Overexpression of vascular endothelial growth factor isoforms drives oxygenation and growth but not progression to glioblastoma multiforme in a human model of gliomagenesis

Cancer Res. 2003 Apr 15;63(8):1962-8.

Abstract

Vascular endothelial growth factor (VEGF) is thought to promote tumor growth and angiogenesis. Whereas VEGF is up-regulated in only a portion of anaplastic astrocytoma (AA), it is overexpressed in most glioblastoma multiforme (GBM), and the level of expression is correlated with grade of glioma. To explore the possibility that VEGF may act as a driving force in the progression of AA to GBM, the VEGF isoforms VEGF(121) and VEGF(165) were overexpressed in genetically modified, mutant H-Ras-transformed human astrocytes that on intracranial implantation form AA-like tumors. The ability of the VEGF isoforms to stimulate growth, angiogenesis, oxygenation, and the formation of necrotic GBM-like tumors was then monitored. The parental mutant H-Ras-modified astrocytes expressed four times more endogenous VEGF than normal human astrocytes, but on intracranial implantation formed hypovascular, hypoxic, small AA-like tumors. Whereas these modest levels of VEGF overexpression were insufficient to drive oxygenation and GBM formation, an additional 8-fold increase in VEGF expression mediated by retroviral infection with constructs encoding either VEGF (121) or VEGF (165) resulted in cells which, after intracranial implantation, formed tumors that were larger, more vascular, and better oxygenated than those formed by the mutant H-ras parental cells. However, the tumors formed by the cells expressing exogenous VEGF (121) or VEGF (165) retained the phenotype of AA, lacking areas of necrosis that are the hallmark of the GBM phenotype. These results suggest that whereas the VEGF(121) and VEGF(165) isoforms can contribute to glioma vascularization, oxygenation, and growth, they do not in and of themselves drive the formation of the GBM phenotype.

MeSH terms

  • Astrocytes / metabolism
  • Astrocytes / physiology
  • Astrocytoma / blood supply
  • Astrocytoma / genetics
  • Astrocytoma / metabolism*
  • Astrocytoma / pathology
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / pathology
  • Cell Division / physiology
  • Disease Progression
  • Endothelial Growth Factors / biosynthesis*
  • Endothelial Growth Factors / genetics
  • Genes, ras
  • Glioblastoma / blood supply
  • Glioblastoma / genetics
  • Glioblastoma / metabolism*
  • Glioblastoma / pathology
  • Humans
  • Intercellular Signaling Peptides and Proteins / biosynthesis*
  • Intercellular Signaling Peptides and Proteins / genetics
  • Lymphokines / biosynthesis*
  • Lymphokines / genetics
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / pathology
  • Oxygen / metabolism*
  • Phenotype
  • Protein Isoforms
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors

Substances

  • Endothelial Growth Factors
  • Intercellular Signaling Peptides and Proteins
  • Lymphokines
  • Protein Isoforms
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Vascular Endothelial Growth Factors
  • Oxygen