No role of IFITM3 in brain tumor formation in vivo.

Nevenka Dudvarski Stankovic,Alf Giese,Frauke Zipp,Marcin Teodorczyk,Mirko H.H Schmidt,Nicola Hoppmann,Matthias Bros,Ella L Kim

doi:10.18632/oncotarget.13199

Abstract

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.

Highlights

Glioblastoma multiforme (GBM) is the most common malignant primary intracranial tumor in adults
A syngeneic model based on the mouse glioma cell line GL261 was applied in order to consider the possibility that interferon-inducible transmembrane protein 3 (IFITM3) relies on an intact immune system to unfold its tumorigenic potential
The line brain tumor-propagating cells (BTPCs)-1080 (1080) derived from a patient diagnosed with primary GBM WHO°IV was irradiated with 2.5 Gy in seven consecutive passages to select for BTPCs with a radio-resistant phenotype in the course of multifractionated irradiation in vitro (Figure 1A)

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common malignant primary intracranial tumor in adults It is characterized by widespread invasion throughout the brain, resistance to various therapeutic approaches, and destruction of brain tissue, leading to death [1]. Www.impactjournals.com/oncotarget the existing standard treatment for GBM, involving maximal surgical resection followed by irradiation and temozolomide (TMZ) chemotherapy, barely prolongs patient median survival from 12.1 to 14.6 months [3]. Such a fast reconstitution of the tumor is in part due to the presence of cancer stem-like cells (glioma stem-like cells [4]) or, more accurately, stem-like brain tumorpropagating cells (BTPCs) [5, 6]. BTPCs can survive currently available GBM treatments, efficiently repair damaged DNA and give rise to recurrent tumors [11, 12]

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