Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGF beta 2 in vascular abnormalization

Lothar C. Dieterich, Sofie Mellberg, Elise Langenkamp, Lei Zhang, Agata Zieba, Henriikka Salomaki, Martin Teichert, Hua Huang, Per-Henrik Edqvist, Theo Kraus, Hellmut G. Augustin, Tommie Olofsson, Erik Larsson, Ola Soderberg, Grietje Molema, Fredrik Ponten, Patrik Georgii-Hemming, Irina Alafuzoff, Anna Dimberg*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

81 Citations (Scopus)

Abstract

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 TGF beta 2 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 TGF beta signalling in regulating vascular phenotype and suggests that, in addition to VEGF-A, TGF beta 2 may represent a new target for vascular normalization therapy. Copyright (c) 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Original languageEnglish
Pages (from-to)378-390
Number of pages13
JournalJOURNAL OF PATHOLOGY
Volume228
Issue number3
DOIs
Publication statusPublished - Nov-2012

Keywords

  • brain tumour
  • vasculature
  • laser microdissection
  • microarray
  • growth factor
  • angiogenesis
  • tumour endothelial marker
  • ENDOTHELIAL GROWTH-FACTOR
  • TO-MESENCHYMAL TRANSITION
  • RECEPTOR TYROSINE KINASES
  • HUMAN PROTEIN ATLAS
  • STEM-LIKE CELLS
  • BRAIN-TUMORS
  • ASTROCYTIC TUMORS
  • MALIGNANT GLIOMAS
  • FACTOR-BETA
  • TGF-BETA

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