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A hypoxic niche regulates glioblastoma stem cells through hypoxia inducible factor 2 alpha
KTH, School of Biotechnology (BIO), Gene Technology.ORCID iD: 0000-0003-3811-5439
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2010 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 133, 983-995 p.Article in journal (Refereed) Published
Abstract [en]

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 2 alpha 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.

Place, publisher, year, edition, pages
2010. Vol. 133, 983-995 p.
Keyword [en]
tumour stem cells, side population, glioblastoma, hypoxia, hypoxia inducible factor, hypoxic niche
National Category
Cell and Molecular Biology
URN: urn:nbn:se:kth:diva-28237DOI: 10.1093/brain/awq042ISI: 000277225600006OAI: diva2:389404
Swedish Research Council
QC 20110119Available from: 2011-01-19 Created: 2011-01-12 Last updated: 2011-01-19Bibliographically approved

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Wirta, ValtteriLundeberg, Joakim
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