Glioma gene therapy with soluble transforming growth factor-β receptors II and III

Abstract

Transforming growth factor-ß (TGF-ß) is abundantly expressed in malignant gliomas and is crucial for the tumor micromilieu. TGF-ß not only enhances migration and invasion of glioma cells but also inhibits an effective anti-glioma immune response. TGF-ß mediates its biologic effects through interactions with TGF-ß receptors (TBR)-I to -III. Binding of TGF-ß leads to the activation of an intracellular signaling cascade and subsequent phosphorylation of Sma and MAD-related proteins (SMAD). Soluble TGF-ß receptors (TßRs) abrogate the TGF-ß effect by competing for the binding of the ligand to its receptor. Here we used adenoviral gene transfer to express TßR-IIs and -IIIs in human glioma cell lines. TßR-IIs reduced SMAD2 phosphorylation and TGF-ß-dependent reporter activity. Furthermore, it enhanced glioma cell lysis by natural killer cells. TßR-IIIs alone were inactive in these assays, but enhanced the effects of TßR-IIs. Transduction of LN-308 cells with TßRs markedly delayed growth of intracerebral xenografts in nude mice in vivo. These data commend TßRs for possible experimental therapy of gliomas.