title: Priming Endothelial Cells With a Melanoma-Derived Extracellular Matrix Triggers the Activation of αvβ3/VEGFR2 Axis.
abstract: The unique composition of tumor-produced extracellular matrix (ECM) can be a determining factor in changing the profile of endothelial cells in the tumor microenvironment. As the main receptor for ECM proteins, integrins can activate a series of signaling pathways related to cell adhesion, migration, and differentiation of endothelial cells that interact with ECM proteins. We studied the direct impact of the decellularized ECM produced by a highly metastatic human melanoma cell line (MV3) on the activation of endothelial cells and identified the intracellular signaling pathways associated with cell differentiation. Our data show that compared to the ECM derived from a human melanocyte cell line (NGM-ECM), ECM produced by a melanoma cell line (MV3-ECM) is considerably different in ultrastructural organization and composition and possesses a higher content of tenascin-C and laminin and a lower expression of fibronectin. When cultured directly on MV3-ECM, endothelial cells change morphology and show increased adhesion, migration, proliferation, and tubulogenesis. Interaction of endothelial cells with MV3-ECM induces the activation of integrin signaling, increasing FAK phosphorylation and its association with Src, which activates VEGFR2, potentiating the receptor response to VEGF. The blockage of αvβ3 integrin inhibited the FAK-Src association and VEGFR activation, thus reducing tubulogenesis. Together, our data suggest that the interaction of endothelial cells with the melanoma-ECM triggers integrin-dependent signaling, leading to Src pathway activation that may potentiate VEGFR2 activation and up-regulate angiogenesis. J. Cell. Physiol. 231: 2464-2473, 2016. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Laboratório de Farmacologia Celular e Molecular, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.|Laboratório de Biologia da Célula Endotelial e da Angiogênese, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Edward
authors.initials: E
authors.lastname: Helal-Neto
authors.affiliation: Laboratório de Farmacologia Celular e Molecular, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Renata M
authors.initials: RM
authors.lastname: Brandão-Costa
authors.affiliation: Laboratório de Farmacologia Celular e Molecular, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Roberta
authors.initials: R
authors.lastname: Saldanha-Gama
authors.affiliation: Laboratório de Farmacologia Celular e Molecular, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Cristiane
authors.initials: C
authors.lastname: Ribeiro-Pereira
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Midlej
authors.affiliation: Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.|Unigranrio, Universidade do Grande Rio, Rio de Janeiro, Brazil.
authors.forename: Marlene
authors.initials: M
authors.lastname: Benchimol
authors.affiliation: Laboratório de Biologia da Célula Endotelial e da Angiogênese, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Verônica
authors.initials: V
authors.lastname: Morandi
authors.affiliation: Laboratório de Farmacologia Celular e Molecular, IBRAG, Universidade do Estado do Rio de Janeiro, Rio de Janeiro, Brazil.
authors.forename: Christina
authors.initials: C
authors.lastname: Barja-Fidalgo
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D042783:Endothelial Cells / Q000201:enzymology / Q000378:metabolism*; D004789:Enzyme Activation; D005109:Extracellular Matrix / Q000378:metabolism* / Q000648:ultrastructure; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism*; D008544:Melanocytes / Q000378:metabolism; D008545:Melanoma / Q000378:metabolism*; D018919:Neovascularization, Physiologic; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
chemical_list: D039302:Integrin alphaVbeta3; D040301:Vascular Endothelial Growth Factor Receptor-2; D051416:Focal Adhesion Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt