The effects of anti-VEGFR and anti-EGFR agents on glioma cell migration through implication of growth factors with integrins
Objective: The aim of this study was to assess the antitumor effect of an anti-VEGFR (sunitinib) and the anti-EGFR multitargeted agent (lapatinib), applied either alone or in combination on the migration capacity of two glioma cell lines. Furthermore, we sought to evaluate the effect of lapatinib in the formation of EGFR-integrin β1 complex, as well as the effect of sunitinib in the VEGFR-integrin β3 and PDGFR-integrin β3 complexes formation.
Material and methods: U87 and M059K cells were cultured as recommended by 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 localization was evaluated using immunofluorescence assay.
Results: We found that both agents administered either alone or in combination, reduced the ability of U87 and M059K cells to migrate 4 h after their application. The time course study of the effect of lapatinib on EGFR-integrin β1 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 β3 complex within 2h after its application without affecting PDGFR-integrin β3 complex. The previously-described interruption of complexes formation was confirmed with an immunofluorescence assay.
Conclusions: The preliminary results of our 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 cells migration, through a mechanism implying interruption of growth factor receptor -integrin complexes formation.