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 chemotactic 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.
Matsuo
Mitsuhiro
M
Department of Anatomy, Faculty of Medicine, University of Toyama, Toyama, Japan.
Yamada
Sanae
S
Koizumi
Keiichi
K
Sakurai
Hiroaki
H
Saiki
Ikuo
I
D000818:Animals; D002450:Cell Communication / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D042783:Endothelial Cells; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D008207:Lymphatic Metastasis; D008297:Male; D008870:Microtubules / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011471:Prostatic Neoplasms / Q000201:enzymology*; D051381:Rats; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000037:antagonists & inhibitors / Q000502:physiology*; D020123:Sirolimus / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D002867:Chromones; D004791:Enzyme Inhibitors; D009025:Morpholines; D010879:Piperazines; C105687:SU 4984; D016222:Fibroblast Growth Factor 2; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D020123:Sirolimus