title: VE-Cadherin Disassembly and Cell Contractility in the Endothelium are Necessary for Barrier Disruption Induced by Tumor Cells.
abstract: During metastasis, breakdown of the endothelial barrier is critical for tumor cell extravasation through blood vessel walls and is mediated by a combination of tumor secreted soluble factors and receptor-ligand interactions. However, a complete mechanism governing tumor cell transendothelial migration remains unclear. Here, we investigate the roles of tumor-associated signals in regulating endothelial cell contractility and adherens junction disassembly leading to endothelial barrier breakdown. We show that Src mediates VE-cadherin disassembly in response to metastatic melanoma cells. Through the use of pharmacological inhibitors of cytoskeletal contractility we find that endothelial cell contractility is responsive to interactions with metastatic cancer cells and that reducing endothelial cell contractility abrogates migration of melanoma cells across endothelial monolayers. Furthermore, we find that a combination of tumor secreted soluble factors and receptor-ligand interactions mediate activation of Src within endothelial cells that is necessary for phosphorylation of VE-cadherin and for breakdown of the endothelial barrier. Together, these results provide insight into how tumor cell signals act in concert to modulate cytoskeletal contractility and adherens junctions disassembly during extravasation and may aid in identification of therapeutic targets to block metastasis.
authors.affiliation: Department of Biomedical Engineering, Pennsylvania State university, University Park, PA, 16802, USA.
authors.forename: Virginia
authors.initials: V
authors.lastname: Aragon-Sanabria
authors.affiliation: Department of Chemical Engineering, Pennsylvania State University, University Park, PA, 16802, USA.
authors.forename: Steven E
authors.initials: SE
authors.lastname: Pohler
authors.affiliation: Department of Biomedical Engineering, Pennsylvania State university, University Park, PA, 16802, USA.
authors.forename: Vikram J
authors.initials: VJ
authors.lastname: Eswar
authors.affiliation: Department of Chemical Engineering, Pennsylvania State University, University Park, PA, 16802, USA.
authors.forename: Matthew
authors.initials: M
authors.lastname: Bierowski
authors.affiliation: Department of Biomedical Engineering, Pennsylvania State university, University Park, PA, 16802, USA.|Department of Chemical Engineering, Pennsylvania State University, University Park, PA, 16802, USA.
authors.forename: Esther W
authors.initials: EW
authors.lastname: Gomez
authors.affiliation: Department of Biomedical Engineering, Pennsylvania State university, University Park, PA, 16802, USA.
authors.forename: Cheng
authors.initials: C
authors.lastname: Dong
mesh_terms: D022005:Adherens Junctions; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D042783:Endothelial Cells / Q000378:metabolism* / Q000473:pathology; D004727:Endothelium / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008545:Melanoma / Q000378:metabolism*; D009362:Neoplasm Metastasis; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D015703:Antigens, CD; D015820:Cadherins; D019010:Vascular Cell Adhesion Molecule-1; D019061:src-Family Kinases; D000099152:Cadherin 5