Transforming growth factor-β pathway activity in glioblastoma

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-β(1-3), platelet-derived growth factor (PDGF)-B, and plasminogen activator inhibitor (PAI)-1 mRNA by RT-PCR and for the levels of TGF-β(1-3) protein, phosphorylated Smad2 (pSmad2), pSmad1/5/8 and PAI-1 by immunohistochemistry. Among the TGF-β isoforms, TGF-β(1) mRNA was the most, whereas TGF-β(3) mRNA was the least abundant. TGF-β(1-3) mRNA expression was strongly correlated, as was the expression of TGF-β(1-3) mRNA, and of the TGF-β(1-3) target genes, PDGF-B and PAI-1. TGF-β(2) and TGF-β(3) protein levels correlated well, whereas the comparison of the other TGF-βisoforms did not. Positive correlation was also observed between TGF-β(1) 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-β(2) 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.