|Glioma gene therapy with soluble transforming growth factor-β receptors II and III|
Authors: Ulrike Naumann, Philipp Maass, Anne-Kathrin Gleske, Steffen Aulwurm, Michael Weller, Guenter Eisele
Department of General Neurology, Hertie Institute for Clinical Brain Research, D-72076 Tuebingen, Germany. firstname.lastname@example.org
Transforming growth factor-β (TGF-β) is abundantly expressed in malignant gliomas and is crucial for the tumor micromilieu. TGF-β not only enhances migration and invasion of glioma cells but also inhibits an effective anti-glioma immune response. TGF-β mediates its biologic effects through interactions with TGF-β receptors (TβR)-I to -III. Binding of TGF-β leads to the activation of an intracellular signaling cascade and subsequent phosphorylation of Sma and MAD-related proteins (SMAD). Soluble TGF-β receptors (TβRs) abrogate the TGF-β effect by competing for the binding of the ligand to its receptor. Here we used adenoviral gene transfer to express TβR-IIs and -IIIs in human glioma cell lines. TβR-IIs reduced SMAD2 phosphorylation and TGF-β-dependent reporter activity. Furthermore, it enhanced glioma cell lysis by natural killer cells. TβR-IIIs alone were inactive in these assays, but enhanced the effects of TβR-IIs. Transduction of LN-308 cells with TβRs markedly delayed growth of intracerebral xenografts in nude mice in vivo. These data commend TβRs for possible experimental therapy of gliomas.