Advanced

Hypoxia, pseudohypoxia and cellular differentiation

Mohlin, Sofie LU ; Wigerup, Caroline LU ; Jögi, Annika LU and Påhlman, Sven LU (2017) In Experimental Cell Research 356(2). p.192-196
Abstract

Tumor hypoxia correlates to aggressive disease, and while this is explained by a variety of factors, one clue to understand this phenomena was the finding that hypoxia induces a de-differentiated, stem cell-like phenotype in neuroblastoma and breast tumor cells. The hypoxia inducible transcription factors (HIFs) are regulated at the translational level by fluctuating oxygen concentrations, but emerging data reveal that both HIF-1α and HIF-2α expression can be induced by aberrantly activated growth factor signaling independently of oxygen levels. Furthermore, HIF-2α is regulated by hypoxia also at the transcriptional level in neuroblastoma and glioma cells. In cultured tumor cells, HIF-2α is stabilized at physiological oxygen... (More)

Tumor hypoxia correlates to aggressive disease, and while this is explained by a variety of factors, one clue to understand this phenomena was the finding that hypoxia induces a de-differentiated, stem cell-like phenotype in neuroblastoma and breast tumor cells. The hypoxia inducible transcription factors (HIFs) are regulated at the translational level by fluctuating oxygen concentrations, but emerging data reveal that both HIF-1α and HIF-2α expression can be induced by aberrantly activated growth factor signaling independently of oxygen levels. Furthermore, HIF-2α is regulated by hypoxia also at the transcriptional level in neuroblastoma and glioma cells. In cultured tumor cells, HIF-2α is stabilized at physiological oxygen concentrations followed by induced expression of classical hypoxia-driven genes, resulting in a pseudohypoxic phenotype. In addition, in neuroblastoma and glioma specimens, a small subset of HIF-2α positive, HIF-1α negative, tumor cells is found adjacent to blood vessels, i.e. in areas with presumably adequate oxygenation. These tumor niches are thus pseudohypoxic, and the HIF-2α expressing cells present immature features. We have postulated that this niche in neuroblastomas encompass the tumor stem cells. Oncogenes or tumor suppressor genes associated with pseudohypoxia are frequently mutated or deleted in the germline, implicating that the pseudohypoxic phenotype indeed is tumorigenic. In summary, the hypoxic and pseudohypoxic phenotypes of solid tumors are attractive therapeutic targets.

(Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Breast cancer, Cancer stem cells, De-differentiation, Hypoxia, Neuroblastoma, Paraganglioma, Pheochromocytoma, Pseudo-hypoxia
in
Experimental Cell Research
volume
356
issue
2
pages
5 pages
publisher
Academic Press
external identifiers
  • scopus:85014838356
  • wos:000404318600014
ISSN
0014-4827
DOI
10.1016/j.yexcr.2017.03.007
language
English
LU publication?
yes
id
7284debc-71fe-48be-8881-ba82328539b3
date added to LUP
2017-07-26 11:08:25
date last changed
2018-05-13 04:33:58
@article{7284debc-71fe-48be-8881-ba82328539b3,
  abstract     = {<p>Tumor hypoxia correlates to aggressive disease, and while this is explained by a variety of factors, one clue to understand this phenomena was the finding that hypoxia induces a de-differentiated, stem cell-like phenotype in neuroblastoma and breast tumor cells. The hypoxia inducible transcription factors (HIFs) are regulated at the translational level by fluctuating oxygen concentrations, but emerging data reveal that both HIF-1α and HIF-2α expression can be induced by aberrantly activated growth factor signaling independently of oxygen levels. Furthermore, HIF-2α is regulated by hypoxia also at the transcriptional level in neuroblastoma and glioma cells. In cultured tumor cells, HIF-2α is stabilized at physiological oxygen concentrations followed by induced expression of classical hypoxia-driven genes, resulting in a pseudohypoxic phenotype. In addition, in neuroblastoma and glioma specimens, a small subset of HIF-2α positive, HIF-1α negative, tumor cells is found adjacent to blood vessels, i.e. in areas with presumably adequate oxygenation. These tumor niches are thus pseudohypoxic, and the HIF-2α expressing cells present immature features. We have postulated that this niche in neuroblastomas encompass the tumor stem cells. Oncogenes or tumor suppressor genes associated with pseudohypoxia are frequently mutated or deleted in the germline, implicating that the pseudohypoxic phenotype indeed is tumorigenic. In summary, the hypoxic and pseudohypoxic phenotypes of solid tumors are attractive therapeutic targets.</p>},
  author       = {Mohlin, Sofie and Wigerup, Caroline and Jögi, Annika and Påhlman, Sven},
  issn         = {0014-4827},
  keyword      = {Breast cancer,Cancer stem cells,De-differentiation,Hypoxia,Neuroblastoma,Paraganglioma,Pheochromocytoma,Pseudo-hypoxia},
  language     = {eng},
  month        = {07},
  number       = {2},
  pages        = {192--196},
  publisher    = {Academic Press},
  series       = {Experimental Cell Research},
  title        = {Hypoxia, pseudohypoxia and cellular differentiation},
  url          = {http://dx.doi.org/10.1016/j.yexcr.2017.03.007},
  volume       = {356},
  year         = {2017},
}