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Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF‐A and TGFβ2 in vascular abnormalization
Author(s) -
Dieterich Lothar C,
Mellberg Sofie,
Langenkamp Elise,
Zhang Lei,
Zieba Agata,
Salomäki Henriikka,
Teichert Martin,
Huang Hua,
Edqvist PerHenrik,
Kraus Theo,
Augustin Hellmut G,
Olofsson Tommie,
Larsson Erik,
Söderberg Ola,
Molema Grietje,
Pontén Fredrik,
GeorgiiHemming Patrik,
Alafuzoff Irina,
Dimberg Anna
Publication year - 2012
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4072
Subject(s) - glioma , smad , gene expression profiling , pathology , biology , gene signature , vascular endothelial growth factor , cancer research , phenotype , immunohistochemistry , transcriptome , gene expression , glioblastoma , microarray , gene , vegf receptors , transforming growth factor , medicine , microbiology and biotechnology , genetics
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. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.