The HIF-2alpha-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization.

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Cellular adaptation to diminished tissue oxygen tensions, hypoxia, is largely governed by the hypoxia inducible transcription factors, HIF-1 and HIF-2. Tumor hypoxia and high HIF protein levels are frequently associated with aggressive disease. In recent years, high tumor cell levels of HIF-2 and the oxygen sensitive subunit HIF-2alpha have been associated with unfavorable disease and shown to be highly expressed in tumor stem/initiating cells originating from neuroblastoma and glioma, respectively. In these cells, HIF-2 is active under nonhypoxic conditions as well, creating a pseudo-hypoxic phenotype with clear influence on tumor behavior. Neuroblastoma tumor initiating cells are immature with a neural crest-like phenotype and downregulation of HIF-2alpha in these cells results in neuronal sympathetic differentiation and the cells become phenotypically similar to the bulk of neuroblastoma cells found in clinical specimens. Knockdown of HIF-2alpha in neuroblastoma and glioma tumor stem/initiating cells leads to reduced levels of VEGF and poorly vascularized, highly necrotic tumors. As high HIF-2alpha expression further correlates with disseminated disease as demonstrated in neuroblastoma, glioma, and breast carcinoma, we propose that targeting HIF-2alpha and/or the pseudo-hypoxic phenotype induced by HIF-2 under normoxic conditions has great clinical potential.
Original languageEnglish
Title of host publicationDiverse Effects of Hypoxia on Tumor Progression
EditorsM. Celeste Simon
ISBN (Electronic)978-3-642-13329-9
ISBN (Print)978-3-642-13328-2
Publication statusPublished - 2010

Publication series

NameCurrent Topics in Microbiology and Immunology
ISSN (Print)0070-217X

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Molecular Medicine (013031200)

Subject classification (UKÄ)

  • Cancer and Oncology


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