Transforming growth factor-β pathway activity in glioblastoma
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Karl Frei1,*, Dorothee Gramatzki2,*, Isabel Tritschler2, Judith Johanna Schroeder2, Larisa Espinoza1, Elisabeth Jane Rushing3 and Michael Weller2,4
1 Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland
2 Laboratory for Molecular Neuro-Oncology, Department of Neurology, University Hospital Zurich, Zurich, Switzerland
3 Department of Neuropathology, University Hospital Zurich, Zurich, Switzerland
4 Neuroscience Center Zurich, University of Zurich, Zurich, Switzerland
* These authors share first authorship
Michael Weller, email:
Keywords: TGF-β, PDGF-B, PAI-1, glioblastoma, biomarker
Received: November 20, 2014 Accepted: January 22, 2015 Published: February 28, 2015
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.
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