COX-2/VEGF-dependent facilitation of tumor-associated angiogenesis and tumor growth in vivo.
Nonsteroidal anti-inflammatory drugs are known to suppress the occurrence and progression of malignancies such as colorectal cancers. However, the precise mechanism of these actions remains unknown. We have evaluated the role of an inducible cyclo-oxygenase (COX-2) in tumor-associated angiogenesis and tumor growth, and identified the downstream molecules involved using a ddy mouse model of sponge angiogenesis, which mimics tumor angiogenesis and is COX-2 and vascular endothelial growth factor (VEGF) dependent. In this model, VEGF expression was down-regulated by selective COX-2 inhibition with NS-398. To find out the involvement of COX-2/VEGF pathway in tumor-associated angiogenesis, we estimated angiogenesis occurring around implanted Millipore chambers containing sarcoma-180 (S-180) cells or Lewis lung carcinoma cells. Daily oral administration of NS-398 or of aspirin, a nonselective COX inhibitor, suppressed angiogenesis seen around the Millipore chambers. S-180 cells implanted in ddy mice formed substantial tumors with extensive angiogenesis markedly suppressed by aspirin and COX-2 inhibitors NS-398 and JTE522, but not by mofezolac, an inhibitor of constitutive COX-1. Tumor-associated angiogenesis was also significantly suppressed by a neutralizing antibody against VEGF. S-180 tumor growth in the subcutaneous tissues was also suppressed by aspirin, COX-2 selective inhibitors, and the VEGF antibody, but not by the COX-1 inhibitor. These results demonstrate that the inhibition of the COX-2/VEGF-dependent pathway was effective in tumor-associated angiogenesis, tumor growth, and tumor metastasis.
Yoshida
Satoko
S
Department of Pharmacology, Kitasato University School of Medicine, Sagamihara, Japan.
Amano
Hideki
H
Hayashi
Izumi
I
Kitasato
Hidero
H
Kamata
Mariko
M
Inukai
Madoka
M
Yoshimura
Hirokuni
H
Majima
Masataka
M
D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use; D001241:Aspirin / Q000494:pharmacology / Q000627:therapeutic use; D001557:Benzenesulfonates / Q000627:therapeutic use; D018827:Carcinoma, Lewis Lung / Q000098:blood supply / Q000201:enzymology* / Q000556:secondary; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D004195:Disease Models, Animal; D016228:Endothelial Growth Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007555:Isoxazoles / Q000627:therapeutic use; D008222:Lymphokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000201:enzymology*; D009578:Nitrobenzenes / Q000494:pharmacology; D010080:Oxazoles / Q000627:therapeutic use; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012510:Sarcoma 180 / Q000098:blood supply / Q000201:enzymology* / Q000473:pathology; D013449:Sulfonamides / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D000096926:Benzenesulfonamides
D019138:Antibodies, Blocking; D001241:Aspirin; D001557:Benzenesulfonates; D016861:Cyclooxygenase Inhibitors; D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D007555:Isoxazoles; D008222:Lymphokines; D009578:Nitrobenzenes; D010080:Oxazoles; D011451:Prostaglandin-Endoperoxide Synthases; D012333:RNA, Messenger; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C110453:4-(4-cyclohexyl-2-methyloxazol-5-yl)-2-fluorobenzenesulfonamide; D000096926:Benzenesulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; C054999:mofezolac