title: Adult mouse subventricular zones stimulate glioblastoma stem cells specific invasion through CXCL12/CXCR4 signaling.
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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Taken together, these data demonstrate the significant role of the CXCL12/CXCR4 signaling in this original model of brain cancer invasion.
authors.affiliation: 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.).
authors.forename: Nicolas
authors.initials: N
authors.lastname: Goffart
authors.affiliation: 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.).
authors.forename: Jérôme
authors.initials: J
authors.lastname: Kroonen
authors.affiliation: 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.).
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Di Valentin
authors.affiliation: 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.).
authors.forename: Matthias
authors.initials: M
authors.lastname: Dedobbeleer
authors.affiliation: 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.).
authors.forename: Alexandre
authors.initials: A
authors.lastname: Denne
authors.affiliation: 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.).
authors.forename: Philippe
authors.initials: P
authors.lastname: Martinive
authors.affiliation: 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.).
authors.forename: Bernard
authors.initials: B
authors.lastname: Rogister
mesh_terms: D000818:Animals; D001596:Benzylamines; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D054377:Chemokine CXCL12 / Q000378:metabolism*; D000080027:Cyclams; D004195:Disease Models, Animal; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006571:Heterocyclic Compounds / Q000494:pharmacology; D006801:Humans; D020547:Lateral Ventricles / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000503:physiopathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D001596:Benzylamines; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; C088327:plerixafor
keywords: CXCL12; cancer stem cells; invasion; stem cell microenvironment
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