Transforming growth factor-β pathway activity in glioblastoma

Transforming growth factor (TGF)-beta is a central molecule maintaining the malignant phenotype of glioblastoma. Anti-TGF-beta strategies are currently being explored in early clinical trials. Yet, there is little contemporary data on the differential expression of TGF-beta isoforms at the mRNA and protein level or TGF-beta/Smad pathway activity in glioblastomas in vivo. Here we studied 64 newly diagnosed and 16 recurrent glioblastomas for the expression of TGF-beta 1-3, platelet-derived growth factor (PDGF)-B, and plasminogen activator inhibitor (PAI)-1 mRNA by RT-PCR and for the levels of TGF-beta 1-3 protein, phosphorylated Smad2 (pSmad2), pSmad1/5/8 and PAI-1 by immunohistochemistry. Among the TGF-beta isoforms, TGF-beta 1 mRNA was the most, whereas TGF-beta 3 mRNA was the least abundant. TGF-beta 1-3 mRNA expression was strongly correlated, as was the expression of TGF-beta 1-3 mRNA, and of the TGF-beta 1-3 target genes, PDGF-B and PAI1. TGF-beta 2 and TGF-beta 3 protein levels correlated well, whereas the comparison of the other TGF-beta isoforms did not. Positive correlation was also observed between TGF-beta 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-beta 2 mRNA or pSmad1/5/8 protein have inferior outcome. We thus provide potential biomarkers for patient stratification in clinical trials of anti-TGF-beta therapies in glioblastoma.