Abstract
AbstractGlioblastomas use pro-angiogenic factors such as vascular endothelial growth factor (VEGF) for new blood vessel formation. Glioma-associated endothelial cells may support glioblastoma growth and specifically maintain glioma stem cells (GSC). Yet, anti-VEGF therapy does not prolong overall survival: gliomas acquire resistance to VEGF inhibition and appear to be rather refractory to all further treatments. Thus, investigations of alternative angiogenic pathways in gliomas which may then serve as essential drug targets are pivotal. Activin receptor-like kinases (ALK) are type I TGF-beta receptors (TGF-bR). Nonoverlapping expression patterns of ALK-1 and ALK-5 have been demonstrated with primarily endothelial expression of ALK-1. Both GSC and glioma-associated endothelial cells produce TGF-beta superfamily ligands which may sustain glioma self-renewal and promote immunosuppression in the tumor microenvironment. This is mediated by TGF-bR, specifically type I TGF-bR and type II TGF-bR, forming heteromeric complexes upon binding of TGF-bR superfamily ligands. We demonstrate an enrichment of ALK-1 and TGF-bR II in GSC and glioma-associated endothelial cells in a cohort of newly diagnosed and recurrent glioblastomas. This may define ALK-1 and TGF-bR II as promising future therapeutic targets in antiangiogenic therapy for glioblastoma.
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