title: The contribution of tumor and host tissue factor expression to oncogene-driven gliomagenesis.
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.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Magnus
authors.forename: Brian
authors.initials: B
authors.lastname: Meehan
authors.forename: Delphine
authors.initials: D
authors.lastname: Garnier
authors.forename: Maryam
authors.initials: M
authors.lastname: Hashemi
authors.forename: Laura
authors.initials: L
authors.lastname: Montermini
authors.forename: Tae Hoon
authors.initials: TH
authors.lastname: Lee
authors.forename: Chloe
authors.initials: C
authors.lastname: Milsom
authors.forename: Rafal
authors.initials: R
authors.lastname: Pawlinski
authors.forename: John
authors.initials: J
authors.lastname: Ohlfest
authors.forename: Mark
authors.initials: M
authors.lastname: Anderson
authors.forename: Nigel
authors.initials: N
authors.lastname: Mackman
authors.forename: Janusz
authors.initials: J
authors.lastname: Rak
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D009857:Oncogenes; D011379:Prognosis; D013925:Thromboplastin / Q000235:genetics* / Q000378:metabolism
chemical_list: C410723:epidermal growth factor receptor VIII; D013925:Thromboplastin; D066246:ErbB Receptors