Netrin-4 induces lymphangiogenesis in vivo
Netrin-4 induces lymphangiogenesis in vivo
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DOI：
10.1182/blood-2009-11-252338
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发表时间：
2010-07-01
期刊：
影响因子：
20.3
通讯作者：
Li, Dean Y.
中科院分区：
文献类型：
--
作者：
Larrieu-Lahargue, Frederic;Welm, Alana L.;Li, Dean Y.
Netrin-4是一种层粘连蛋白相关的分泌蛋白，是最近显示在神经系统外必不可少的轴突导向因子，调节乳腺和肺的形态发生以及血管发育。在这里，我们表明，Netrin-4，在生理剂量下，诱导增殖，迁移，粘附，管形成和人淋巴管内皮细胞在体外的生存相当的特征性淋巴管生成因子成纤维细胞生长因子-2（FGF-2），肝细胞生长因子（HGF），血管内皮生长因子-A（VEGF-A），和血管内皮生长因子-C（VEGF-C）。Netrin-4刺激细胞内信号传导组分Akt、Erk和S6的磷酸化，并且它们的特异性抑制拮抗Netrin-4诱导的增殖。尽管Netrin受体Unc 5 B和再生蛋白由人淋巴管内皮细胞表达，但抑制其中一种或两种并不能抑制Netrin-4促进的体外作用。在体内，Netrin-4诱导转基因小鼠皮肤和乳腺肿瘤中淋巴管和血管的生长。其在人和小鼠乳腺癌癌细胞中的过表达导致增强的转移。最后，Netrin-4通过激活小GTP酶和Src家族激酶/FAK并下调紧密连接蛋白来刺激体外和体内淋巴渗透性。总之，这些数据提供了证据，表明Netrin-4是一种有助于肿瘤扩散的淋巴管生成因子，并代表了抑制转移形成的潜在靶点。（血。2010; 115（26）：5418-5426）
Netrin-4, a laminin-related secreted protein is an axon guidance cue recently shown essential outside of the nervous system, regulating mammary and lung morphogenesis as well as blood vascular development. Here, we show that Netrin-4, at physiologic doses, induces proliferation, migration, adhesion, tube formation and survival of human lymphatic endothelial cells in vitro comparable to well-characterized lymphangiogenic factors fibroblast growth factor-2 (FGF-2), hepatocyte growth factor (HGF), vascular endothelial growth factor-A (VEGF-A), and vascular endothelial growth factor-C (VEGF-C). Netrin-4 stimulates phosphorylation of intracellular signaling components Akt, Erk and S6, and their specific inhibition antagonizes Netrin-4-induced proliferation. Although Netrin receptors Unc5B and neogenin, are expressed by human lymphatic endothelial cells, suppression of either or both does not suppress Netrin-4-promoted in vitro effects. In vivo, Netrin-4 induces growth of lymphatic and blood vessels in the skin of transgenic mice and in breast tumors. Its overexpression in human and mouse mammary carcinoma cancer cells leads to enhanced metastasis. Finally, Netrin-4 stimulates in vitro and in vivo lymphatic permeability by activating small GTPases and Src family kinases/FAK, and down-regulating tight junction proteins. Together, these data provide evidence that Netrin-4 is a lymphangiogenic factor contributing to tumor dissemination and represents a potential target to inhibit metastasis formation. (Blood. 2010; 115(26):5418-5426)