No role of IFITM3 in brain tumor formationin vivo

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.

IFITM3 promotes glioblastoma stem cell-mediated angiogenesis via regulating JAK/STAT3/bFGF signaling pathway

“…3A ). In fact, IFITM3 has been reported to exert no effect on cell proliferation and invasion in glioma cell lines [ 45 ], indicating that IFITM3 had no direct effect on glioma cells. These evidences suggest that IFITM3 might not be an indispensable factor in stemness maintenance of cancer cells, despite the close correlation between protein expression and stemness status.…”

Gamma Irradiation Triggers Immune Escape in Glioma-Propagating Cells

“…For this purpose, we investigated a model of patient-derived GPCs that were treated with clinically relevant doses of fractionated radiation (2.5 Gy) in seven consecutive cellular passages to select for GPCs with higher intrinsic or radiation-induced resistance mechanisms. The irradiation dose was adapted according to clinical relevance, the spheroide formation capacity, and usual doses for in vitro fractionated radiation [ 23 , 35 ]. In standard radiotherapy of newly diagnosed glioblastoma, 1.8–2 Gy/fraction with a total dose of 50 to 60 Gy is applied according to the Stupp protocol [ 1 ].…”

Malignancy and IFITM3: Friend or Foe?

“…IFITM3 expression is positively correlated with cancer stage and differentiation status with higher expression levels in invasive ductal carcinomas as compared to ductal carcinoma in-situs ( 25 ) and non-differentiated lung cancers as compared to well-differentiated lung cancers ( 27 ). Additionally, IFITM3 is a negative prognostic marker in treatment outcome in esophageal ( 39 ) and hepatocellular cancer ( 28 , 40 ), but, interestingly, not in glioblastomas ( 41 ). Conversely, another report suggests IFITM3 plays a crucial role in paracrine senescence via small extracellular vesicles, which are important in cancer treatment ( 33 ).…”