TGF-beta INDUCES AND BMP SUPPRESSES VEGF RELEASE DEPENDING ON SMAD2/3 VERSUS SMAD1/5/8 SIGNALING IN GLIOBLASTOMA

The transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) and vascular endothelial growth factor (VEGF) pathways have been attributed a major role in the pathogenesis in glioblastoma, but their interactions have remained poorly understood. Thus, we characterized TGF-β/BMP pathway activity in nine long-term glioma cell lines (LTC) and 4 glioma-initiating cell lines (GIC) in relation to constitutive and exogenous TGF-β/BMP-induced VEGF release. As reflected by TGF-β-induced SMAD2/3-phoshorylation and TGF-β/BMP-induced SMAD1/5/8 phosphorylation, glioma cells exhibit heterogeneous patterns of constitutive BMP/TGF-β pathway activation. Constitutive TGF-β pathway activity accounts for up to 69% of constitutive VEGF release which is positively regulated by SMAD2/3 and negatively by SMAD1/5/8 signaling in a cell line-specific manner. Exogenous TGF-β induces and exogenous BMP reduces VEGF release in most cell lines. Overall, TGF-β regulates VEGF release by glioma cells in an ALK-5-dependent manner involving SMAD2, SMAD3 and SMAD1/5/8 signaling. This crosstalk between the TGF-β and VEGF pathways may open up new avenues of biomarker-driven exploratory clinical trials. Beyond, BMP-dependent differentiation therapy as anti-glioma therapy may include VEGF-inhibitory effects.