Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis

Balveen Kaur, Fatima W. Khwaja, Eric A. Severson, Shannon L. Matheny, Daniel J. Brat, Erwin G. Van Meir*

*Corresponding author for this work

Research output: Contribution to journalReview article

425 Scopus citations

Abstract

Glioblastomas, like other solid tumors, have extensive areas of hypoxia and necrosis. The importance of hypoxia in driving tumor growth is receiving increased attention. Hypoxia-inducible factor 1 (HIF-1) is one of the master regulators that orchestrate the cellular responses to hypoxia. It is a heterodimeric transcription factor composed of α and β subunits. The α subunit is stable in hypoxic conditions but is rapidly degraded in normoxia. The function of HIF-1 is also modulated by several molecular mechanisms that regulate its synthesis, degradation, and transcriptional activity. Upon stabilization or activation, HIF-1 translocates to the nucleus and induces transcription of its downstream target genes. Most important to gliomagenesis, HIF-1 is a potent activator of angiogenesis and invasion through its upregulation of target genes critical for these functions. Activation of the HIF-1 pathway is a common feature of gliomas and may explain the intense vascular hyperplasia. often seen in glioblastoma multiforme. Activation of HIF results in the activation of vascular endothelial growth factors, vascular endothelial growth factor receptors, matrix metalloproteinases, plasminogen activator inhibitor, transforming growth factors α and β, angiopoietin and Tie receptors, endothelin-1, inducible nitric oxide synthase, adrenomedullin, and erythropoietin, which all affect glioma angiogenesis. In conclusion, HIF is a critical regulatory factor in the tumor microenvironment because of its central role in promoting proangiogenic and invasive properties. While HIF activation strongly promotes angiogenesis, the emerging vasculature is often abnormal, leading to a vicious cycle that causes further hypoxia and HIF upregulation.

Original languageEnglish (US)
Pages (from-to)134-153
Number of pages20
JournalNeuro-Oncology
Volume7
Issue number2
DOIs
StatePublished - Apr 2005

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Clinical Neurology

Fingerprint Dive into the research topics of 'Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis'. Together they form a unique fingerprint.

  • Cite this

    Kaur, B., Khwaja, F. W., Severson, E. A., Matheny, S. L., Brat, D. J., & Van Meir, E. G. (2005). Hypoxia and the hypoxia-inducible-factor pathway in glioma growth and angiogenesis. Neuro-Oncology, 7(2), 134-153. https://doi.org/10.1215/S1152851704001115