title: The effects of anti-VEGFR and anti-EGFR agents on glioma cell migration through implication of growth factors with integrins.
abstract: OBJECTIVE
  The aim of this study was to assess the antitumour effect of an anti-VEGFR (sunitinib) and the anti-EGFR multi-targeted agent (lapatinib), applied either alone or in combination on the migration capacity of two glioma cell lines. Furthermore, this study sought to evaluate the effect of lapatinib in the formation of EGFR-integrin β(1) complex, as well as the effect of sunitinib in the VEGFR-integrin β(3) and PDGFR-integrin β(3) complexes formation.
  
  
  METHODS
  U87 and M059K cells were cultured as recommended by the American Type Culture Collection (ATCC). Migration assays were performed in Boyden chambers, using uncoated polycarbonate membranes. Immunoprecipitation and Western blot analysis were used for studying the complex formation of EGFR, PDGFR and VEGFR with integrins. The protein localisation was evaluated using immunofluorescence assay.
  
  
  RESULTS
  It was found that both agents, administered either alone or in combination, reduced the ability of U87 and M059K cells to migrate four h after their application. The time course study of the effect of lapatinib on EGFR-integrin β(1) complex revealed an inhibition in complex formation up to 30 min after the application of the agent. Likewise, sunitinib inhibited complex formation of VEGFR-integrin β(3) complex within two h after its application without affecting PDGFR-integrin β(3) complex. The previously described interruption of complexes formation was confirmed with an immunofluorescence assay.
  
  
  CONCLUSIONS
  The preliminary results of this study are the first to support the implication of a dual anti-EGFR/HER-2 agent, lapatinib and a multi-targeted agent, sunitinib in glioma cell migration, through a mechanism implying interruption of growth factor receptor integrin complexes formation.
authors.affiliation: Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University Hospital of Patras, Patras Medical School, Rion, Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Dimitropoulos
authors.forename: Efstathia
authors.initials: E
authors.lastname: Giannopoulou
authors.forename: Andreas A
authors.initials: AA
authors.lastname: Argyriou
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Zolota
authors.forename: Theodore
authors.initials: T
authors.lastname: Petsas
authors.forename: Ekaterini
authors.initials: E
authors.lastname: Tsiata
authors.forename: Haralabos P
authors.initials: HP
authors.lastname: Kalofonos
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects* / Q000502:physiology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D019012:Integrin beta1 / Q000378:metabolism; D039661:Integrin beta3 / Q000378:metabolism; D016023:Integrins / Q000378:metabolism*; D000077341:Lapatinib; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D000077210:Sunitinib; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D007211:Indoles; D019012:Integrin beta1; D039661:Integrin beta3; D016023:Integrins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; D000077341:Lapatinib; D066246:ErbB Receptors; C501162:FLT1 protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D000077210:Sunitinib