Differential regulation of TGF-β–induced, ALK-5–mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma. Issue 2 (27th August 2014)

• Record Type: Journal Article
• Authors: Seystahl, Katharina; Tritschler, Isabel; Szabo, Emese; Tabatabai, Ghazaleh; Weller, Michael
• Is Part Of: Neuro-oncology. Volume 17:Issue 2(2015:Feb.)
• Page Start: 254
• Page End: 265
• Publication Date: 2014-08-27
• Subjects: angiogenesis -- glioblastoma -- TGF-β -- VEGF; Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/nou218
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Background: The transforming growth factor (TGF)-β and vascular endothelial growth factor (VEGF) pathways have a major role in the pathogenesis of glioblastoma, notably immunosuppression, migration, and angiogenesis, but their interactions have remained poorly understood. Methods: We characterized TGF-β pathway activity in 9 long-term glioma cell lines (LTCs) and 4 glioma-initiating cell lines (GICs) in relation to constitutive and exogenous TGF-β-induced VEGF release. Results were validated using The Cancer Genome Atlas transcriptomics data. Results: Glioma cells exhibit heterogeneous patterns of constitutive TGF-β pathway activation reflected by phosphorylation not only of SMAD2 and SMAD3 but also of SMAD1/5/8. Constitutive TGF-β pathway activity depends on the type I TGF-β receptor, ALK-5, and accounts for up to 69% of constitutive VEGF release, which is positively regulated by SMAD2/3 and negatively regulated by SMAD1/5/8 signaling in a cell line-specific manner. Exogenous TGF-β induces VEGF release in most cell lines in a SMAD- and ALK-5–dependent manner. There is no correlation between the fold induction of VEGF secretion induced by TGF-β compared with hypoxia. The role of 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. Conclusions: 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 focusing on the microenvironment in glioblastoma.