title: Short-Term Differentiation of Glioblastoma Stem Cells Induces Hypoxia Tolerance.
abstract: Glioblastoma is the most common and malignant brain cancer. In spite of surgical removal, radiation and chemotherapy, this cancer recurs within short time and median survival after diagnosis is less than a year. Glioblastoma stem cells (GSCs) left in the brain after surgery is thought to explain the inevitable recurrence of the tumor. Although hypoxia is a prime factor contributing to treatment resistance in many cancers, its effect on GSC has been little studied. Especially how differentiation influences the tolerance to acute hypoxia in GSCs is not well explored. We cultured GSCs from three patient biopsies and exposed these and their differentiated (1- and 4-weeks) progeny to acute hypoxia while monitoring intracellular calcium and mitochondrial membrane potential (ΔΨm). Undifferentiated GSCs were not hypoxia tolerant, showing both calcium overload and mitochondrial depolarization. One week differentiated cells were the most tolerant to hypoxia, preserving intracellular calcium stability and ΔΨm during 15 min of acute hypoxia. After 4 weeks of differentiation, mitochondrial mass was significantly reduced. In these cells calcium homeostasis was maintained during hypoxia, although the mitochondria were depolarized, suggesting a reduced mitochondrial dependency. Basal metabolic rate increased by differentiation, however, low oxygen consumption and high ΔΨm in undifferentiated GSCs did not provide hypoxia tolerance. The results suggest that undifferentiated GSCs are oxygen dependent, and that limited differentiation induces relative hypoxia tolerance. Hypoxia tolerance may be a factor involved in high-grade malignancy. This warrants a careful approach to differentiation as a glioblastoma treatment strategy.
authors.affiliation: Vilhelm Magnus Laboratory for Neurosurgical Research, Department of Neurosurgery and Institute for Surgical Research, Oslo University Hospital, Oslo, Norway. havard@skjellegrind.no.
authors.forename: Håvard K
authors.initials: HK
authors.lastname: Skjellegrind
authors.affiliation: Vilhelm Magnus Laboratory for Neurosurgical Research, Department of Neurosurgery and Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Artem
authors.initials: A
authors.lastname: Fayzullin
authors.affiliation: Center for Eye Research, Department of Ophthalmology, Oslo University Hospital, Oslo, Norway.
authors.forename: Erik O
authors.initials: EO
authors.lastname: Johnsen
authors.affiliation: Department of Medical Biochemistry, University of Oslo, Oslo, Norway.
authors.forename: Lars
authors.initials: L
authors.lastname: Eide
authors.affiliation: Vilhelm Magnus Laboratory for Neurosurgical Research, Department of Neurosurgery and Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Iver A
authors.initials: IA
authors.lastname: Langmoen
authors.affiliation: Center for Eye Research, Department of Ophthalmology, Oslo University Hospital, Oslo, Norway.
authors.forename: Morten C
authors.initials: MC
authors.lastname: Moe
authors.affiliation: Vilhelm Magnus Laboratory for Neurosurgical Research, Department of Neurosurgery and Institute for Surgical Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Einar O
authors.initials: EO
authors.lastname: Vik-Mo
mesh_terms: D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014407:Tumor Cells, Cultured
keywords: Anoxia; Brain cancer stem cell; Differentiation; GSC; Glioblastoma; Hypoxia tolerance