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Direct Effect of Bevacizumab on Glioblastoma Cell Lines In Vitro

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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.

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Abbreviations

CNS:

Central nervous system

ECM:

Extracellular matrix

HA:

Hyaluronic acid

IgG1:

Immunoglobulin G1

PlGF:

Placental growth factor

VEGF:

Vascular and endothelial growth factor

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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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Authors and Affiliations

  1. Groupe de Recherche «Micro-Environnement et Renouvellement Cellulaire Intégrés» MERCI UPRES EA 3829, Faculté de Médecine et Pharmacie, Université de Rouen, 22 Boulevard Gambetta, 76183, Rouen Cedex, France

    Thomas Simon, Bérénice Coquerel, Alexandre Petit, Yusra Kassim, Elise Demange, Valérie Perrot & Jean-Pierre Vannier

  2. Normandie Université, Rouen Cedex, France

    Thomas Simon, Bérénice Coquerel, Alexandre Petit, Yusra Kassim, Elise Demange, Valérie Perrot & Jean-Pierre Vannier

  3. Celenys, Biopolis 75 Route de Lyons la Forêt, 76000, Rouen Cedex, France

    Elise Demange

  4. Laboratoire Polymères Biopolymères Surfaces, Faculté des Sciences et des Techniques, Université de Rouen, Place Emile Blondel, 76821, Mont-Saint-Aignan Cedex, France

    Didier Le Cerf

  5. CNRS UMR 6270 and FR 3038, 76821, Mont-Saint-Aignan Cedex, France

    Didier Le Cerf

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  1. Thomas Simon
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Simon, T., Coquerel, B., Petit, A. et al. Direct Effect of Bevacizumab on Glioblastoma Cell Lines In Vitro. Neuromol Med 16, 752–771 (2014). https://doi.org/10.1007/s12017-014-8324-8

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