No role of IFITM3 in brain tumor formation in vivo
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Nevenka Dudvarski Stankovic1,3,4,*, Nicola Hoppmann2,*, Marcin Teodorczyk1,*, Ella L. Kim5, Matthias Bros6, Alf Giese5, Frauke Zipp2,*, Mirko H.H. Schmidt1,3,4,*
1Molecular Signal Transduction Laboratories, Institute for Microscopic Anatomy and Neurobiology, Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University, School of Medicine, Mainz, Germany
2Department of Neurology, Focus Program Translational Neuroscience (FTN) and Research Center for Immunotherapy (FZI), Rhine Main Neuroscience Network (rmn2), Johannes Gutenberg University, School of Medicine, Mainz, Germany
3German Cancer Consortium (DKTK), Heidelberg, Germany
4German Cancer Research Center (DKFZ), Heidelberg, Germany
5Translational Oncology Research Group, Department of Neurosurgery, Johannes Gutenberg University, School of Medicine, Mainz, Germany
6Department of Dermatology, Johannes Gutenberg University, School of Medicine, Mainz, Germany
*These authors have contributed equally to this work
Mirko H.H. Schmidt, email: [email protected]
Keywords: brain tumors, cancer stem cells, glioma, IFITM3, irradiation
Received: April 28, 2016 Accepted: October 29, 2016 Published: November 08, 2016
Glioblastoma multiforme (GBM) is one of the most lethal solid tumors in adults. Despite aggressive treatment approaches for patients, GBM recurrence is inevitable, in part due to the existence of stem-like brain tumor-propagating cells (BTPCs), which produce factors rendering them resistant to radio- and chemotherapy. Comparative transcriptome analysis of irradiated, patient-derived BTPCs revealed a significant upregulation of the interferon-inducible transmembrane protein 3 (IFITM3), suggesting the protein as a factor mediating radio resistance. Previously, IFITM3 has been described to affect glioma cells; therefore, the role of IFITM3 in the formation and progression of brain tumors has been investigated in vivo. Intracranial implantation studies using radio-selected BTPCs alongside non-irradiated parental BTPCs in immunodeficient mice displayed no influence of irradiation on animal survival. Furthermore, gain and loss of function studies using BTPCs ectopically expressing IFITM3 or having IFITM3 down-modulated by a shRNA approach, did affect neither tumor growth nor animal survival. Additionally, a syngeneic model based on the mouse glioma cell line GL261 was applied in order to consider the possibility that IFITM3 relies on an intact immune system to unfold its tumorigenic potential. GL261 cells ectopically expressing IFITM3 were implanted into the striatum of immunocompetent mice without influencing the survival of glioma-bearing animals. Lastly, the vasculature and the extent of microglia/macrophage invasion into the tumor were studied in BTPC and GL261 tumors but neither parameter was altered by IFITM3. This report presents for the first time that IFITM3 is upregulated in patient-derived BTPCs upon irradiation but does not affect brain tumor formation or progression in vivo.
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