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

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RESEARCH PRODUCT

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

Marta Piqueras Samuel Navarro Rosa Noguera Sven Påhlman Erik Fredlund Alexander Pietras Siv Beckman

subject

Male Vascular Endothelial Growth Factor A CD31 Cancer Research Pathology medicine.medical_specialty Biology Models Biological Neovascularization chemistry.chemical_compound In vivo Neoplasms Neuroblastoma Basic Helix-Loop-Helix Transcription Factors medicine Humans Hypoxia Regulation of gene expression Neovascularization Pathologic Infant Cancer Hypoxia-Inducible Factor 1 alpha Subunit medicine.disease Gene Expression Regulation Neoplastic Platelet Endothelial Cell Adhesion Molecule-1 Vascular endothelial growth factor Treatment Outcome HIF1A Oncology chemistry Child Preschool Cancer research Female medicine.symptom

description

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-1α and HIF-2α 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-1α, HIF-2α, 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-1α (P &lt; 0.001) and HIF-2α (P &lt; 0.001) correlated positively to VEGF expression, they did not fully correlate with each other. Moreover, HIF-1α (P = 0.002) and VEGF (P &lt; 0.001), but not HIF-2α, 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-1α 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-1α and HIF-2α suggest that these two proteins are differentially regulated in vivo, thus reflecting distinctive protein expression/stabilization mechanisms. The association between HIF-1α and favorable outcome stresses the importance of discriminating HIF-2α from HIF-1α expression and has implications for using HIFs as treatment targets. (Clin Cancer Res 2009;15(23):7130–6)

year	journal	country	edition	language
2009-11-12	Clinical Cancer Research

https://doi.org/10.1158/1078-0432.ccr-09-0223