title: Direct effect of bevacizumab on glioblastoma cell lines in vitro.
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.
authors.affiliation: 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.simon1@univ-rouen.fr.
authors.forename: Thomas
authors.initials: T
authors.lastname: Simon
authors.forename: Bérénice
authors.initials: B
authors.lastname: Coquerel
authors.forename: Alexandre
authors.initials: A
authors.lastname: Petit
authors.forename: Yusra
authors.initials: Y
authors.lastname: Kassim
authors.forename: Elise
authors.initials: E
authors.lastname: Demange
authors.forename: Didier
authors.initials: D
authors.lastname: Le Cerf
authors.forename: Valérie
authors.initials: V
authors.lastname: Perrot
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vannier
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D019898:Autocrine Communication / Q000187:drug effects; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000473:pathology*; D020013:Calcium Signaling / Q000187:drug effects; D018929:Cell Culture Techniques; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D005909:Glioblastoma / Q000473:pathology*; D006801:Humans; D006820:Hyaluronic Acid; D020100:Hydrogels; D007211:Indoles / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D000072483:Placenta Growth Factor; D011257:Pregnancy Proteins / Q000096:biosynthesis / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics
chemical_list: D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D020100:Hydrogels; D007211:Indoles; D009363:Neoplasm Proteins; C000608036:PGF protein, human; D011257:Pregnancy Proteins; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000072483:Placenta Growth Factor; D000068258:Bevacizumab; D006820:Hyaluronic Acid; C000588866:KDR protein, human; D040281:Vascular Endothelial Growth Factor Receptor-1; D040301:Vascular Endothelial Growth Factor Receptor-2; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; D000077210:Sunitinib
references.citation: Crit Rev Oncol Hematol. 2006 Sep;59(3):181-93
references.pmid: 16860996
references.citation: Eur Cytokine Netw. 2009 Dec;20(4):158-63
references.pmid: 20167554
references.citation: BMC Cancer. 2010 Jun 02;10:252
references.pmid: 20525214
references.citation: Mol Cell Endocrinol. 2000 Dec 22;170(1-2):197-209
references.pmid: 11162903
references.citation: FEBS J. 2013 May;280(10):2399-417
references.pmid: 23281850
references.citation: Eur J Cancer. 1992;28A(6-7):1129-34
references.pmid: 1378293
references.citation: N Engl J Med. 1971 Nov 18;285(21):1182-6
references.pmid: 4938153
references.citation: N Engl J Med. 2008 Jul 31;359(5):492-507
references.pmid: 18669428
references.citation: Target Oncol. 2010 Sep;5(3):175-81
references.pmid: 20820929
references.citation: Clin Cancer Res. 2007 Feb 15;13(4):1253-9
references.pmid: 17317837
references.citation: J Oncol. 2010;2010:251231
references.pmid: 20414333
references.citation: Glia. 2011 Aug;59(8):1205-12
references.pmid: 21351155
references.citation: J Clin Oncol. 2009 Oct 1;27(28):4733-40
references.pmid: 19720927
references.citation: Glia. 2009 Dec;57(16):1716-26
references.pmid: 19373935
references.citation: Acta Biomater. 2008 Mar;4(2):256-63
references.pmid: 17936097
references.citation: BMC Cancer. 2013 May 07;13:229
references.pmid: 23651517
references.citation: Neurology. 2011 Jan 4;76(1):87-93
references.pmid: 21205697
references.citation: Acta Neuropathol. 2012 Dec;124(6):763-75
references.pmid: 23143192
references.citation: Urol Int. 2011;86(1):95-101
references.pmid: 21212629
references.citation: Expert Opin Ther Targets. 2009 Apr;13(4):455-68
references.pmid: 19335067
references.citation: Mol Biol Cell. 2010 Mar 1;21(5):687-90
references.pmid: 20185770
references.citation: Proc Natl Acad Sci U S A. 2011 Mar 1;108(9):3749-54
references.pmid: 21321221
references.citation: Nat Rev Mol Cell Biol. 2006 May;7(5):359-71
references.pmid: 16633338
references.citation: Cancer Res. 2009 Oct 15;69(20):7905-10
references.pmid: 19826039
references.citation: Q J Nucl Med Mol Imaging. 2012 Apr;56(2):103-11
references.pmid: 22617234
references.citation: Blood. 2001 Sep 15;98(6):1904-13
references.pmid: 11535528
references.citation: N Engl J Med. 2001 Jan 11;344(2):114-23
references.pmid: 11150363
references.citation: J Natl Cancer Inst. 2007 Nov 7;99(21):1583-93
references.pmid: 17971532
references.citation: Clin Cancer Res. 2012 Jul 15;18(14):3750-61
references.pmid: 22547772
references.citation: J Neurooncol. 2011 Aug;104(1):103-12
references.pmid: 21308397
references.citation: Histochem Cell Biol. 2008 Oct;130(4):635-53
references.pmid: 18696101
references.citation: Brain Tumor Pathol. 2010 Oct;27(2):89-94
references.pmid: 21046310
references.citation: J Cell Mol Med. 2008 Jan-Feb;12(1):111-25
references.pmid: 18031298
references.citation: Lancet Oncol. 2009 May;10(5):459-66
references.pmid: 19269895
references.citation: Cancer Lett. 2011 Oct 28;309(2):145-50
references.pmid: 21683519
references.citation: J Cell Biol. 2005 May 23;169(4):681-91
references.pmid: 15911882
references.citation: Acta Neuropathol. 2003 Jan;105(1):49-57
references.pmid: 12471461
references.citation: Neurotherapeutics. 2009 Jul;6(3):447-57
references.pmid: 19560735
references.citation: Neuro Oncol. 2010 Mar;12(3):233-42
references.pmid: 20167811
references.citation: Clin Cancer Res. 2008 Oct 15;14(20):6371-5
references.pmid: 18927275
references.citation: Dev Cell. 2007 Feb;12(2):181-94
references.pmid: 17276337
references.citation: Clin Cancer Res. 2009 Jul 15;15(14):4589-99
references.pmid: 19567589
references.citation: Glia. 2012 Mar;60(3):502-14
references.pmid: 22379614
references.citation: Matrix Biol. 2004 Jun;23(3):183-93
references.pmid: 15296946
references.citation: Biochem Biophys Res Commun. 2005 Jul 29;333(2):328-35
references.pmid: 15961063
references.citation: Cancer Lett. 2006 May 8;236(1):39-45
references.pmid: 15967572
references.citation: Cell Mol Life Sci. 2007 Feb;64(4):458-78
references.pmid: 17260089
references.citation: Cell. 2007 Nov 2;131(3):463-75
references.pmid: 17981115
references.citation: Cell Cycle. 2008 Aug 15;7(16):2553-61
references.pmid: 18719373
references.citation: Trends Neurosci. 2012 Sep;35(9):546-56
references.pmid: 22683220
references.citation: Semin Cancer Biol. 2009 Oct;19(5):338-43
references.pmid: 19481151
references.citation: Br J Cancer. 2011 Apr 12;104(8):1270-7
references.pmid: 21407219
references.citation: FEBS Lett. 1987 May 25;216(1):35-9
references.pmid: 3108033
references.citation: Adv Exp Med Biol. 2013;986:121-41
references.pmid: 22879067