Modulation of cerebral endothelial cell function by TGF-β in glioblastoma: VEGF-dependent angiogenesis versus endothelial mesenchymal transition
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Shanmugarajan Krishnan1, Emese Szabo1, Isabel Burghardt1, Karl Frei2, Ghazaleh Tabatabai1,3, Michael Weller1
1Laboratory of Molecular Neuro-Oncology, Department of Neurology and Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
2Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland
3Interdisciplinary Division of Neuro-Oncology, Departments of Vascular Neurology and Neurosurgery, University Hospital Tübingen, Tübingen, Germany
Michael Weller, e-mail: [email protected]
Keywords: angiogenesis, glioblastoma, TGF-β, VEGF, PlGF
Received: January 26, 2015 Accepted: June 03, 2015 Published: June 15, 2015
Glioblastoma are among the most angiogenic tumors. The molecular mechanisms that control blood vessel formation by endothelial cells (EC) in glioblastoma remain incompletely understood. Transforming growth factor-β (TGF-β) is a key regulatory cytokine that has proinvasive and stemness-maintaining autocrine properties in glioblastoma and confers immunosuppression to the tumor microenvironment. Here we characterize potential pro- and anti-angiogenic activities of TGF-β in the context of glioblastoma in vitro, using human brain-derived microvascular endothelial cells (hCMEC/D3) and glioblastoma-derived endothelial cells (GMEC) as model systems. We find that TGF-β induces vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) mRNA expression and protein release in a TGF-β receptor (TβR) II / activin-like kinase (ALK)-5-dependent manner under normoxia and hypoxia, defining potential indirect proangiogenic activity of TGF-β in glioblastoma. In parallel, exogenous TGF-β has also inhibitory effects on EC properties and induces endothelial-mesenchymal transition (EndMT) in hCMEC and GMEC. Accordingly, direct inhibition of endogenous TGF-β/ALK-5 signalling increases EC properties such as tube formation, von-Willebrand factor (vWF) and claudin (CLDN) 5 expression. Yet, the supernatant of TGF-β-stimulated hCMEC and GMEC strongly promotes EC-related gene expression and tube formation in a cediranib-sensitive manner. These observations shed light on the complex pro- and anti-angiogenic pathways involving the cross-talk between TGF-β and VEGF/PLGF signalling in glioblastoma which may involve parallel stimulation of angiogenesis and EndMT in distinct target cell populations.
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