Journal of Neuro-Oncology

, Volume 78, Issue 3, pp 233–247

Inhibition of hypoxia inducible factor-1α (HIF-1α) decreases vascular endothelial growth factor (VEGF) secretion and tumor growth in malignant gliomas

Authors

    • Department of NeurosurgeryUniversity of Utah
    • Huntsman Cancer Institute,University of Utah
    • Department of NeurosurgeryUniversity of Utah
  • Brian T. Ragel
    • Department of NeurosurgeryUniversity of Utah
  • Kum Whang
    • Huntsman Cancer Institute,University of Utah
    • Yonsei University, Wonju College of Medicine
  • David Gillespie
    • Department of NeurosurgeryUniversity of Utah
    • Huntsman Cancer Institute,University of Utah
Laboratory Investigation

DOI: 10.1007/s11060-005-9103-z

Cite this article as:
Jensen, R.L., Ragel, B.T., Whang, K. et al. J Neurooncol (2006) 78: 233. doi:10.1007/s11060-005-9103-z

Summary

Introduction

Hypoxia inducible factor-1α (HIF-1α) regulates vascular endothelial growth factor (VEGF), the presumed principal mediator of angiogenesis in malignant gliomas, under normal physiologic conditions. We examined the effect of HIF-1α on VEGF secretion, tumor growth, and angiogenesis in malignant gliomas.

Methods

We examined 175 human gliomas for expression of HIF-1α and its downstream-regulated proteins. HIF-1α expression and VEGF secretion in glioma cell lines under normoxia and hypoxia were examined using␣ELISA and Western blot. Malignant glioma cell lines were transfected with dominant-negative HIF-1α (DN-HIF-1α) expression vector or siRNA constructs against the HIF-1α gene. Growth studies were conducted on cells with the highest VEGF/HIF-1α inhibition isolated from stable transfected cell lines. MIB-1-labeling index and microvascular density (MVD) measurements were performed on the in vivo tumors.

Results

HIF-1 expression correlates with malignant glioma phenotype and was not confined to perinecrotic, pseudopalisading cells. VEGF and HIF-1 expression was high in glioma cell lines even under normoxia, and increased after exposure to hypoxia or growth factor stimulation. Cells transfected with DN-HIF-1α or HIF-1α siRNA demonstrated decreased HIF-1α and VEGF secretion. In vivo but not in vitro growth decreased in response to VEGF and HIF-1 inhibition. HIF-1 siRNA studies showed decreased VEGF secretion and in vitro and in vivo growth of glioma cell lines. MVD was unchanged but MIB-1 proliferation index decreased for both types of HIF-1 inhibition.

Conclusions

VEGF and HIF-1α are elevated in malignant gliomas. HIF-1α inhibition results in VEGF secretion inhibition. HIF-1α expression affects glioma tumor growth, suggesting clinical applications for malignant glioma treatment.

Keywords

angiogenesisbrain tumorglioblastoma multiformehypoxia inducible factorsiRNAvascular endothelial growth factor

Copyright information

© Springer Science+Business Media, Inc. 2006