Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells

Oncogene. 2000 Aug 31;19(37):4210-20. doi: 10.1038/sj.onc.1203783.


Cellular resistance to multiple proapoptotic stimuli and invasion of surrounding brain tissue by migrating tumor cells are main obstacles to an effective therapy for human malignant glioma. Here, we report that the Wnt family of embryonic differentiation genes modulate growth of malignant glioma cells in vitro and in vivo and inhibit cellular migration in vitro. sFRPs (soluble Frizzled-related proteins) are soluble proteins that bind to Wnt and interfere with Wnt signaling. We find that sFRP-1 and sFRP-2 are produced by the majority of longterm and ex vivo malignant glioma cell lines. Glioma cells that ectopically express sFRPs exhibit increased clonogenicity and enhanced resistance to serum starvation. In contrast, sFRPs do not modulate glioma cell susceptibility to apoptosis induced by the cytotoxic cytokines, CD95 (Fas/APO-1) ligand (CD95L) or Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL), or various cytotoxic drugs. sFRP-2 strongly promotes the growth of intracranial glioma xenografts in nude mice. In contrast, enhanced expression of sFRPs inhibits the motility of glioma cells in vitro. sFRP-mediated effects on glioma cells are accompanied by decreased expression and activity of matrix metalloproteinase-2 (MMP-2) and decreased tyrosine phosphorylation of beta-catenin. Thus, sFRPs promote survival under non-supportive conditions and inhibit the migration of glioma cells. We suggest that the regulation of these cellular processes involves expression of MMP-2 and tyrosine phosphorylation of beta-catenin. These data support a function for Wnt signaling and its modulation by sFRPs in the biology of human gliomas. Oncogene (2000) 19, 4210 - 4220

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology*
  • Cell Division / drug effects
  • Cell Movement / drug effects
  • Cell Survival
  • Clone Cells / pathology
  • Culture Media, Serum-Free
  • Cytoskeletal Proteins / metabolism
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Matrix Metalloproteinase 2 / physiology
  • Membrane Proteins*
  • Mice
  • Mice, Nude
  • Neoplasm Proteins / physiology*
  • Neoplasm Transplantation
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Proteins / physiology*
  • Proto-Oncogene Proteins / antagonists & inhibitors
  • Proto-Oncogene Proteins / physiology
  • Trans-Activators*
  • Transplantation, Heterologous
  • Tumor Cells, Cultured / drug effects
  • Tumor Cells, Cultured / metabolism
  • Tumor Cells, Cultured / transplantation
  • Wnt Proteins
  • Zebrafish Proteins*
  • beta Catenin


  • Antineoplastic Agents
  • CTNNB1 protein, human
  • CTNNB1 protein, mouse
  • Culture Media, Serum-Free
  • Cytoskeletal Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Neoplasm Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • SFRP2 protein, human
  • Sfrp2 protein, mouse
  • Trans-Activators
  • WD repeat containing planar cell polarity effector
  • Wnt Proteins
  • Zebrafish Proteins
  • beta Catenin
  • Matrix Metalloproteinase 2