[en] Cytokines such as transforming growth factor-beta (TGF-beta) are thought to mediate escape from immune surveillance in human malignant glioma. Here, we report that ectopic expression of the small TGF-beta-binding proteoglycan, decorin, inhibits not only TGF-beta bioactivity but also TGF-beta 1 and TGF-beta 2 mRNA transcription and TGF-beta protein synthesis by human LN-18, LN-229, T98G and rat C6 glioma cells in vitro. Ectopic expression of decorin in C6 rat glioma cells results in strong inhibition of tumor formation in vivo. Decorin-expressing C6 gliomas grow initially but regress to very small residual tumors at 12 weeks after implantation whereas all control animals die or have to be killed within 4 weeks. Decorin-expressing tumors show a four-fold increase of infiltration by activated T cells and a 1.6-fold increase in total B and T cells. Chronic steroid-mediated immunosuppression abrogates the inhibitory effects of decorin gene transfer. We conclude that decorin-induced inhibition of TGF-beta release by glioma cells significantly enhances antiglioma immune responses in vivo. Clinical evaluation of decorin gene therapy for human malignant gliomas may be warranted.
Disciplines :
Neurologie
Auteur, co-auteur :
Ständer, M; Department of Neurology, University of Tuebingen, Germany
Naumann, U; Department of Neurology, University of Tuebingen, Germany
Dumitrescu, L; Department of Neurology, University of Tuebingen, Germany
HENEKA, Michael ; Department of Neurology, University of Tuebingen, Germany
Löschmann, P; Department of Neurology, University of Tuebingen, Germany
Gulbins, E; Institute of Physiology, University of Tuebingen, Germany
Dichgans, J; Department of Neurology, University of Tuebingen, Germany
Weller, M; Department of Neurology, University of Tuebingen, Germany ; Lab. of Molecular Neuro-Oncology, Department of Neurology, Univ. of Tuebingen, Medical School, 72076 Tuebingen, Germany
Co-auteurs externes :
yes
Langue du document :
Anglais
Titre :
Decorin gene transfer-mediated suppression of TGF-beta synthesis abrogates experimental malignant glioma growth in vivo.
This study was supported by the Else-Übelmesser-Foundation and the Deutsche Krebshilfe. The authors thank E Ruoslahti (San Diego, CA, USA) for the human decorin cDNA and Dr U Malipiero and Dr A Fontana for helpful discussions.
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