Tmic-15. mutant idh1 suppresses the procoagulant and promalignant effects of tissue factor in gliomas

Gliomas are one of the cancers most at risk of causing life-threatening venous thromboemboli (VTE). Previously, we discovered that gliomas with mutations in isocitrate dehydrogenase (IDH1mut) are much less likely to contain intratumoral microthrombi, and are much less likely to cause peripheral VTE, compared to IDH1 wild-type (IDH1wt) gliomas. We also found that IDH1mut gliomas have methylation-associated suppression of Tissue Factor (TF), a key initiator of thrombosis. Furthermore, prior studies have shown that TF directly increases the malignancy of many cancers through multiple transmembrane signaling pathways. In the current study, we further explored the significance of TF in IDH1wt and IDH1mut gliomas. Three IDH1wt patient derived cell lines (GBM6, GBM12, GBM43) had high levels of TF protein and TF procoagulant activity in vitro, whereas 3 lines of patient-derived endogenous IDH1mut glioma cells (TB09, GBM164, BT142) had very low TF expression and activity. Exogenous treatment with the product of IDH1mut enzyme, D-2-hydroxyglutarate, suppressed the procoagulant activity of TF by up to 28% in IDH1wt cells. Likewise, induced expression of IDH1mut suppressed TF activity by 36% in IDH1wt cells. Thus far, in an ongoing prospective assessment of TF activity in the systemic circulation of glioma patients, 7/32 (22%) IDH1wt patients have had highly active circulating TF (defined as >2.0 pg/mL factor Xa generation), whereas 0/15 (0%) IDH1mut gliomas did—a pattern alread...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MICROENVIRONMENT Source Type: research