Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness

被引:212
作者
Galaup, Ariane
Cazes, Aurelie
Le Jan, Sebastien
Philippe, Josette
Connault, Elisabeth
Le Coz, Emmanuelle
Mekid, Halima
Mir, Lluis M.
Opolon, Paule
Corvol, Pierre
Monnot, Catherine
Germain, Stephane
机构
[1] INSERM, U36, F-75005 Paris, France
[2] Coll France, F-75005 Paris, France
[3] CNRS, UMR 8121, IGR, F-94805 Villejuif, France
[4] Hop Europeen Georges Pompidou, AP HP, Serv Hematol Biol A, F-75908 Paris 15, France
关键词
angiogenesis; cancer; hypoxia;
D O I
10.1073/pnas.0609025103
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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.
引用
收藏
页码:18721 / 18726
页数:6
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