Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness
Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness
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DOI：
10.1073/pnas.0609025103
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发表时间：
2006-12-05
影响因子：
11.1
通讯作者：
Germain, Stephane
中科院分区：
文献类型：
--
作者：
Galaup, Ariane;Cazes, Aurelie;Germain, Stephane
血管生成素样4（ANGPTL4）是血管生成素样家族的一种分泌蛋白，在肿瘤细胞和内皮细胞以及许多癌症的缺氧周围坏死区中由缺氧诱导。在这里，我们研究了ANGPTL4是否可能影响肿瘤生长以及转移。因此，将转移性3LL细胞异种移植到对照小鼠和通过体内DNA电转移表达ANGPTL 4的小鼠中。尽管两组中原发性肿瘤以相似的速度生长，但3LL细胞转移到表达ANGPTL4的小鼠的肺部的效率较低。在原发性肿瘤中观察到较少的3LL栓塞，表明ANGPTL4抑制了3LL细胞的内渗。此外，注射到眶后窦中的黑素瘤B16FO细胞在表达ANGPTL4的小鼠中也转移效率较低。虽然在肺血管中观察到B16FO细胞，但它们很少侵入实质，表明ANGPTL4影响外渗。此外，产生了过表达ANGPTL4的重组B16FO细胞，其显示出比对照细胞更低的体外迁移、侵袭和粘附能力。ANGPTL4的表达通过抑制肌动蛋白应力纤维的形成和黏着斑蛋白在焦点接触处的定位诱导肌动蛋白细胞骨架的重组。总之，这些结果表明ANGPTL4通过其对血管和肿瘤区室的作用，通过抑制血管活性以及肿瘤细胞运动性和侵袭性来预防转移过程。
Angiopoietin-like 4 (ANGPTL4), a secreted protein of the angiopoietin-like family, is induced by hypoxia in both tumor and endothelial cells as well as in hypoxic perinecrotic areas of numerous cancers. Here, we investigated whether ANGPTL4 might affect tumor growth as well as metastasis. Metastatic 3LL cells were therefore xenografted into control mice and mice in which ANGPTL4 was expressed by using in vivo DNA electrotransfer. Whereas primary tumors grew at a similar rate in both groups, 3LL cells metastasized less efficiently to the lungs of mice that expressed ANGPTL4. Fewer 3LL emboli were observed in primary tumors, suggesting that intravasation of 3LL cells was inhibited by ANGPTL4. Furthermore, melanoma B16FO cells injected into the retro-orbital sinus also metastasized less efficiently in mice expressing ANGPTL4. Although B16FO cells were observed in lung vessels, they rarely invaded the parenchyma, suggesting that ANGPTL4 affects extravasation. In addition, recombinant B16FO cells that overexpress ANGPTL4 were generated, showing a lower capacity for in vitro migration, invasion, and adhesion than control cells. Expression of ANGPTL4 induced reorganization of the actin cytoskeleton through inhibition of actin stress fiber formation and vinculin localization at focal contacts. Together, these results show that ANGPTL4, through its action on both vascular and tumor compartments, prevents the metastatic process by inhibiting vascular activity as well as tumor cell motility and invasiveness.