Expression of hypoxia‐inducible factor 1α in tumours of patients with glioblastoma

Abstract

Angiogenesis is a prominent feature of glioblastomas but the mechanisms involved in the control of this process are poorly understood. We have investigated the potential role of a recently described transcription factor, hypoxia-inducible factor 1 (HIF-1), which initiates the transcription of a number of hypoxia-inducible genes, including those encoding vascular endothelial growth factor and its receptors. HIF-1 protein expression was assessed by immunocytochemistry, using a monoclonal antibody to the alpha subunit (HIF-1alpha). HIF-1 mRNA expression was assessed by reverse transcriptase-polymerase chain reaction (RT-PCR) and the ribonuclease protection assay (RPA). Strong nuclear expression of HIF-1alpha protein was seen in the majority of glioblastomas and anaplastic astrocytomas, particularly surrounding areas of necrosis in glioblastomas. In the majority of these tumours upregulation of HIF-1alpha mRNA was also demonstrated, with a significant increase in glioblastomas compared to lower grade tumours. No correlation was found between the presence of HIF-1alpha protein and immunohistochemical expression of p53 protein. These findings are in keeping with an important role of HIF-1alpha in the vascularization of glioblastomas and suggest that upregulation is at least partly at a transcriptional level.

Akt-Dependent Proapoptotic Effects of Dietary Restriction on Late-Stage Management of a Phosphatase and Tensin Homologue/Tuberous Sclerosis Complex 2–Deficient Mouse Astrocytoma

“…These observations agree with evidence that (a) HIF-1a, GLUT1, and PKM2 are constitutively overexpressed in malignant astrocytomas (55,56); (b) reduced PTEN expression and constitutive activation of Akt could potentiate HIF-1a protein stabilization and increase HIF-1a transcription (16,52); and (c) increased HIF-1a expression is associated with the up-regulation of molecules that promote cell growth, glucose uptake, and glycolysis (52,57). Our findings suggest an important role for glucose/IGF-I metabolism in sustaining an elevated level of HIF-1a activity in CT-2A.…”

Regional Hypoxia in Glioblastoma Multiforme Quantified with [18F]Fluoromisonidazole Positron Emission Tomography before Radiotherapy: Correlation with Time to Progression and Survival

“…Other investigators have confirmed up-regulation of HIF1a mRNA in glioblastoma multiforme compared with lower grade lesions and increased nuclear expression of HIF1a protein especially surrounding necrotic areas (44). The failure of our survey of the immunocytochemical variables to show significant correlations with HV or T/B max could be the result of the small sample size (n = 19) or the specimens being collected without attention to location in relation to the FMISO distribution.…”

Prominent Microvascular Proliferation in Clinically Aggressive Neuroblastoma

“…In glioblastoma multiforme, where glomeruloid microvessel proliferations and MVP were first described, a spatial relationship between GMP and necrosis is observed (31,32). Furthermore, the hypoxic conditions associated with necrosis leads to up-regulation of HIF-1a, a major regulator of the proangiogenic factor vascular endothelial growth factor, and chaotic blood vessel growth (33).…”