Tissue factor mediates the HGF/Met-induced anti-apoptotic pathway in DAOY medulloblastoma cells

Abstract

The classical treatment scheme for medulloblastoma (MB) is based on a tri-therapy approach consisting of surgical tumor resection, craniospinal axis radiation and chemotherapy. With current treatments relying mainly on non-specific cytotoxic therapy, a better understanding of the mechanisms underlying resistance to these treatments is important in order to improve their effectiveness. In this study, we report that stimulation of DAOY with HGF resulted in the protection of these cells against etoposide-induced apoptosis, this anti-apoptotic effect being correlated with an increase in the expression of tissue factor (TF), the initiator of the extrinsic pathway of coagulation. HGF-mediated protection from apoptosis was abolished by a c-Met inhibitor as well as by siRNA-mediated reduction of TF levels, implying a central role of Met-dependent induction of TF expression in this process. Accordingly, stimulation of DAOY with FVIIa, the physiological ligand of TF, also resulted in a significant protection from etoposide-mediated cytotoxicity. Overall, our results suggest the participation of the haemostatic system to drug resistance in MB and may thus provide novel therapeutic approaches for the treatment of these tumors.