title: Evidence for label-retaining tumour-initiating cells in human glioblastoma.
abstract: Individual tumour cells display diverse functional behaviours in terms of proliferation rate, cell-cell interactions, metastatic potential and sensitivity to therapy. Moreover, sequencing studies have demonstrated surprising levels of genetic diversity between individual patient tumours of the same type. Tumour heterogeneity presents a significant therapeutic challenge as diverse cell types within a tumour can respond differently to therapies, and inter-patient heterogeneity may prevent the development of general treatments for cancer. One strategy that may help overcome tumour heterogeneity is the identification of tumour sub-populations that drive specific disease pathologies for the development of therapies targeting these clinically relevant sub-populations. Here, we have identified a dye-retaining brain tumour population that displays all the hallmarks of a tumour-initiating sub-population. Using a limiting dilution transplantation assay in immunocompromised mice, label-retaining brain tumour cells display elevated tumour-initiation properties relative to the bulk population. Importantly, tumours generated from these label-retaining cells exhibit all the pathological features of the primary disease. Together, these findings confirm dye-retaining brain tumour cells exhibit tumour-initiation ability and are therefore viable targets for the development of therapeutics targeting this sub-population.
authors.affiliation: McKnight Brain Institute, Department of Neurosurgery, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Loic P
authors.initials: LP
authors.lastname: Deleyrolle
authors.forename: Angus
authors.initials: A
authors.lastname: Harding
authors.forename: Kathleen
authors.initials: K
authors.lastname: Cato
authors.forename: Florian A
authors.initials: FA
authors.lastname: Siebzehnrubl
authors.forename: Maryam
authors.initials: M
authors.lastname: Rahman
authors.forename: Hassan
authors.initials: H
authors.lastname: Azari
authors.forename: Sarah
authors.initials: S
authors.lastname: Olson
authors.forename: Brian
authors.initials: B
authors.lastname: Gabrielli
authors.forename: Geoffrey
authors.initials: G
authors.lastname: Osborne
authors.forename: Angelo
authors.initials: A
authors.lastname: Vescovi
authors.forename: Brent A
authors.initials: BA
authors.lastname: Reynolds
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D005452:Fluoresceins / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007381:Intermediate Filament Proteins / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D064111:Minichromosome Maintenance Complex Component 2; D009368:Neoplasm Transplantation / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D064231:Nestin; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000378:metabolism; D019081:O Antigens / Q000378:metabolism; D013388:Succinimides / Q000378:metabolism
chemical_list: C087165:5-(6)-carboxyfluorescein diacetate succinimidyl ester; D015703:Antigens, CD; D018797:Cell Cycle Proteins; D005452:Fluoresceins; D005904:Glial Fibrillary Acidic Protein; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D009687:Nuclear Proteins; D019081:O Antigens; D013388:Succinimides; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2