Differential expression of vascular endothelial growth factor A, its receptors VEGFR-1, -2, and -3 and co-receptors neuropilin-1 and -2 does not predict bevacizumab response in human astrocytomas

Neuro Oncol. 2016 Feb;18(2):173-83. doi: 10.1093/neuonc/nov288. Epub 2015 Nov 30.

Abstract

Background: A major hallmark of malignant progression in human astrocytomas is the formation of new blood vessels. Antiangiogenic therapy using the anti-vascular endothelial growth factor (VEGF)-antibody bevacizumab leads to increased progression-free survival in glioblastoma patients but does not influence their overall survival. To date, it is unclear why antiangiogenic therapy fails in many glioblastoma patients, while a small subpopulation profits considerably from this treatment.

Methods: The aim of our study was to determine the expression of VEGF-A and its (co-) receptors by immunohistochemistry and to test the association with patient survival in 350 glioma patients. Additionally, VEGF-A expression was analyzed by in-situ hybridization. In 18 patients, the protein expression was compared with the bevacizumab response according to extended and modified RANO criteria.

Results: We found a heterogeneous expression pattern of VEGF and its receptors in glioblastoma patients with significantly lower levels in WHO grade II and III tumors and normal-appearing brain tissue (P < .001). Pilocytic astrocytomas (WHO grade I) showed significantly higher VEGFR-1, -2 and neuropilin-1 levels as compared to WHO grade II and III astrocytomas (P < .01) but at lower levels than glioblastomas. The expression of neuropilin-2 was low in all tumors. There was neither a significant correlation between protein expression and patient survival nor between protein levels and bevacizumab response after modified RANO criteria.

Conclusion: Since our data indicate that beneficial response to bevacizumab treatment is independent of the expression of VEGF-A and its (co-) receptors, further investigation is needed to decipher the underlying mechanisms of antiangiogenic treatment response.

Keywords: VEGF; VEGF receptors; antiangiogenic therapy; bevacizumab; glioma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Angiogenesis Inhibitors / therapeutic use
  • Astrocytoma / drug therapy*
  • Astrocytoma / metabolism
  • Astrocytoma / pathology
  • Bevacizumab / therapeutic use*
  • Biomarkers, Tumor / metabolism
  • Brain Neoplasms / drug therapy*
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology
  • Child
  • Child, Preschool
  • Female
  • Follow-Up Studies
  • Humans
  • Immunoenzyme Techniques
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neoplasm Staging
  • Neuropilin-1 / metabolism*
  • Neuropilin-2 / metabolism*
  • Prognosis
  • Receptors, Vascular Endothelial Growth Factor / metabolism*
  • Survival Rate
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors
  • Vascular Endothelial Growth Factor A / metabolism*
  • Vascular Endothelial Growth Factor Receptor-1 / metabolism
  • Vascular Endothelial Growth Factor Receptor-2 / metabolism
  • Vascular Endothelial Growth Factor Receptor-3 / metabolism
  • Young Adult

Substances

  • Angiogenesis Inhibitors
  • Biomarkers, Tumor
  • Neuropilin-2
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • neuropilin-2, human
  • Neuropilin-1
  • Bevacizumab
  • Receptors, Vascular Endothelial Growth Factor
  • Vascular Endothelial Growth Factor Receptor-1
  • Vascular Endothelial Growth Factor Receptor-2
  • Vascular Endothelial Growth Factor Receptor-3