Semaphorin-3F is an inhibitor of tumor angiogenesis
Semaphorin-3F is an inhibitor of tumor angiogenesis
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DOI：
10.1158/0008-5472.can-03-3090
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发表时间：
2004-02-01
期刊：
影响因子：
11.2
通讯作者：
Neufeld, G
中科院分区：
文献类型：
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作者：
Kessler, O;Shraga-Heled, N;Neufeld, G
神经粘连蛋白-1(Np1)和神经粘连蛋白-2(Np2)受体与A型神经丛形成复合体。这些复合体作为特定的3类信号素的信号受体。Np1和np2还作为肝素结合形式的血管内皮生长因子(VEGF6)的受体发挥作用。人脐静脉内皮细胞(HUVEC)表达血管内皮生长因子(VEGF)和碱性成纤维细胞生长因子(BFGF)的酪氨酸激酶受体，以及np1、np2和几种A型网络蛋白。我们发现信号素-3F(S3F)，一种通过np2受体传递信号的信号素，能够抑制血管内皮细胞生长因子65和碱性成纤维细胞生长因子诱导的内皮细胞的增殖。此外，s3f还可抑制血管内皮细胞生长因子和碱性成纤维细胞生长因子诱导的细胞外信号调节激酶-1/2的磷酸化。我们的实验表明，碱性成纤维细胞生长因子不与神经鞘蛋白结合，也不抑制碱性成纤维细胞生长因子与成纤维细胞生长因子受体的结合。因此，s3f可能通过一种需要主动的s3f信号转导而不是通过抑制bFGF与成纤维细胞生长因子受体结合的机制来抑制bFGF的活性。藻酸盐微胶囊和Matrigel Plug试验表明，S3f还抑制了血管内皮生长因子65和碱性成纤维细胞生长因子诱导的体内血管生成。S3f在致瘤性人HEK293细胞中的过表达抑制了细胞的成瘤能力，但不抑制细胞的增殖。从表达s3f的HEK293细胞发展而来的肿瘤的发展速度要慢得多，并且肿瘤相关血管的浓度明显较低，这表明s3f是肿瘤血管生成的抑制因子。
The neuropilin-1 (np1) and neuropilin-2 (np2) receptors form complexes with type-A plexins. These complexes serve as signaling receptors for specific class-3 semaphorins. Np1 and np2 function in addition as receptors for heparin-binding forms of vascular endothelial growth factor (VEGF), such as VEGF,6,. Human umbilical vein endothelial cells (HUVEC) express tyrosine-kinase receptors for VEGF and basic fibroblast growth factor (bFGF), as well as np1, np2, and several type-A plexins. We have found that semaphorin-3F (s3f), a semaphorin which signals through the np2 receptor, was able to inhibit VEGF,65, as well as bFGF-induced proliferation of HUVECs. Furthermore, s3f inhibited VEGF as well as bFGF-induced phosphorylation of extracellular signal-regulated kinase-1/2. Our experiments indicate that bFGF does not bind to neuropilins, nor does s3f inhibit the binding of bFGF to FGF receptors. It is therefore possible that s3f inhibits the activity of bFGF by a mechanism that requires active s3f signal transduction rather than by inhibition of bFGF binding to FGF receptors. s3f also inhibited VEGF,65, as well as bFGF-induced in vivo angiogenesis as determined by the alginate micro-encapsulation and Matrigel plug assays. Overexpression of s3f in tumorigenic human HEK293 cells inhibited their tumor-forming ability but not their proliferation in cell culture. The tumors that did develop from s3f-expressing HEK293 cells developed at a much slower rate and had a significantly lower concentration of tumor-associated blood vessels, indicating that s3f is an inhibitor of tumor angiogenesis.