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TGF‐β activates pericytes via induction of the epithelial‐to‐mesenchymal transition protein SLUG in glioblastoma
Author(s) -
Wirsik Naita M.,
Ehlers Jakob,
Mäder Lisa,
Ilina Elena I.,
Blank AnnaEva,
Grote Anne,
Feuerhake Friedrich,
Baumgarten Peter,
Devraj Kavi,
Harter Patrick N.,
Mittelbronn Michel,
Naumann Ulrike
Publication year - 2021
Publication title -
neuropathology and applied neurobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.538
H-Index - 95
eISSN - 1365-2990
pISSN - 0305-1846
DOI - 10.1111/nan.12714
Subject(s) - slug , epithelial–mesenchymal transition , glioblastoma , mesenchymal stem cell , transition (genetics) , transforming growth factor , microbiology and biotechnology , cancer research , pathology , biology , medicine , gene , biochemistry
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.