Angiopoietin-like 4 prevents metastasis through inhibition of vascular permeability and tumor cell motility and invasiveness.
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 B16F0 cells injected into the retro-orbital sinus also metastasized less efficiently in mice expressing ANGPTL4. Although B16F0 cells were observed in lung vessels, they rarely invaded the parenchyma, suggesting that ANGPTL4 affects extravasation. In addition, recombinant B16F0 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.
Galaup
Ariane
A
Institut National de la Santé et de la Recherche Médicale, Unit 36, 11 Place Marcelin Berthelot, 75005 Paris, France.
Cazes
Aurelie
A
Le Jan
Sebastien
S
Philippe
Josette
J
Connault
Elisabeth
E
Le Coz
Emmanuelle
E
Mekid
Halima
H
Mir
Lluis M
LM
Opolon
Paule
P
Corvol
Pierre
P
Monnot
Catherine
C
Germain
Stephane
S
D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D018827:Carcinoma, Lewis Lung / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D008175:Lung Neoplasms / Q000473:pathology / Q000517:prevention & control; D008198:Lymph Nodes / Q000473:pathology; D008207:Lymphatic Metastasis / Q000473:pathology / Q000517:prevention & control; D038041:Lymphopoiesis / Q000502:physiology; D008546:Melanoma, Experimental / Q000473:pathology / Q000517:prevention & control / Q000556:secondary; D051379:Mice; D008810:Mice, Inbred C57BL; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000473:pathology / Q000517:prevention & control*; D018919:Neovascularization, Physiologic
C474772:ANGPTL4 protein, human; D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D036341:Intercellular Signaling Peptides and Proteins