Dataset Information

Differential regulation of TGF-?-induced, ALK-5-mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma.

ABSTRACT:

Background

The transforming growth factor (TGF)-? 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-? pathway activity in 9 long-term glioma cell lines (LTCs) and 4 glioma-initiating cell lines (GICs) in relation to constitutive and exogenous TGF-?-induced VEGF release. Results were validated using The Cancer Genome Atlas transcriptomics data.

Results

Glioma cells exhibit heterogeneous patterns of constitutive TGF-? pathway activation reflected by phosphorylation not only of SMAD2 and SMAD3 but also of SMAD1/5/8. Constitutive TGF-? pathway activity depends on the type I TGF-? 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-? 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-? compared with hypoxia. The role of SMAD5 signaling is highly context and cell-line dependent with a VEGF inhibitory effect at low TGF-? and pSMAD2 levels and a stimulatory effect when TGF-? is abundant.

Conclusions

TGF-? 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-? and VEGF pathways may open up new avenues of biomarker-driven exploratory clinical trials focusing on the microenvironment in glioblastoma.

SUBMITTER: Seystahl K

PROVIDER: S-EPMC4288525 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Publications

Differential regulation of TGF-β-induced, ALK-5-mediated VEGF release by SMAD2/3 versus SMAD1/5/8 signaling in glioblastoma.

Seystahl Katharina K Tritschler Isabel I Szabo Emese E Tabatabai Ghazaleh G Tabatabai Ghazaleh G Weller Michael M

Neuro-oncology 20140827 2

<h4>Background</h4>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.<h4>Methods</h4>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 ...[more]

PMID: 25165192

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