title: Wnt inhibition is dysregulated in gliomas and its re-establishment inhibits proliferation and tumor sphere formation.
abstract: 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.
authors.affiliation: Vilhelm Magnus Lab, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway; Cancer Stem Cell Innovation Center (CAST), Oslo University Hospital and University of Oslo, Gaustadalléen 34, 0372 Oslo, Norway; Norwegian Stem Cell Center, Oslo University Hospital and University of Oslo, P.O. Box 1112 Blindern, 0317 Oslo, Norway.
authors.forename: Kirsten Strømme
authors.initials: KS
authors.lastname: Kierulf-Vieira
authors.affiliation: Vilhelm Magnus Lab, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway; Cancer Stem Cell Innovation Center (CAST), Oslo University Hospital and University of Oslo, Gaustadalléen 34, 0372 Oslo, Norway; Norwegian Stem Cell Center, Oslo University Hospital and University of Oslo, P.O. Box 1112 Blindern, 0317 Oslo, Norway.
authors.forename: Cecilie J
authors.initials: CJ
authors.lastname: Sandberg
authors.affiliation: Vilhelm Magnus Lab, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway; Cancer Stem Cell Innovation Center (CAST), Oslo University Hospital and University of Oslo, Gaustadalléen 34, 0372 Oslo, Norway; Norwegian Stem Cell Center, Oslo University Hospital and University of Oslo, P.O. Box 1112 Blindern, 0317 Oslo, Norway.
authors.forename: Zanina
authors.initials: Z
authors.lastname: Grieg
authors.affiliation: Norwegian Computing Center, P.O. Box 114 Blindern, 0314 Oslo, Norway.
authors.forename: Clara-Cecilie
authors.initials: CC
authors.lastname: Günther
authors.affiliation: Vilhelm Magnus Lab, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway; Cancer Stem Cell Innovation Center (CAST), Oslo University Hospital and University of Oslo, Gaustadalléen 34, 0372 Oslo, Norway; Norwegian Stem Cell Center, Oslo University Hospital and University of Oslo, P.O. Box 1112 Blindern, 0317 Oslo, Norway; Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950/4956 Nydalen, 0424 Oslo, Norway.
authors.forename: Iver A
authors.initials: IA
authors.lastname: Langmoen
authors.affiliation: Vilhelm Magnus Lab, Institute for Surgical Research and Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950 Nydalen, 0424 Oslo, Norway; Cancer Stem Cell Innovation Center (CAST), Oslo University Hospital and University of Oslo, Gaustadalléen 34, 0372 Oslo, Norway; Norwegian Stem Cell Center, Oslo University Hospital and University of Oslo, P.O. Box 1112 Blindern, 0317 Oslo, Norway; Department of Neurosurgery, Oslo University Hospital, P.O. Box 4950/4956 Nydalen, 0424 Oslo, Norway.
authors.forename: Einar O
authors.initials: EO
authors.lastname: Vik-Mo
mesh_terms: D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism* / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D011994:Recombinant Proteins; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins
keywords: Cell cycle; Glioma stem cells; Prognosis; Secreted Frizzled-related protein 1 (SFRP1); Wnt