Wnt inhibition is dysregulated in gliomas and its re-establishment inhibits proliferation and tumor sphere formation.
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.
['Kierulf-Vieira|Kirsten Strømme|KS|', 'Sandberg|Cecilie J|CJ|', 'Grieg|Zanina|Z|', 'Günther|Clara-Cecilie|CC|', 'Langmoen|Iver A|IA|', 'Vik-Mo|Einar O|EO|']
D001932:Brain Neoplasms D049109:Cell Proliferation D004305:Dose-Response Relationship, Drug D005909:Glioblastoma D005910:Glioma D006801:Humans D036341:Intercellular Signaling Peptides and Proteins D008565:Membrane Proteins D011994:Recombinant Proteins D060449:Wnt Signaling Pathway
Wnt Glioma stem cells Cell cycle Prognosis Secreted Frizzled-related protein 1 (SFRP1)