Nicolas Goffart1, Jérôme Kroonen1, Emmanuel Di Valentin1, Matthias Dedobbeleer1, Alexandre Denne1, Philippe Martinive1, Bernard Rogister1. 1. Laboratory of Developmental Neurobiology, GIGA-Neurosciences Research Center, University of Liège, Liège, Belgium (N.G., A.D., M.D., B.R.); Human Genetics, CHU and University of Liège, Liège, Belgium (J.K.); The T&P Bohnenn Laboratory for Neuro-Oncology, Department of Neurosurgery, University Medical Center Utrecht, Utrecht, The Netherlands (J.K.); GIGA-Viral Vector Platform, University of Liège, Liège, Belgium (E.D.V.); Unit of Radiology and Radiotherapy, CHU and University of Liège, Liège, Belgium (P.M.); Department of Neurology, CHU and University of Liège, Liège, Belgium (B.R.); GIGA-Development, Stem Cells and Regenerative Medicine, University of Liège, Liège, Belgium (B.R.).
Abstract
BACKGROUND: Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months. This catastrophic survival rate is the consequence of systematic relapses that could arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. We previously demonstrated that GSCs are able to escape the tumor mass and specifically colonize the adult subventricular zones (SVZs) after transplantation. This specific localization, away from the initial injection site, therefore represents a high-quality model of a clinical obstacle to therapy and relapses because GSCs notably retain the ability to form secondary tumors. METHOD: In this work, we questioned the role of the CXCL12/CXCR4 signaling in the GSC-specific invasion of the SVZs. RESULTS: We demonstrated that both receptor and ligand are respectively expressed by different GBM cell populations and by the SVZ itself. In vitro migration bio-assays highlighted that human U87MG GSCs isolated from the SVZs (U87MG-SVZ) display stronger migratory abilities in response to recombinant CXCL12 and/or SVZ-conditioned medium (SVZ-CM) compared with cancer cells isolated from the tumor mass (U87MG-TM). Moreover, in vitro inhibition of the CXCR4 signaling significantly decreased the U87MG-SVZ cell migration in response to the SVZ-CM. Very interestingly, treating U87MG-xenografted mice with daily doses of AMD3100, a specific CXCR4 antagonist, prevented the specific invasion of the SVZ. Another in vivo experiment, using CXCR4-invalidated GBM cells, displayed similar results. CONCLUSION: Taken together, these data demonstrate the significant role of the CXCL12/CXCR4 signaling in this original model of brain cancer invasion.
BACKGROUND:Patients with glioblastoma multiforme (GBM) have an overall median survival of 15 months. This catastrophic survival rate is the consequence of systematic relapses that could arise from remaining glioblastoma stem cells (GSCs) left behind after surgery. We previously demonstrated that GSCs are able to escape the tumor mass and specifically colonize the adult subventricular zones (SVZs) after transplantation. This specific localization, away from the initial injection site, therefore represents a high-quality model of a clinical obstacle to therapy and relapses because GSCs notably retain the ability to form secondary tumors. METHOD: In this work, we questioned the role of the CXCL12/CXCR4 signaling in the GSC-specific invasion of the SVZs. RESULTS: We demonstrated that both receptor and ligand are respectively expressed by different GBM cell populations and by the SVZ itself. In vitro migration bio-assays highlighted that human U87MG GSCs isolated from the SVZs (U87MG-SVZ) display stronger migratory abilities in response to recombinant CXCL12 and/or SVZ-conditioned medium (SVZ-CM) compared with cancer cells isolated from the tumor mass (U87MG-TM). Moreover, in vitro inhibition of the CXCR4 signaling significantly decreased the U87MG-SVZ cell migration in response to the SVZ-CM. Very interestingly, treating U87MG-xenografted mice with daily doses of AMD3100, a specific CXCR4 antagonist, prevented the specific invasion of the SVZ. Another in vivo experiment, using CXCR4-invalidated GBM cells, displayed similar results. CONCLUSION: Taken together, these data demonstrate the significant role of the CXCL12/CXCR4 signaling in this original model of brain cancer invasion.
Authors: Justin D Lathia; Joseph Gallagher; John M Heddleston; Jialiang Wang; Christine E Eyler; Jennifer Macswords; Qiulian Wu; Amit Vasanji; Roger E McLendon; Anita B Hjelmeland; Jeremy N Rich Journal: Cell Stem Cell Date: 2010-05-07 Impact factor: 24.633
Authors: Yi Chieh Lim; Tara L Roberts; Bryan W Day; Angus Harding; Sergei Kozlov; Amanda W Kijas; Kathleen S Ensbey; David G Walker; Martin F Lavin Journal: Mol Cancer Ther Date: 2012-07-06 Impact factor: 6.261
Authors: Jérôme Kroonen; Jessica Nassen; Yves-Gautier Boulanger; Fabian Provenzano; Valérie Capraro; Vincent Bours; Didier Martin; Manuel Deprez; Pierre Robe; Bernard Rogister Journal: Int J Cancer Date: 2010-11-23 Impact factor: 7.396
Authors: M J Dugan; R T Maziarz; W I Bensinger; A Nademanee; J Liesveld; K Badel; C Dehner; C Gibney; G Bridger; G Calandra Journal: Bone Marrow Transplant Date: 2009-06-01 Impact factor: 5.483
Authors: Jean-Pierre Gagner; Yasmeen Sarfraz; Valerio Ortenzi; Fawaz M Alotaibi; Luis A Chiriboga; Awab T Tayyib; Garry J Douglas; Eric Chevalier; Barbara Romagnoli; Gérald Tuffin; Michel Schmitt; Guillaume Lemercier; Klaus Dembowsky; David Zagzag Journal: Am J Pathol Date: 2017-07-20 Impact factor: 4.307
Authors: Akshitkumar M Mistry; Michael C Dewan; Gabrielle A White-Dzuro; Philip R Brinson; Kyle D Weaver; Reid C Thompson; Rebecca A Ihrie; Lola B Chambless Journal: J Neurooncol Date: 2017-01-10 Impact factor: 4.130
Authors: Jorrit De Waele; Elly Marcq; Jonas Rm Van Audenaerde; Jinthe Van Loenhout; Christophe Deben; Karen Zwaenepoel; Erik Van de Kelft; David Van der Planken; Tomas Menovsky; Johan Mj Van den Bergh; Yannick Willemen; Patrick Pauwels; Zwi N Berneman; Filip Lardon; Marc Peeters; An Wouters; Evelien Lj Smits Journal: Oncoimmunology Date: 2017-12-12 Impact factor: 8.110
Authors: Akshitkumar M Mistry; Andrew T Hale; Lola B Chambless; Kyle D Weaver; Reid C Thompson; Rebecca A Ihrie Journal: J Neurooncol Date: 2016-09-19 Impact factor: 4.130
Authors: Anda-Alexandra Calinescu; Viveka Nand Yadav; Erica Carballo; Padma Kadiyala; Dustin Tran; Daniel B Zamler; Robert Doherty; Maithreyi Srikanth; Pedro Ricardo Lowenstein; Maria Graciela Castro Journal: Clin Cancer Res Date: 2016-08-19 Impact factor: 12.531
Authors: Nicolas Goffart; Arnaud Lombard; François Lallemand; Jérôme Kroonen; Jessica Nassen; Emmanuel Di Valentin; Sharon Berendsen; Matthias Dedobbeleer; Estelle Willems; Pierre Robe; Vincent Bours; Didier Martin; Philippe Martinive; Pierre Maquet; Bernard Rogister Journal: Neuro Oncol Date: 2016-07-01 Impact factor: 12.300