Tumour-derived fibroblast growth factor-2 exerts lymphangiogenic effects through Akt/mTOR/p70S6kinase pathway in rat lymphatic endothelial cells

Fibroblast growth factor-2 (FGF-2) has been shown to induce both angiogenesis and lymphangiogenesis in the mouse corneum; however, the signalling mechanism underlying FGF-2-induced lymphangiogenesis remains unknown. Here we investigated the effect of FGF-2 on newly developed temperature-sensitive rat lymphatic endothelial (TR-LE) cells. The supernatant of PC-3 prostate cancer cells facilitated tube-like formation in TR-LE cells, and formation was inhibited by neutralising antibodies against FGF-2. The addition of FGF-2 stimulated tube-like formation as well as proliferation and chernotactic migration of TR-LE cells. Blockade of the Akt signalling pathway by LY294002 abolished the elongation of tubes induced by FGF-2, whereas inhibition of the extracellular signal-regulated kinase (ERK) signalling pathway had no effect. Rapamycin abrogated the phosphorylation of p70S6kinase and consistently inhibited the formation of tubes induced by FGF-2. Furthermore, tube-like formation induced by the supernatant of PC-3 cells was inhibited by LY294002 or rapamycin. These data suggest that FGF-2 exerts lymphangiogenic effects by activating the Akt/mammalian target of rapamycin (mTOR)/p70S6kinase pathway in lymphatic endothelial cells, and that the pathway provides a potent target for tumour lymphangiogenesis. (c) 2007 Elsevier Ltd. All rights reserved.