Control of VEGF release via TGF-β superfamily members in glioblastoma (P4.246)

Objective: The aim of this study is to identify hallmarks of TGF-β/BMP signaling with regard to VEGF release in glioma cell lines and patient-derived glioma-initiating cells. Background: Members of the transforming growth factor (TGF)-β superfamily including TGF-β isoforms and bone morphogenetic proteins (BMP) play a pivotal role in the pathogenesis of glioblastoma. Their effect on vascular endothelial growth factor (VEGF) expression is controversial in endothelial cells and poorly established in glioma cells. Design/Methods: We inhibited components of the TGF-β/BMP pathway in glioma cell culture models and patient-derived glioma-initiating cell lines to examine the regulation of constitutive VEGF as well as VEGF release that is induced by exogenously added members of the TGF-β superfamily. Results: Glioma cells exhibit heterogeneous patterns of constitutive BMP/TGF-β pathway activation. SMAD2/3 signaling positively and SMAD1/5/8 signaling negatively controls constitutive VEGF release in a cell line-specific manner. Patient derived glioma-initiating cells exhibiting higher constitutive levels of hypoxia-induced factor-1α (HIF-1α) show robust constitutive VEGF release not sensitive to inhibition of TGF-β- or BMP-pathway components. Mimicking paracrine signals of the tumor microenvironment, we explored the effect of exogenously added TGF-β/BMP in our models. VEGF release depends on both TGF-β-induced SMAD2/3 and SMAD1/5/8 phosphorylation while BMP-induced SMAD1/5/8 phosphorylation reduces VEGF release. The role of TGF-β induced SMAD5 signaling is highly context- and cell line dependent with a VEGF inhibitory effect at low TGF-β and pSMAD2 levels, and a stimulatory effect when TGF-β is abundant. Conclusion: Overall, TGF-β positively and BMP negatively controls VEGF release in glioma cells, involving SMAD2, SMAD3 and SMAD1/5/8 signaling pathways. These results may open up new avenues of biomarker-driven exploratory clinical trials focusing on TGF-β or VEGF-directed compounds in glioblastoma. Study Supported by: Oncosuisse, Koetser Foundation, University of Zurich to IT (Forschungskredit) Disclosure: Dr. Seystahl has received personal compensation for activities with Roche Diagnostics Corporation as an advisory board participant. Dr. Tritschler has nothing to disclose. Dr. Szabo has nothing to disclose. Dr. Gramatzki has nothing to disclose. Dr. Tabatabai has received personal compensation for activities with Merck Sharp & Dohme Ltd. and Roche Diagnostics Corporation as an advisory board member. Dr. Weller has nothing to disclose.