Teresa
MT
D002196:Capillaries / Q000187:drug effects / Q000473:pathology; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D016228:Endothelial Growth Factors / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006706:Homeostasis; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008222:Lymphokines / Q000378:metabolism; D008565:Membrane Proteins; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000517:prevention & control; D009578:Nitrobenzenes / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008222:Lymphokines; D008565:Membrane Proteins; D009578:Nitrobenzenes; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D015232:Dinoprostone