title: Anti-VEGF treatment reduces blood supply and increases tumor cell invasion in glioblastoma.
abstract: Bevacizumab, an antibody against vascular endothelial growth factor (VEGF), is a promising, yet controversial, drug in human glioblastoma treatment (GBM). Its effects on tumor burden, recurrence, and vascular physiology are unclear. We therefore determined the tumor response to bevacizumab at the phenotypic, physiological, and molecular level in a clinically relevant intracranial GBM xenograft model derived from patient tumor spheroids. Using anatomical and physiological magnetic resonance imaging (MRI), we show that bevacizumab causes a strong decrease in contrast enhancement while having only a marginal effect on tumor growth. Interestingly, dynamic contrast-enhanced MRI revealed a significant reduction of the vascular supply, as evidenced by a decrease in intratumoral blood flow and volume and, at the morphological level, by a strong reduction of large- and medium-sized blood vessels. Electron microscopy revealed fewer mitochondria in the treated tumor cells. Importantly, this was accompanied by a 68% increase in infiltrating tumor cells in the brain parenchyma. At the molecular level we observed an increase in lactate and alanine metabolites, together with an induction of hypoxia-inducible factor 1α and an activation of the phosphatidyl-inositol-3-kinase pathway. These data strongly suggest that vascular remodeling induced by anti-VEGF treatment leads to a more hypoxic tumor microenvironment. This favors a metabolic change in the tumor cells toward glycolysis, which leads to enhanced tumor cell invasion into the normal brain. The present work underlines the need to combine anti-angiogenic treatment in GBMs with drugs targeting specific signaling or metabolic pathways linked to the glycolytic phenotype.
authors.affiliation: NorLux Neuro-Oncology Laboratory, Oncology Department, Centre de Recherche Public de la Santé, 1526 Luxembourg, Luxembourg.
authors.forename: Olivier
authors.initials: O
authors.lastname: Keunen
authors.forename: Mikael
authors.initials: M
authors.lastname: Johansson
authors.forename: Anaïs
authors.initials: A
authors.lastname: Oudin
authors.forename: Morgane
authors.initials: M
authors.lastname: Sanzey
authors.forename: Siti A Abdul
authors.initials: SA
authors.lastname: Rahim
authors.forename: Fred
authors.initials: F
authors.lastname: Fack
authors.forename: Frits
authors.initials: F
authors.lastname: Thorsen
authors.forename: Torfinn
authors.initials: T
authors.lastname: Taxt
authors.forename: Michal
authors.initials: M
authors.lastname: Bartos
authors.forename: Radovan
authors.initials: R
authors.lastname: Jirik
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Daniel
authors.initials: D
authors.lastname: Stieber
authors.forename: Linda
authors.initials: L
authors.lastname: Stuhr
authors.forename: Ingrid
authors.initials: I
authors.lastname: Moen
authors.forename: Cecilie Brekke
authors.initials: CB
authors.lastname: Rygh
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D001810:Blood Volume / Q000187:drug effects; D002199:Capillary Permeability / Q000187:drug effects; D015687:Cell Hypoxia / Q000187:drug effects; D003287:Contrast Media; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D005909:Glioblastoma / Q000098:blood supply* / Q000201:enzymology / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D008279:Magnetic Resonance Imaging; D009361:Neoplasm Invasiveness; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051381:Rats; D011923:Rats, Nude; D015398:Signal Transduction / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D003287:Contrast Media; D042461:Vascular Endothelial Growth Factor A; D051153:Wnt Proteins; D000068258:Bevacizumab; D019869:Phosphatidylinositol 3-Kinases