Glioma gene therapy with soluble transforming growth factor-beta receptors II and III.
Transforming growth factor-beta (TGF-beta) is abundantly expressed in malignant gliomas and is crucial for the tumor micromilieu. TGF-beta not only enhances migration and invasion of glioma cells but also inhibits an effective anti-glioma immune response. TGF-beta mediates its biologic effects through interactions with TGF-beta receptors (TbetaR)-I to -III. Binding of TGF-beta leads to the activation of an intracellular signaling cascade and subsequent phosphorylation of Sma and MAD-related proteins (SMAD). Soluble TGF-beta receptors (TbetaRs) abrogate the TGF-beta effect by competing for the binding of the ligand to its receptor. Here we used adenoviral gene transfer to express TbetaR-IIs and -IIIs in human glioma cell lines. TbetaR-IIs reduced SMAD2 phosphorylation and TGF-beta-dependent reporter activity. Furthermore, it enhanced glioma cell lysis by natural killer cells. TbetaR-IIIs alone were inactive in these assays, but enhanced the effects of TbetaR-IIs. Transduction of LN-308 cells with TbetaRs markedly delayed growth of intracerebral xenografts in nude mice in vivo. These data commend TbetaRs for possible experimental therapy of gliomas.
Naumann
Ulrike
U
Department of General Neurology, Hertie Institute for Clinical Brain Research, University of Tuebingen, Tuebingen, Germany. ulrike.naumann@uni-tuebingen.de
Maass
Philipp
P
Gleske
Anne-Kathrin
AK
Aulwurm
Steffen
S
Weller
Michael
M
Eisele
Guenter
G
D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics* / Q000628:therapy*; D045744:Cell Line, Tumor; D002470:Cell Survival; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007694:Killer Cells, Natural / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D011509:Proteoglycans / Q000235:genetics*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000378:metabolism
D011509:Proteoglycans; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; C071736:betaglycan; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II