High TGFβ-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene

TGF beta acts as a tumor suppressor in normal epithelial cells and early-stage tumors and becomes an oncogenic factor in advanced tumors. The molecular mechanisms involved in the malignant function of TGF beta are not fully elucidated. We demonstrate that high TGF beta-Smad activity is present in aggressive, highly proliferative gliomas and confers poor prognosis in patients with glioma. We discern the mechanisms and molecular determinants of the TGF beta oncogenic response with a transcriptomic approach and by analyzing primary cultured patient-derived gliomas and human glioma biopsies. The TGF beta-Smad pathway promotes proliferation through the induction of PDGF-B in gliomas with an unmethylated PDGF-B gene. The epigenetic regulation of the PDGF-B gene dictates whether TGF beta acts as an oncogenic factor inducing PDGF-B and proliferation in human glioma.