title: ATL-1, a synthetic analog of lipoxin, modulates endothelial permeability and interaction with tumor cells through a VEGF-dependent mechanism.
abstract: 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 18 h, 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 18 h, 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.
authors.affiliation: Department of Cell Biology, Laboratory of Endothelial Cell Biology and Angiogenesis (LabAngio), Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Brazil.
authors.forename: A M
authors.initials: AM
authors.lastname: Vieira
authors.affiliation: Department of Cell Biology, Laboratory of Endothelial Cell Biology and Angiogenesis (LabAngio), Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Brazil.
authors.forename: E H
authors.initials: EH
authors.lastname: Neto
authors.affiliation: Department of Cell Biology, Laboratory of Endothelial Cell Biology and Angiogenesis (LabAngio), Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Brazil.
authors.forename: C C
authors.initials: CC
authors.lastname: Figueiredo
authors.affiliation: Department of Cell Biology, Laboratory of Biochemical and Cellular Pharmacology, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Brazil.
authors.forename: C
authors.initials: C
authors.lastname: Barja Fidalgo
authors.affiliation: Department of Pharmacology, Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Brazil.
authors.forename: I M
authors.initials: IM
authors.lastname: Fierro
authors.affiliation: Department of Cell Biology, Laboratory of Endothelial Cell Biology and Angiogenesis (LabAngio), Instituto de Biologia Roberto Alcantara Gomes, Universidade do Estado do Rio de Janeiro (UERJ), Rio de Janeiro, Brazil. Electronic address: veronica@uerj.br.
authors.forename: V
authors.initials: V
authors.lastname: Morandi
mesh_terms: D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D044045:Lipoxins / Q000494:pharmacology*; D008545:Melanoma / Q000473:pathology; D008856:Microscopy, Fluorescence; D010539:Permeability; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology*
chemical_list: C447621:16-(4-fluorophenoxy)lipoxin A4; D044045:Lipoxins; D042461:Vascular Endothelial Growth Factor A
keywords: Adherens junctions; Endothelial permeability; Lipoxin; VE-cadherin; VEGF