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

  • Laboratory Investigation - Human/Animal Tissue
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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.

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Abbreviations

MB:

Medulloblastoma

TF:

Tissue factor

RTK:

Receptor tyrosine kinase

HGF:

Hepatocyte growth factor

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Acknowledgements

We thank the Natural Sciences and Engineering Research Council of Canada (NSERC) and the Chair Claude-Bertrand in Neurosurgery for support of this work. Scholarship funding to Mathieu Provençal was provided by the MCETC/FRSQ/CIHR Strategic Training program in cancer Experimental Therapeutic. This work was supported by grants from the Natural Sciences and Engineering Research Council of Canada (NSERC).

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Authors and Affiliations

  1. Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, C.P. 8888, Succ. Centre-ville, Montreal, QC, H3C 3P8, Canada

    Mathieu Provençal, Nancy Berger-Thibault, David Labbé, Ryan Veitch, Dominique Boivin, Denis Gingras & Richard Béliveau

  2. Service d’Hématologie-Oncologie, Hôpital Ste-Justine, 3175, Chemin Côte-Sainte-Catherine, Montreal, QC, H3T 1C5, Canada

    Georges-Étienne Rivard

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  1. Mathieu Provençal
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  2. Nancy Berger-Thibault
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Correspondence to Richard Béliveau.

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Provençal, M., Berger-Thibault, N., Labbé, D. et al. Tissue factor mediates the HGF/Met-induced anti-apoptotic pathway in DAOY medulloblastoma cells. J Neurooncol 97, 365–372 (2010). https://doi.org/10.1007/s11060-009-0041-z

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  • DOI: https://doi.org/10.1007/s11060-009-0041-z

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