Abstract
BackgroundGlioma cells not only secrete high levels of vascular endothelial growth factor (VEGF) but also express VEGF receptors (VEGFR), supporting the existence of an autocrine loop. The direct impact on glioma cells metabolism of drugs targeting the VEGF pathway, such as Bevacizumab (Bev) or VEGFR Tyrosine Kinase Inhibitor (TKI), is poorly known.Material and MethodsU87 cells were treated with Bev or SU1498, a selective VEGFR2 TKI. VEGFR expression was checked with FACS flow cytometry and Quantitative Real-Time PCR. VEGF secretion into the medium was assessed with an ELISA kit. Metabolomic studies on cells were performed using High Resolution Magic Angle Spinning Spectroscopy (HR-MAS).ResultsU87 cells secreted VEGF and expressed low level of VEGFR2, but no detectable VEGFR1. Exposure to SU1498, but not Bev, significantly impacted cell proliferation and apoptosis. Metabolomic studies with HR MAS showed that Bev had no significant effect on cell metabolism, while SU1498 induced a marked increase in lipids and a decrease in glycerophosphocholine. Accordingly, accumulation of lipid droplets was seen in the cytoplasm of SU1498-treated U87 cells.ConclusionAlthough both drugs target the VEGF pathway, only SU1498 showed a clear impact on cell proliferation, cell morphology and metabolism. Bevacizumab is thus less likely to modify glioma cells phenotype due to a direct therapeutic pressure on the VEGF autocrine loop. In patients treated with VEGFR TKI, monitoring lipids with magnetic resonance spectroscopic (MRS) might be a valuable marker to assess drug cytotoxicity.
Highlights
Glioblastomas (GBMs) are rapidly growing tumors that extensively invade the brain
Metabolomic studies with HR MAS showed that Bev had no significant effect on cell metabolism, while SU1498 induced a marked increase in lipids and a decrease in glycerophosphocholine
Accumulation of lipid droplets was seen in the cytoplasm of SU1498-treated U87 cells
Summary
Glioblastomas (GBMs) are rapidly growing tumors that extensively invade the brain. Despite surgical resection followed by radiation therapy and concomitant temozolomide, the prognostic remains dismal with a median survival of less than 15 months [1]. GBMs secrete high levels of vascular endothelial growth factor (VEGF) that promotes endothelial cell proliferation, blood brain barrier (BBB) permeability, and angiogenesis [2]. VEGF Receptor 1 (VEGFR1) and VEGFR2 are expressed by the vascular endothelial cells. Several studies reported that glioma cells secrete high levels of VEGF and express VEGF receptors, supporting the existence of an autocrine loop [4,5,6,7]. Glioma cells secrete high levels of vascular endothelial growth factor (VEGF) and express VEGF receptors (VEGFR), supporting the existence of an autocrine loop. The direct impact on glioma cells metabolism of drugs targeting the VEGF pathway, such as Bevacizumab (Bev) or VEGFR Tyrosine Kinase Inhibitor (TKI), is poorly known
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