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NeuroMolecular Medicine

, Volume 16, Issue 4, pp 752–771 | Cite as

Direct Effect of Bevacizumab on Glioblastoma Cell Lines In Vitro

  • Thomas SimonEmail author
  • Bérénice Coquerel
  • Alexandre Petit
  • Yusra Kassim
  • Elise Demange
  • Didier Le Cerf
  • Valérie Perrot
  • Jean-Pierre Vannier
Original Paper

Abstract

Bevacizumab is a humanized monoclonal antibody directed against the pro-angiogenic factor vascular and endothelial growth factor-A (VEGF-A) used in the treatment of glioblastomas. Although most patients respond initially to this treatment, studies have shown that glioblastomas eventually recur. Several non-mutually exclusive theories based on the anti-angiogenic effect of bevacizumab have been proposed to explain these mechanisms of resistance. In this report, we studied whether bevacizumab can act directly on malignant glioblastoma cells. We observe changes in the expression profiles of components of the VEGF/VEGF-R pathway and in the response to a VEGF-A stimulus following bevacizumab treatment. In addition, we show that bevacizumab itself acts on glioblastoma cells by activating the Akt and Erks survival signaling pathways. Bevacizumab also enhances proliferation and invasiveness of glioblastoma cells in hyaluronic acid hydrogel. We propose that the paradoxical effect of bevacizumab on glioblastoma cells could be due to changes in the VEGF-A-dependent autocrine loop as well as in the intracellular survival pathways, leading to the enhancement of tumor aggressiveness. Investigation of how bevacizumab interacts with glioblastoma cells and the resulting downstream signaling pathways will help targeting populations of resistant glioblastoma cells.

Keywords

Anti-angiogenic therapies Autocrine loop Brain extracellular matrix Glioblastoma VEGF-A 

Abbreviations

CNS

Central nervous system

ECM

Extracellular matrix

HA

Hyaluronic acid

IgG1

Immunoglobulin G1

PlGF

Placental growth factor

VEGF

Vascular and endothelial growth factor

Notes

Acknowledgments

The authors would like to thank Catherine Buquet, Wiem Khelil, Laure Klosek, and Elisabeth Legrand for their technical help. The authors are very grateful to Dr. Flore Gouel and Pr. Isabelle Dubus for fruitful discussions. T. Simon is recipient of a fellowship from the “Conseil Régional de Haute-Normandie.” A. Petit is recipient of a fellowship from “Ministère de l’Enseignement supérieur et de la Recherche”.

Conflict of interest

The authors declare that they have no conflict of interest.

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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Thomas Simon
    • 1
    • 2
    Email author
  • Bérénice Coquerel
    • 1
    • 2
  • Alexandre Petit
    • 1
    • 2
  • Yusra Kassim
    • 1
    • 2
  • Elise Demange
    • 1
    • 2
    • 3
  • Didier Le Cerf
    • 4
    • 5
  • Valérie Perrot
    • 1
    • 2
  • Jean-Pierre Vannier
    • 1
    • 2
  1. 1.Groupe de Recherche «Micro-Environnement et Renouvellement Cellulaire Intégrés» MERCI UPRES EA 3829, Faculté de Médecine et PharmacieUniversité de RouenRouen CedexFrance
  2. 2.Normandie UniversitéRouen CedexFrance
  3. 3.CelenysRouen CedexFrance
  4. 4.Laboratoire Polymères Biopolymères Surfaces, Faculté des Sciences et des TechniquesUniversité de RouenMont-Saint-Aignan CedexFrance
  5. 5.CNRS UMR 6270 and FR 3038Mont-Saint-Aignan CedexFrance

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