Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization

J Pathol. 2012 Nov;228(3):378-90. doi: 10.1002/path.4072. Epub 2012 Aug 31.


Glioblastoma are aggressive astrocytic brain tumours characterized by microvascular proliferation and an abnormal vasculature, giving rise to brain oedema and increased patient morbidity. Here, we have characterized the transcriptome of tumour-associated blood vessels and describe a gene signature clearly associated with pleomorphic, pathologically altered vessels in human glioblastoma (grade IV glioma). We identified 95 genes differentially expressed in glioblastoma vessels, while no significant differences in gene expression were detected between vessels in non-malignant brain and grade II glioma. Differential vascular expression of ANGPT2, CD93, ESM1, ELTD1, FILIP1L and TENC1 in human glioblastoma was validated by immunohistochemistry, using a tissue microarray. Through qPCR analysis of gene induction in primary endothelial cells, we provide evidence that increased VEGF-A and TGFβ2 signalling in the tumour microenvironment is sufficient to invoke many of the changes in gene expression noted in glioblastoma vessels. Notably, we found an enrichment of Smad target genes within the distinct gene signature of glioblastoma vessels and a significant increase of Smad signalling complexes in the vasculature of human glioblastoma in situ. This indicates a key role of TGFβ signalling in regulating vascular phenotype and suggests that, in addition to VEGF-A, TGFβ2 may represent a new target for vascular normalization therapy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Blood Vessels / physiopathology*
  • Brain Neoplasms / blood supply
  • Brain Neoplasms / pathology
  • Brain Neoplasms / physiopathology*
  • Case-Control Studies
  • Endothelium, Vascular / pathology
  • Endothelium, Vascular / physiopathology
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic / physiology
  • Glioblastoma / blood supply
  • Glioblastoma / pathology
  • Glioblastoma / physiopathology*
  • Humans
  • Laser Capture Microdissection
  • Microarray Analysis
  • Middle Aged
  • Neoplasm Grading
  • Pericytes / pathology
  • Pericytes / physiology
  • Signal Transduction / physiology
  • Transforming Growth Factor beta2 / genetics
  • Transforming Growth Factor beta2 / physiology*
  • Vascular Endothelial Growth Factor A / genetics
  • Vascular Endothelial Growth Factor A / physiology*


  • Transforming Growth Factor beta2
  • Vascular Endothelial Growth Factor A