Hypoxia‐inducible factor 1α/vascular endothelial growth factor axis in astrocytomas. Associations with microvessel morphometry, proliferation and prognosis

Abstract

Hypoxia-inducible factor (HIF)-1alpha is a transcription factor that promotes ischaemia-driven angiogenesis. The aim of this study was to determine the relation of HIF-1alpha to vascular endothelial growth factor (VEGF; an important angiogenic molecule in brain tumours), p53 expression, angiogenesis, proliferative potential and clinical outcome in a large series of diffuse astrocytomas. Expression of HIF-1alpha, VEGF, Ki-67 (a proliferation-associated marker) and p53 was determined immunohistochemically in 83 adult patients with supratentorial diffuse astrocytomas. Microvessels, highlighted by means of anti-CD34 immunohistochemistry, were enumerated with computer-assisted image analysis. Although HIF-1alpha and VEGF were expressed in the majority of cases, their levels increased significantly with increasing grade and proliferative potential. HIF-1alpha positively correlated with microvessel counts and VEGF with total vascular area and the presence of rounder vessel sections. There was a positive correlation of VEGF with p53 expression in astrocytomas and anaplastic astrocytomas. In univariate analysis, both VEGF and HIF-1alpha were associated with shortened survival in the entire cohort, but lost significance when grades II/III and grade IV were analysed separately. Multivariate analysis revealed that the combination of HIF-1alpha with grade was a significant prognostic indicator. HIF-1alpha expression may be used to refine the prognostic information provided by grade in patients with diffuse astrocytomas. Its adverse prognostic effect is most likely mediated by hypoxia, the driving force for HIF-1alpha accumulation.

Correlations between Perfusion MR Imaging Cerebral Blood Volume, Microvessel Quantification, and Clinical Outcome Using Stereotactic Analysis in Recurrent High-Grade Glioma

“…[1][2][3][4][5][6][7][8][9][10] Most glioma studies have measured angiogenesis by using vessel number counts or MVD. [11][12][13][14] Both precedent and the relative ease of MVD calculation have made this technique a logical first choice to study outcome; however, while MVD shows good predictive power for non-central nervous system tumors, the correlation with glioma survival has been marginal at best.…”

“…This assertion is supported by studies showing that MVA correlates more strongly with survival compared with MVD, even in tumors with similar histologic grades. 1,4,[8][9][10] Despite this evidence, histologically quantifying MVA remains a research tool because the technique is time-consuming, labor-intensive, and thus impractical for routine clinical use. 6,7 For Ͼ2 decades, DSC-MR imaging has been used to study glioma angiogenesis.…”

“…To date, nearly all DSC-MR imaging correlative data are from animal models by using only MVD. 21,[23][24][25][26][27] Although MVA likely represents a more clinically relevant parameter, 1,4,[6][7][8][9][10] no human studies have been done and only 1 group has reported MVA correlation with rCBV in the rat 9L gliosarcoma model. 22,28 Basing the clinical translation of DSC-MR imaging primarily on animal data has several distinct limitations.…”

“…Animal models often lack the broad variations in vessel growth pattern and size that are observed in human HGG, [6][7][8]21,22,29 and it is unclear how the heterogeneity of human tumors impacts rCBV correlations with MVD and MVA. Additionally, largearea vessels in human HGG cause MVD and MVA to be inversely related [6][7][8][9][10] ; this feature would directly challenge the consensus from animal studies that rCBV correlates well with both measures. [21][22][23][24][25][26][27][28] Finally, the rationale for using rCBV to predict glioma outcome has not been reconciled with extensive clinical data comparing histologically derived MVD and MVA with survival.…”

“…Specifically, whether rCBV more strongly reports MVD versus MVA directly impacts the utility of rCBV as a clinical predictor of glioma outcome. 4,[6][7][8][9][10] That these relationships are currently unproved in humans might explain why DSC-MR imaging has not yet gained significant traction as a part of clinical standard of care, with the exception of select academic institutions. 30 To address these issues, we present data from a pilot study correlating localized coregistered rCBV with histologically derived MVD and MVA from stereotactic biopsies in human HGG.…”