Wnt inhibition is dysregulated in gliomas and its re-establishment inhibits proliferation and tumor sphere formation
- Vilhelm Magnus Lab, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo (Norway)
- Norwegian Computing Center, P.O. Box 114 Blindern, 0314 Oslo (Norway)
Evidence indicates that the growth of glioblastoma (GBM), the most common and malignant primary brain cancer, is driven by glioma stem cells (GSCs) resistant to current treatment. As Wnt-signaling is pivotal in stem cell maintenance, we wanted to explore its role in GSCs with the objective of finding distinct signaling mechanisms that could serve as potential therapeutic targets. We compared gene expression in GSCs (n=9) and neural stem cells from the adult human brain (ahNSC; n=3) to identify dysregulated genes in the Wnt signaling pathway. This identified a six-gene Wnt signature present in all nine primary GSC cultures, and the combined expression of three of these genes (SFRP1, SFRP4 and FZD7) reduced median survival of glioma patients from 38 to 17 months. Treatment with recombinant SFRP1 protein in primary cell cultures downregulated nuclear β-catenin and decreased in vitro proliferation and sphere formation in a dose-dependent manner. Furthermore, expressional and functional analysis of SFRP1-treated GSCs revealed that SFRP1 halts cell cycling and induces apoptosis. These observations demonstrate that Wnt signaling is dysregulated in GSC, and that inhibition of the Wnt pathway could serve as a therapeutic strategy in the treatment of GBM. - Highlights: • A comparison of GSCs to ahNSCs reveals Wnt-pathway dysregulation. • A signature of six Wnt-genes is present in all nine primary tumors. • The expression of three Wnt-genes reduces median survival from 38 to 17 months. • Treatment with SFRP1 decreases in vitro proliferation and sphere formation. • SFRP1 regulates GSC tumorigenicity through regulation of cell cycle and apoptosis.
- OSTI ID:
- 22746398
- Journal Information:
- Experimental Cell Research, Vol. 340, Issue 1; Other Information: Copyright (c) 2015 Elsevier Science B.V., Amsterdam, The Netherlands, All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0014-4827
- Country of Publication:
- United States
- Language:
- English
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