ATL-1, a synthetic analog of lipoxin, modulates endothelial permeability and interaction with tumor cells through a VEGF-dependent mechanism

Lipoxins (LX) and 15-epi-LX are lipids with a potent inhibitory effect on angiogenesis, in different models in vivo and in vitro. ATL-1, a synthetic analog of 15-epi-LXA4, inhibits various actions stimulated by vascular endothelial growth factor (VEGF). However, LX actions on endothelial cells (EC) in tumor-related contexts are still unknown. Here, we investigated the modulation of EC by ATL-1, in a model that mimics tumor extravasation. We observed that the analog inhibited endothelial permeability induced by VEGF, through the stabilization of VE-cadherin/β-catenin-dependent adherens junctions. We tested the ability of MV3 cells, a highly metastatic melanoma cell line, to transmigrate across unchallenged EC monolayers for 18h, as compared to NGM normal melanocytes. ATL-1 was able to inhibit only melanoma extravasation. MV3 cells secrete large amounts of VEGF and we observed that ATL-1 per se did not alter this ability. Melanoma cells skills to crossing endothelial monolayers were due to the steady accumulation of tumor-derived VEGF. When endothelial cells were challenged with exogenous VEGF, added at levels comparable to those secreted by MV3 cells over 18h, and a short-term (4h) transendothelial migration assay was performed, both melanoma and melanocyte cells were able to extravasate, and ATL-1 was able to block the passage of both cells. These results indicate that ATL-1 has a potent inhibitory effect on the permeability induced by VEGF, and that this pharmacological effect could be used to block tumor extravasation across endothelial barriers, with a possible prospect of reducing the haematogenic spread of cancer cells.