Blocking TGF-β- and Epithelial-to-Mesenchymal Transition (EMT)-mediated activation of brain pericytes in glioblastoma impacts tumor angiogenesis

Abstract

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. GBM displays excessive and unfunctional vascularization which may, among others, be a reason for its devastating prognosis. Pericytes have been identified as the major component of the irregular vessel structure in GBM. In vitro data suggest an epithelial-to-mesenchymal transition (EMT)-like activation of glioma-associated pericytes (GA-Peris), stimulated by GBM-secreted TGF-β, to be involved in the formation of a chaotic and dysfunctional tumor vasculature. This study investigated whether TGF-β impacts pericyte functions in vivo via the induction of the EMT transcription factor SLUG and whether this is associated with the development of GBM-associated vascular abnormalities. Upon prohibiting the TGF-β-/SLUG-mediated EMT induction in GA-Peris, the number of PDGFRβ and αSMA positive pericytes was significantly reduced, regardless of whether TGF-β secretion by GBM cells was blocked or whether SLUG was specifically knocked out in GA-Peris. The reduced amount of PDGFRβ+ or αSMA+ pericytes observed under those conditions correlated with a lower vessel density and fewer vascular abnormalities. Our data provide evidence that the SLUG-mediated modulation of pericyte activity is induced by GBM-secreted TGF-β­ and that activated pericytes are key contributors in neo-angiogenic processes. We suggest that a pathologically altered activation of GA-Peris in the tumor microenvironment is responsible for the unstructured tumor vasculature. There is emerging evidence that vessel normalization alleviates tumor hypoxia, reduces tumor-associated edema and improves drug delivery. Therefore, avoiding the generation of an unstructured and non-functional tumor vasculature during tumor recurrence might be a promising treatment approach for GBM and identifies pericytes as a potential novel therapeutic target.

Keywords

• Glioblastoma
• Tumor vasculature
• Pericytes
• TGF-β
• EMT