Transcriptional profiling of human glioblastoma vessels indicates a key role of VEGF-A and TGFβ2 in vascular abnormalization.
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.
Department of Immunology, Genetics and Pathology, Rudbeck Laboratory, Uppsala University, Sweden.
Lothar C
LC
Dieterich
Sofie
S
Mellberg
Elise
E
Langenkamp
Lei
L
Zhang
Agata
A
Zieba
Henriikka
H
Salomäki
Martin
M
Teichert
Hua
H
Huang
Per-Henrik
PH
Edqvist
Theo
T
Kraus
Hellmut G
HG
Augustin
Tommie
T
Olofsson
Erik
E
Larsson
Ola
O
Söderberg
Grietje
G
Molema
Fredrik
F
Pontén
Patrik
P
Georgii-Hemming
Irina
I
Alafuzoff
Anna
A
Dimberg
D000328:Adult; D000368:Aged; D001808:Blood Vessels / Q000503:physiopathology*; D001932:Brain Neoplasms / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D016022:Case-Control Studies; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D005909:Glioblastoma / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D061346:Laser Capture Microdissection; D046228:Microarray Analysis; D008875:Middle Aged; D060787:Neoplasm Grading; D020286:Pericytes / Q000473:pathology / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000502:physiology*
D053781:Transforming Growth Factor beta2; D042461:Vascular Endothelial Growth Factor A