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.
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.
Authors: J Leitlein; S Aulwurm; R Waltereit; U Naumann; B Wagenknecht; W Garten; M Weller; M Platten Journal: J Immunol Date: 2001-06-15 Impact factor: 5.422
Authors: Manuel A Friese; Jörg Wischhusen; Wolfgang Wick; Markus Weiler; Günter Eisele; Alexander Steinle; Michael Weller Journal: Cancer Res Date: 2004-10-15 Impact factor: 12.701
Authors: Olivier L Chinot; Wolfgang Wick; Warren Mason; Roger Henriksson; Frank Saran; Ryo Nishikawa; Antoine F Carpentier; Khe Hoang-Xuan; Petr Kavan; Dana Cernea; Alba A Brandes; Magalie Hilton; Lauren Abrey; Timothy Cloughesy Journal: N Engl J Med Date: 2014-02-20 Impact factor: 91.245
Authors: Mark D Hjelmeland; Anita B Hjelmeland; Sith Sathornsumetee; Elizabeth D Reese; Michael H Herbstreith; Nicholas J Laping; Henry S Friedman; Darell D Bigner; Xiao-Fan Wang; Jeremy N Rich Journal: Mol Cancer Ther Date: 2004-06 Impact factor: 6.261
Authors: Marie José Goumans; Gudrun Valdimarsdottir; Susumu Itoh; Franck Lebrin; Jonas Larsson; Christine Mummery; Stefan Karlsson; Peter ten Dijke Journal: Mol Cell Date: 2003-10 Impact factor: 17.970