Tumour-derived fibroblast growth factor-2 exerts lymphangiogenic effects through Akt/mTOR/p70S6kinase pathway in rat lymphatic endothelial cells
Tumour-derived fibroblast growth factor-2 exerts lymphangiogenic effects through Akt/mTOR/p70S6kinase pathway in rat lymphatic endothelial cells
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DOI：
10.1016/j.ejca.2007.04.024
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发表时间：
2007-07-01
影响因子：
8.4
通讯作者：
Saiki, Ikuo
中科院分区：
文献类型：
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作者：
Matsuo, Mitsuhiro;Yamada, Sanae;Saiki, Ikuo
成纤维细胞生长因子-2(成纤维细胞生长因子-2)可诱导小鼠角膜新生血管和淋巴管生成，但其诱导淋巴管生成的信号机制尚不清楚。在这里，我们研究了成纤维细胞生长因子-2对新培养的温度敏感型大鼠淋巴管内皮细胞的影响。前列腺癌PC-3细胞上清液可促进TR-LE细胞的管状形成，而抗成纤维细胞生长因子-2的抗体可抑制其形成。加入成纤维细胞生长因子-2可促进TRLE细胞的管样形成、增殖和趋化迁移。LY294002阻断Akt信号通路可阻断成纤维细胞生长因子-2诱导的小管延长，而对细胞外信号调节激酶(ERK)信号通路的抑制作用不明显。雷帕霉素可抑制p70S6蛋白的磷酸化，并持续抑制成纤维细胞生长因子-2诱导的小管形成。此外，LY294002或雷帕霉素可抑制PC-3细胞上清液诱导的管样生长。这些结果表明，成纤维细胞生长因子-2通过激活淋巴管内皮细胞中Akt/哺乳动物靶标雷帕霉素(MTOR)/p70S6激酶通路而发挥淋巴管生成作用，该通路为肿瘤淋巴管生成提供了一个有效的靶点。(C)2007爱思唯尔有限公司。保留所有权利。
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.