VEGFR-2 Inhibitor Apatinib Hinders Endothelial Cells Progression Triggered by Irradiated Gastric Cancer Cells-derived Exosomes

Background: Radiotherapy is a standard treatment for a significant fraction of cancer patients. Nonetheless, to this day radiation resistance is a key impediment in gastric cancer (GC) treatment. Moreover, GC is characterized by its substantial neo-angiogenesis, driven by high levels of vascular endothelial growth factor (VEGF) correlated with the presence of stomach cancer. The aim of our study was to address if VEGFR inhibitors treatments impact the negative effect of radiotherapy regiments of gastric cancer. Materials and methods: Isolation of exosomes released by SGC-7901 and BGC-823 lines after irradiation at 0 Gy or 6 Gy was performed by differential ultra-centrifugation. Incubation of Human Umbilical Vein Endothelial Cells (HUVEC) was carried out with different concentrations of exosomes from non- or irradiated GC cells to address their proliferation and survival fraction (SF) by MTS. 6 Gy irradiated cells exosomes at concentration of 20 µg/ml were compared to EC incubated with the same exosome concentration from non-irradiated human GC cells over 72-hour time course. Wound-healing and Transwell assays were performed in a migration buffer consisting of exosomes released by non- or irradiated SGC-7901 and BGC-823 cells over 24-hour time course. HUVEC cells stained with DAPI that have passed through a gluten gel were counted in order to monitor their invasion capacity. Employing IC50, 60 µg/ml was determined as the optimal Apatinib (YN968D1) concentration for the half-life of HUVEC, and incubated with exosomes from irradiated GC cells. The aforementioned assays were performed in the background of the same conditions in order to analyse the effect of Apatinib on HUVEC progression. Results: We show that proliferation, motility and invasive capacity of HUVEC are enhanced upon incubation with exosomes released by irradiated GC cell lines. Importantly, the latter is counteracted by the VEGFR-2 inhibitor Apatinib which hinders ECs progression. Conclusion / Significance: Combining radiotherapy and VEGFR inhibitors treatment can provide potentially a substantial impact in decreasing cancer death rates by averting the negative effect of radiotherapy regiments and provide better standard for cancer patients.