Heterogeneous activation of the TGFβ pathway in glioblastomas identified by gene expression-based classification using TGFβ-responsive genes

Background: TGF beta has emerged as an attractive target for the therapeutic intervention of glioblastomas. Aberrant TGF beta overproduction in glioblastoma and other high-grade gliomas has been reported, however, to date, none of these reports has systematically examined the components of TGF beta signaling to gain a comprehensive view of TGF beta activation in large cohorts of human glioma patients. Methods: TGF beta activation in mammalian cells leads to a transcriptional program that typically affects 5-10% of the genes in the genome. To systematically examine the status of TGF beta activation in high-grade glial tumors, we compiled a gene set of transcriptional response to TGF beta stimulation from tissue culture and in vivo animal studies. These genes were used to examine the status of TGF beta activation in high-grade gliomas including a large cohort of glioblastomas. Unsupervised and supervised classification analysis was performed in two independent, publicly available glioma microarray datasets. Results: Unsupervised and supervised classification using the TGF beta-responsive gene list in two independent glial tumor gene expression data sets revealed various levels of TGF beta activation in these tumors. Among glioblastomas, one of the most devastating human cancers, two subgroups were identified that showed distinct TGF beta activation patterns as measured from transcriptional responses. Approximately 62% of glioblastoma samples analyzed showed strong TGF beta activation, while the rest showed a weak TGF beta transcriptional response. Conclusion: Our findings suggest heterogeneous TGF beta activation in glioblastomas, which may cause potential differences in responses to anti-TGF beta therapies in these two distinct subgroups of glioblastomas patients.