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

Yukihiko Sonoda, Masayuki Kanamori, Dennis F. Deen, Shi Yuan Cheng, Mitchel S. Berger, Russell O. Pieper

Research output: Contribution to journalArticlepeer-review

30 Citations (Scopus)

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 VEGF121 and VEGF165 were overexpressed in genetically modified, mutant H-Rastransformed 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 VEGF121 or VEGF165 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 VEGF121 or VEGF165 retained the phenotype of AA, lacking areas of necrosis that are the hallmark of the GBM pheno-type. These results suggest that whereas the VEGF121 and VEGF165 isoforms can contribute to glioma vascularization, oxygenation, and growth, they do not in and of themselves drive the formation of the GBM phenotype.

Original languageEnglish
Pages (from-to)1962-1968
Number of pages7
JournalCancer Research
Volume63
Issue number8
Publication statusPublished - 2003 Apr 15
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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