Secreted Frizzled-related proteins inhibit motility and promote growth of human malignant glioma cells.
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
Roth
W
W
Laboratory of Molecular Neuro-Oncology, Department of Neurology, University of Tübingen, School of Medicine, Hoppe-Seyler-Strasse 3, 72076 Tübingen, Germany.
Wild-Bode
C
C
Platten
M
M
Grimmel
C
C
Melkonyan
H S
HS
Dichgans
J
J
Weller
M
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology*; D002455:Cell Division / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival; D002999:Clone Cells / Q000473:pathology; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020778:Matrix Metalloproteinase 2 / Q000502:physiology; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000502:physiology*; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology; D015534:Trans-Activators; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; D000094742:Secreted Frizzled-Related Proteins
D000970:Antineoplastic Agents; D016895:Culture Media, Serum-Free; D003598:Cytoskeletal Proteins; D047908:Intracellular Signaling Peptides and Proteins; D020778:Matrix Metalloproteinase 2; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D000099274:Frizzled-Related Proteins; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; C109618:SFRP2 protein, human; D000094742:Secreted Frizzled-Related Proteins; C491628:Sfrp2 protein, mouse