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

Pietras, Alexander LU ; Mohlin, Sofie LU and Påhlman, Sven LU (2010) In Current Topics in Microbiology and Immunology 345. p.1-20
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Chapter in Book/Report/Conference proceeding
publication status
published
subject
in
Current Topics in Microbiology and Immunology
editor
Celeste Simon, M. and
volume
345
pages
1 - 20
publisher
Springer Berlin Heidelberg
external identifiers
  • wos:000282105100001
  • pmid:20517717
  • scopus:78349283042
ISSN
0070-217X
ISBN
978-3-642-13329-9
978-3-642-13328-2
DOI
10.1007/82_2010_72
language
English
LU publication?
yes
id
ecf3c49f-5038-4d94-a89d-062e1056050f (old id 1626456)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/20517717?dopt=Abstract
date added to LUP
2010-07-05 10:18:02
date last changed
2018-05-29 11:24:54
@inbook{ecf3c49f-5038-4d94-a89d-062e1056050f,
  abstract     = {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.},
  author       = {Pietras, Alexander and Mohlin, Sofie and Påhlman, Sven},
  editor       = {Celeste Simon, M.},
  isbn         = {978-3-642-13329-9},
  issn         = {0070-217X},
  language     = {eng},
  pages        = {1--20},
  publisher    = {Springer Berlin Heidelberg},
  series       = {Current Topics in Microbiology and Immunology},
  title        = {The HIF-2alpha-Driven Pseudo-Hypoxic Phenotype in Tumor Aggressiveness, Differentiation, and Vascularization.},
  url          = {http://dx.doi.org/10.1007/82_2010_72},
  volume       = {345},
  year         = {2010},
}