title: Metalloproteinases ADAM10 and ADAM17 Mediate Migration and Differentiation in Glioblastoma Sphere-Forming Cells.
abstract: Glioblastoma is the most common form of primary malignant brain tumour. These tumours are highly proliferative and infiltrative resulting in a median patient survival of only 14 months from diagnosis. The current treatment regimens are ineffective against the small population of cancer stem cells residing in the tumourigenic niche; however, a new therapeutic approach could involve the removal of these cells from the microenvironment that maintains the cancer stem cell phenotype. We have isolated multipotent sphere-forming cells from human high grade glioma (glioma sphere-forming cells (GSCs)) to investigate the adhesive and migratory properties of these cells in vitro. We have focused on the role of two closely related metalloproteinases ADAM10 and ADAM17 due to their high expression in glioblastoma and GSCs and their ability to activate cytokines and growth factors. Here, we report that ADAM10 and ADAM17 inhibition selectively increases GSC, but not neural stem cell, migration and that the migrated GSCs exhibit a differentiated phenotype. We also observed a correlation between nestin, a stem/progenitor marker, and fibronectin, an extracellular matrix protein, expression in high grade glioma tissues. GSCs adherence on fibronectin is mediated by α5β1 integrin, where fibronectin further promotes GSC migration and is an effective candidate for in vivo cancer stem cell migration out of the tumourigenic niche. Our results suggest that therapies against ADAM10 and ADAM17 may promote cancer stem cell migration away from the tumourigenic niche resulting in a differentiated phenotype that is more susceptible to treatment.
authors.affiliation: Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. ejs304@soton.ac.uk.|Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK. ejs304@soton.ac.uk.|Southampton General Hospital, LF51, South Laboratory Block, Southampton, SO16 6YD, UK. ejs304@soton.ac.uk.
authors.forename: Elodie J
authors.initials: EJ
authors.lastname: Siney
authors.affiliation: Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
authors.forename: Alexander
authors.initials: A
authors.lastname: Holden
authors.affiliation: Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Casselden
authors.affiliation: Wessex Neurological Centre, University Hospital Southampton, Southampton, SO16 6YD, UK.
authors.forename: Harry
authors.initials: H
authors.lastname: Bulstrode
authors.affiliation: Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Thomas
authors.affiliation: Clinical Neurosciences, Faculty of Medicine, University of Southampton, Southampton, SO16 6YD, UK.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Willaime-Morawek
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism*; D000072198:ADAM17 Protein / Q000378:metabolism*; D000328:Adult; D000368:Aged; D016923:Cell Death / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D005109:Extracellular Matrix / Q000648:ultrastructure; D005260:Female; D005353:Fibronectins / Q000494:pharmacology; D005909:Glioblastoma / Q000473:pathology; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors / Q000494:pharmacology; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000473:pathology; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D018874:Spheroids, Cellular / Q000378:metabolism*
chemical_list: D005353:Fibronectins; D039081:Integrin alpha5beta1; D061965:Matrix Metalloproteinase Inhibitors; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein
keywords: Cancer stem cell; Cell differentiation; Cell migration; Disintegrin; Extracellular matrix; Glioma