title: Modulation of cerebral endothelial cell function by TGF-β in glioblastoma: VEGF-dependent angiogenesis versus endothelial mesenchymal transition.
abstract: 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.
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology and Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Shanmugarajan
authors.initials: S
authors.lastname: Krishnan
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology and Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Emese
authors.initials: E
authors.lastname: Szabo
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology and Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Isabel
authors.initials: I
authors.lastname: Burghardt
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurosurgery and Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Karl
authors.initials: K
authors.lastname: Frei
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology and Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.|Interdisciplinary Division of Neuro-Oncology, Departments of Vascular Neurology and Neurosurgery, University Hospital Tübingen, Tübingen, Germany.
authors.forename: Ghazaleh
authors.initials: G
authors.lastname: Tabatabai
authors.affiliation: Laboratory of Molecular Neuro-Oncology, Department of Neurology and Neuroscience Center, University Hospital and University of Zurich, Zurich, Switzerland.
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
mesh_terms: D001932:Brain Neoplasms / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D005909:Glioblastoma / Q000098:blood supply* / Q000235:genetics / Q000473:pathology; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000473:pathology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics
chemical_list: D008565:Membrane Proteins; C098069:PIGF protein, human; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A
keywords: PlGF; TGF-β; VEGF; angiogenesis; glioblastoma