TY  - JOUR
A1  - Wirsik, Naita Maren
A1  - Ehlers, Jakob
A1  - Mäder, Lisa Victoria
A1  - Ilina, Elena
A1  - Blank, Anna-Eva
A1  - Grote, Anne
A1  - Feuerhake, Friedrich
A1  - Baumgarten, Peter
A1  - Devraj, Kavi
A1  - Harter, Patrick Nikolaus
A1  - Mittelbronn, Michel Guy André
A1  - Naumann, Ulrike
T1  - TGF-β activates pericytes via induction of the epithelial-to-mesenchymal transition protein SLUG in glioblastoma
T2  - Neuropathology and applied neurobiology
N2  - Aims: In primary central nervous system tumours, epithelial-to-mesenchymal transition (EMT) gene expression is associated with increased malignancy. However, it has also been shown that EMT factors in gliomas are almost exclusively expressed by glioma vessel-associated pericytes (GA-Peris). In this study, we aimed to identify the mechanism of EMT in GA-Peris and its impact on angiogenic processes.
Methods; In glioma patients, vascular density and the expression of the pericytic markers platelet derived growth factor receptor (PDGFR)-β and smooth muscle actin (αSMA) were examined in relation to the expression of the EMT transcription factor SLUG and were correlated with survival of patients with glioblastoma (GBM). Functional mechanisms of SLUG regulation and the effects on primary human brain vascular pericytes (HBVP) were studied in vitro by measuring proliferation, cell motility and growth characteristics.
Results: The number of PDGFR-β- and αSMA-positive pericytes did not change with increased malignancy nor showed an association with the survival of GBM patients. However, SLUG-expressing pericytes displayed considerable morphological changes in GBM-associated vessels, and TGF-β induced SLUG upregulation led to enhanced proliferation, motility and altered growth patterns in HBVP. Downregulation of SLUG or addition of a TGF-β antagonising antibody abolished these effects.
Conclusions: We provide evidence that in GA-Peris, elevated SLUG expression is mediated by TGF-β, a cytokine secreted by most glioma cells, indicating that the latter actively modulate neovascularisation not only by modulating endothelial cells, but also by influencing pericytes. This process might be responsible for the formation of an unstructured tumour vasculature as well as for the breakdown of the blood–brain barrier in GBM.
KW  - pericytes
KW  - EMT
KW  - SLUG
KW  - TGF-β
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/61893
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-618939
SN  - 1365-2990
VL  - 2020
IS  - Online Version of Record before inclusion in an issue
SP  - 1
EP  - 13
PB  - Wiley-Blackwell
CY  - Oxford
ER  -