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HIF-1{alpha} and HIF-2{alpha} Are Differentially Regulated In vivo in Neuroblastoma: High HIF-1{alpha} Correlates Negatively to Advanced Clinical Stage and Tumor Vascularization.

Noguera, Rosa; Fredlund, Erik LU ; Piqueras, Marta; Pietras, Alexander LU ; Beckman, Siv LU ; Navarro, Samuel and Påhlman, Sven LU (2009) In Clinical Cancer Research 15(23). p.7130-7136
Abstract
PURPOSE: Hypoxia is considered to be a major driving force behind tumor angiogenesis. The stabilization and activation at hypoxia of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha and the concomitant induction of expression of vascular endothelial growth factor (VEGF) and other proangiogenic factors provide a molecular frame for hypoxia-driven tumor angiogenesis. This study has investigated how HIF and VEGF protein levels relate to each other with regard to vascularization, tumor stage, and overall survival in neuroblastoma. EXPERIMENTAL DESIGN: Tissue cores taken from tumor specimens representing 93 children with neuroblastoma were arranged on a microarray and stained for HIF-1alpha, HIF-2alpha, VEGF, and CD31 proteins. Both... (More)
PURPOSE: Hypoxia is considered to be a major driving force behind tumor angiogenesis. The stabilization and activation at hypoxia of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha and the concomitant induction of expression of vascular endothelial growth factor (VEGF) and other proangiogenic factors provide a molecular frame for hypoxia-driven tumor angiogenesis. This study has investigated how HIF and VEGF protein levels relate to each other with regard to vascularization, tumor stage, and overall survival in neuroblastoma. EXPERIMENTAL DESIGN: Tissue cores taken from tumor specimens representing 93 children with neuroblastoma were arranged on a microarray and stained for HIF-1alpha, HIF-2alpha, VEGF, and CD31 proteins. Both fraction of positive cells and staining intensity were evaluated and protein levels were correlated with each other and with clinical variables. RESULTS: Although high levels of both HIF-1alpha (P < 0.001) and HIF-2alpha (P < 0.001) correlated positively to VEGF expression, they did not fully correlate with each other. Moreover, HIF-1alpha (P = 0.002) and VEGF (P < 0.001), but not HIF-2alpha, correlated negatively to vascularization as determined by CD31 staining abundance. VEGF expression or degree of vascularization did not correlate with tumor stage or overall survival. High HIF-1alpha levels correlated with low tumor stage (P < 0.001) and were associated with a favorable patient prognosis (P = 0.08). CONCLUSIONS: The discordant results on expression of HIF-1alpha and HIF-2alpha suggest that these two proteins are differentially regulated in vivo, thus reflecting distinctive protein expression/stabilization mechanisms. The association between HIF-1alpha and favorable outcome stresses the importance of discriminating HIF-2alpha from HIF-1alpha expression and has implications for using HIFs as treatment targets. (Clin Cancer Res 2009;15(23):OF1-7). (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
15
issue
23
pages
7130 - 7136
publisher
American Association for Cancer Research
external identifiers
  • wos:000272363700006
  • pmid:19903792
  • scopus:73149112785
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-09-0223
project
CREATE Health
language
English
LU publication?
yes
id
e85f9a0a-ae29-4ac5-8438-30cf1e0b27c1 (old id 1512079)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19903792?dopt=Abstract
date added to LUP
2009-12-01 15:14:57
date last changed
2017-08-06 03:48:30
@article{e85f9a0a-ae29-4ac5-8438-30cf1e0b27c1,
  abstract     = {PURPOSE: Hypoxia is considered to be a major driving force behind tumor angiogenesis. The stabilization and activation at hypoxia of the hypoxia-inducible factors HIF-1alpha and HIF-2alpha and the concomitant induction of expression of vascular endothelial growth factor (VEGF) and other proangiogenic factors provide a molecular frame for hypoxia-driven tumor angiogenesis. This study has investigated how HIF and VEGF protein levels relate to each other with regard to vascularization, tumor stage, and overall survival in neuroblastoma. EXPERIMENTAL DESIGN: Tissue cores taken from tumor specimens representing 93 children with neuroblastoma were arranged on a microarray and stained for HIF-1alpha, HIF-2alpha, VEGF, and CD31 proteins. Both fraction of positive cells and staining intensity were evaluated and protein levels were correlated with each other and with clinical variables. RESULTS: Although high levels of both HIF-1alpha (P &lt; 0.001) and HIF-2alpha (P &lt; 0.001) correlated positively to VEGF expression, they did not fully correlate with each other. Moreover, HIF-1alpha (P = 0.002) and VEGF (P &lt; 0.001), but not HIF-2alpha, correlated negatively to vascularization as determined by CD31 staining abundance. VEGF expression or degree of vascularization did not correlate with tumor stage or overall survival. High HIF-1alpha levels correlated with low tumor stage (P &lt; 0.001) and were associated with a favorable patient prognosis (P = 0.08). CONCLUSIONS: The discordant results on expression of HIF-1alpha and HIF-2alpha suggest that these two proteins are differentially regulated in vivo, thus reflecting distinctive protein expression/stabilization mechanisms. The association between HIF-1alpha and favorable outcome stresses the importance of discriminating HIF-2alpha from HIF-1alpha expression and has implications for using HIFs as treatment targets. (Clin Cancer Res 2009;15(23):OF1-7).},
  author       = {Noguera, Rosa and Fredlund, Erik and Piqueras, Marta and Pietras, Alexander and Beckman, Siv and Navarro, Samuel and Påhlman, Sven},
  issn         = {1078-0432},
  language     = {eng},
  number       = {23},
  pages        = {7130--7136},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {HIF-1{alpha} and HIF-2{alpha} Are Differentially Regulated In vivo in Neuroblastoma: High HIF-1{alpha} Correlates Negatively to Advanced Clinical Stage and Tumor Vascularization.},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-09-0223},
  volume       = {15},
  year         = {2009},
}