Thromboxane A(2) regulation of endothelial cell migration, angiogenesis, and tumor metastasis.
Prostaglandin endoperoxide H synthases and their arachidonate products have been implicated in modulating angiogenesis during tumor growth and chronic inflammation. Here we report the involvement of thromboxane A(2), a downstream metabolite of prostaglandin H synthase, in angiogenesis. A TXA(2) mimetic, U46619, stimulated endothelial cell migration. Angiogenic basic fibroblast growth factor (bFGF) or vascular endothelial growth factor (VEGF) increased TXA(2) synthesis in endothelial cells three- to fivefold. Inhibition of TXA(2) synthesis with furegrelate or CI reduced HUVEC migration stimulated by VEGF or bFGF. A TXA(2) receptor antagonist, SQ29,548, inhibited VEGF- or bFGF-stimulated endothelial cell migration. In vivo, CI inhibited bFGF-induced angiogenesis. Finally, development of lung metastasis in C57Bl/6J mice intravenously injected with Lewis lung carcinoma or B16a cells was significantly inhibited by thromboxane synthase inhibitors, CI or furegrelate sodium. Our data demonstrate the involvement of TXA(2) in angiogenesis and development of tumor metastasis.
Nie
D
D
Department of Radiation Oncology, Wayne State University School of Medicine, Detroit, Michigan, 48202, USA.
Lamberti
M
M
Zacharek
A
A
Li
L
L
Szekeres
K
K
Tang
K
K
Chen
Y
Y
Honn
K V
KV
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000818:Animals; D001572:Benzofurans / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002633:Chemotaxis / Q000187:drug effects / Q000502:physiology; D015237:Dinoprost / Q000494:pharmacology; D015232:Dinoprostone / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D008175:Lung Neoplasms / Q000098:blood supply* / Q000473:pathology* / Q000556:secondary; D008222:Lymphokines / Q000494:pharmacology; D008297:Male; D008546:Melanoma, Experimental / Q000098:blood supply* / Q000473:pathology* / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D051381:Rats; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors; D013928:Thromboxane A2 / Q000502:physiology*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014471:Umbilical Veins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D001572:Benzofurans; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016228:Endothelial Growth Factors; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D008222:Lymphokines; D017482:Receptors, Thromboxane; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D013928:Thromboxane A2; C026678:carboprostacyclin; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D015237:Dinoprost; D011464:Epoprostenol; D013930:Thromboxane-A Synthase; D015232:Dinoprostone; C039936:furegrelate