title: Transforming growth factor-β pathway activity in glioblastoma.
abstract: Transforming growth factor (TGF)-β is a central molecule maintaining the malignant phenotype of glioblastoma. Anti-TGF-β strategies are currently being explored in early clinical trials. Yet, there is little contemporary data on the differential expression of TGF-β isoforms at the mRNA and protein level or TGF-β/Smad pathway activity in glioblastomas in vivo.Here we studied 64 newly diagnosed and 16 recurrent glioblastomas for the expression of TGF-β1-3, platelet-derived growth factor (PDGF)-B, and plasminogen activator inhibitor (PAI)-1 mRNA by RT-PCR and for the levels of TGF-β1-3 protein, phosphorylated Smad2 (pSmad2), pSmad1/5/8 and PAI-1 by immunohistochemistry.Among the TGF-β isoforms, TGF-β1 mRNA was the most, whereas TGF-β3 mRNA was the least abundant. TGF-β1-3 mRNA expression was strongly correlated, as was the expression of TGF-β1-3 mRNA, and of the TGF-β1-3 target genes, PDGF-B and PAI-1. TGF-β2 and TGF-β3 protein levels correlated well, whereas the comparison of the other TGF-βisoforms did not. Positive correlation was also observed between TGF-β1 and pSmad1/5/8 and between pSmad2 and pSmad1/5/8. Survival analyses indicated that a group of patients with high expression levels of TGF-β2 mRNA or pSmad1/5/8 protein have inferior outcome.We thus provide potential biomarkers for patient stratification in clinical trials of anti-TGF-β therapies in glioblastoma.
authors: Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
authors: Karl
authors: K
authors: Frei
authors: Laboratory for Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors: Dorothee
authors: D
authors: Gramatzki
authors: Laboratory for Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors: Isabel
authors: I
authors: Tritschler
authors: Laboratory for Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland.
authors: Judith Johanna
authors: JJ
authors: Schroeder
authors: Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
authors: Larisa
authors: L
authors: Espinoza
authors: Department of Neuropathology, University Hospital Zurich, Zurich, Switzerland.
authors: Elisabeth Jane
authors: EJ
authors: Rushing
authors: Laboratory for Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland.|Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland.
authors: Michael
authors: M
authors: Weller
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D016212:Transforming Growth Factor beta
keywords: PAI-1; PDGF-B; TGF-β; biomarker; glioblastoma