The contribution of tumor and host tissue factor expression to oncogene-driven gliomagenesis |
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Authors: | Nathalie Magnus Brian Meehan Delphine Garnier Maryam Hashemi Laura Montermini Tae Hoon Lee Chloe Milsom Rafal Pawlinski John Ohlfest G Mark Anderson Nigel Mackman Janusz Rak |
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Institution: | 1. Montreal Children’s Hospital, RI MUHC, McGill University, Montreal, Quebec, Canada;2. Sunnybrook Research Institute, Toronto, Ontario, Canada;3. McAllister Heart Institute, Department of Medicine, University of North Carolina at Chapel Hill, USA;4. Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA;5. Biologics Research, Janssen Research & Development, Radnor, PA, USA |
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Abstract: | Glioblastoma multiforme (GBM) is an aggressive form of glial brain tumors, associated with angiogenesis, thrombosis, and upregulation of tissue factor (TF), the key cellular trigger of coagulation and signaling. Since TF is upregulated by oncogenic mutations occurring in different subsets of human brain tumors we investigated whether TF contributes to tumourigenesis driven by oncogenic activation of EGFR (EGFRvIII) and RAS pathways in the brain. Here we show that TF expression correlates with poor prognosis in glioma, but not in GBM. In situ, the TF protein expression is heterogeneously expressed in adult and pediatric gliomas. GBM cells harboring EGFRvIII (U373vIII) grow aggressively as xenografts in SCID mice and their progression is delayed by administration of monoclonal antibodies blocking coagulant (CNTO 859) and signaling (10H10) effects of TF in vivo. Mice in which TF gene is disrupted in the neuroectodermal lineage exhibit delayed progression of spontaneous brain tumors driven by oncogenic N-ras and SV40 large T antigen (SV40LT) expressed under the control of sleeping beauty transposase. Reduced host TF levels in low-TF/SCID hypomorphic mice mitigated growth of glioma subcutaneously but not in the brain. Thus, we suggest that tumor-associated TF may serve as therapeutic target in the context of oncogene-driven disease progression in a subset of glioma. |
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Keywords: | EGFR epidermal growth factor receptor EGFRvIII EGFR variant III GBM glioblastoma multiforme PAI-1 plasminogen activator inhibitor 1 PAR (1&ndash 4) protease activated receptor (1&ndash 4) RAS rat sarcoma oncogene SCID severe combined immunodeficiency (in mice) TF tissue factor VTE venous thromboembolism |
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