Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo
Insulin-like growth factors 1 and 2 induce lymphangiogenesis in vivo
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DOI：
10.1073/pnas.0507865102
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发表时间：
2005-10-25
影响因子：
11.1
通讯作者：
Cao, YH
中科院分区：
文献类型：
--
作者：
Björndahl, M;Cao, RH;Cao, YH
淋巴管生成是促进癌症扩散的一个重要过程。在这里，我们证明胰岛素样生长因子1 （IGF-1）和2 （IGF-2）在体内诱导淋巴管生成。在小鼠角膜实验中，IGF-1和IGF-2诱导淋巴管生成，用淋巴内皮特异性标志物LYVE-1检测。有趣的是，igf -1诱导的淋巴管生成不能被可溶性血管内皮生长因子受体3阻断，这表明血管内皮生长因子受体3信号通路不是igf诱导的淋巴管生成所必需的。在体外，IGF-1和IGF-2显著刺激淋巴内皮细胞的增殖和迁移。在淋巴内皮细胞中，IGF-1和IGF-2诱导细胞内信号成分磷酸化，如Akt、Src和细胞外信号调节激酶。免疫组织化学、RT-PCR和Affymetrix基因芯片分析显示，IGFs受体存在于淋巴内皮中。总之，我们的研究结果表明，IGFs可能作为直接的淋巴管生成因子，尽管不能排除在诱导淋巴管生成中的任何间接作用。由于IGF配体和受体家族的成员在各种类型的实体瘤中广泛表达，我们的研究结果表明这些因素可能有助于淋巴转移。
Lymphangiogenesis is an important process that contributes to the spread of cancer. Here we show that insulin-like growth factors 1 (IGF-1) and 2 (IGF-2) induce lymphangiogenesis in vivo. In a mouse cornea assay, IGF-1 and IGF-2 induce lymphangiogenesis as detected with LYVE-1, a specific marker for lymphatic endothelium. Interestingly, IGF-1-induced lymphangiogenesis could not be blocked by a soluble vascular endothelial growth factor receptor 3, suggesting that the vascular endothelial growth factor receptor 3-signaling pathway is not required for IGF-induced lymphangiogenesis. In vitro, IGF-1 and IGF-2 significantly stimulated proliferation and migration of primary lymphatic endothelial cells. IGF-1 and IGF-2 induced phosphorylation of intracellular signaling components, such as Akt, Src, and extracellular signal-regulated kinase in lymphatic endothelial cells. Immunohistochemistry, RT-PCR, and Affymetrix GeneChip microarray analysis showed that the receptors for IGFs are present in lymphatic endothelium. Together, our findings suggest that IGFs might act as direct lymphangiogenic factors, although any indirect roles in the induction of lymphangiogenesis cannot be excluded. Because members of the IGF ligand and receptor families are widely expressed in various types of solid tumors, our findings suggest that these factors are likely to contribute to lymphatic metastasis.