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 downst ream metabolite of prostaglandin H synthase, in angiogenesis, A TXA(2) mime tic, U46619, stimulated endothelial cell migration. Angiogenic basic fibrob last growth factor (bFGF) or vascular endothelial growth factor (VEGF) incr eased TXA(2) synthesis in endothelial cells three- to fivefold. Inhibition of TXA(2) synthesis with furegrelate or CI reduced HUVEC migration stimulat ed by VEGF or bFGF, A TXA(2) receptor antagonist, SQ29,548, inhibited VEGF- or bFGF-stimulated endothelial cell migration, In vivo CI inhibited bFGF-i nduced angiogenesis, Finally, development of lung metastasis in C57B1/6J mi ce intravenously injected with Lewis lung carcinoma or B16a cells was signi ficantly inhibited by thromboxane synthase inhibitors, CI or furegrelate so dium, Our data demonstrate the involvement of TXA(2) in angiogenesis and de velopment of tumor metastasis, (C) 2000 Academic Press.