Methylation-dependent Tissue Factor Suppression Contributes to the Reduced Malignancy of IDH1-mutant Gliomas.

PURPOSE

Gliomas with mutations (IDH1) are less aggressive than IDH1 wild-type (IDH1) gliomas and have global genomic hypermethylation. Yet it is unclear how specific hypermethylation events contribute to the IDH1 phenotype. Previously, we showed that the gene encoding the procoagulant tissue factor (TF), , is among the most hypermethylated and downregulated genes in IDH1 gliomas, correlating with greatly reduced thrombosis in patients with IDH1 glioma. Because TF also increases the aggressiveness of many cancers, the current study explored the contribution of TF suppression to the reduced malignancy of IDH1 gliomas. TF expression was manipulated in patient-derived IDH1 and IDH1 glioma cells, followed by evaluation of and behavior and analyses of cell signaling pathways.

RESULTS

A demethylating agent, decitabine, increased transcription and TF-dependent coagulative activity in IDH1 cells, but not in IDH1 cells. TF induction enhanced the proliferation, invasion, and colony formation of IDH1 cells, and increased the intracranial engraftment of IDH1 GBM164 from 0% to 100% ( = 0.0001). Conversely, TF knockdown doubled the median survival of mice engrafted with IDH1/EGFRvIII GBM6, and caused complete regression of IDH1/EGFR GBM12 ( = 0.001). and effects were linked to activation of receptor tyrosine kinases (RTK) by TF through a Src-dependent intracellular pathway, even when extracellular RTK stimulation was blocked. TF stimulated invasion predominately through upregulation of β-catenin.

CONCLUSIONS

These data show that TF suppression is a component of IDH1 glioma behavior, and that it may therefore be an attractive target against IDH1 gliomas.