title: A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha.
abstract: Glioma growth and progression depend on a specialized subpopulation of tumour cells, termed tumour stem cells. Thus, tumour stem cells represent a critical therapeutic target, but the molecular mechanisms that regulate them are poorly understood. Hypoxia plays a key role in tumour progression and in this study we provide evidence that the hypoxic tumour microenvironment also controls tumour stem cells. We define a detailed molecular signature of tumour stem cell genes, which are overexpressed by tumour cells in vascular and perinecrotic/hypoxic niches. Mechanistically, we show that hypoxia plays a key role in the regulation of the tumour stem cell phenotype through hypoxia-inducible factor 2alpha and subsequent induction of specific tumour stem cell signature genes, including mastermind-like protein 3 (Notch pathway), nuclear factor of activated T cells 2 (calcineurin pathway) and aspartate beta-hydroxylase domain-containing protein 2. Notably, a number of these genes belong to pathways regulating the stem cell phenotype. Consistently, tumour stem cell signature genes are overexpressed in newly formed gliomas and are associated with worse clinical prognosis. We propose that tumour stem cells are maintained within a hypoxic niche, providing a functional link between the well-established role of hypoxia in stem cell and tumour biology. The identification of molecular regulators of tumour stem cells in the hypoxic niche points to specific signalling mechanisms that may be used to target the glioblastoma stem cell population.
authors.affiliation: Institute of Neuropathology, Justus Liebig University, Arndtsr. 16, Giessen, Germany.
authors.forename: Sascha
authors.initials: S
authors.lastname: Seidel
authors.forename: Boyan K
authors.initials: BK
authors.lastname: Garvalov
authors.forename: Valtteri
authors.initials: V
authors.lastname: Wirta
authors.forename: Louise
authors.initials: L
authors.lastname: von Stechow
authors.forename: Anne
authors.initials: A
authors.lastname: Schänzer
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Meletis
authors.forename: Marietta
authors.initials: M
authors.lastname: Wolter
authors.forename: Daniel
authors.initials: D
authors.lastname: Sommerlad
authors.forename: Anne-Theres
authors.initials: AT
authors.lastname: Henze
authors.forename: Monica
authors.initials: M
authors.lastname: Nistér
authors.forename: Guido
authors.initials: G
authors.lastname: Reifenberger
authors.forename: Joakim
authors.initials: J
authors.lastname: Lundeberg
authors.forename: Jonas
authors.initials: J
authors.lastname: Frisén
authors.forename: Till
authors.initials: T
authors.lastname: Acker
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques / Q000379:methods; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1