Oncogenic epidermal growth factor receptor up-regulates multiple elements of the tissue factor signaling pathway in human glioma cells.
Cancer cells frequently overexpress tissue factor (TF) and become procoagulant. This conversion may be driven by genetic transformation, including through the expression of the oncogenic epidermal growth factor receptor (EGFR) and its mutant, EGFRvIII, present in glioblastoma multiforme (GBM). Here we show that the EGFRvIII-dependent GBM cell transformation is associated with the onset of the simultaneous overexpression of TF, protease-activated receptors 1 and 2 (PAR1 and PAR2), and ectopic synthesis of factor VII (FVII). Efficient generation of factor Xa by these cells still requires exogenous FVIIa. However, as a result of EGFRvIII-dependent transformation, GBM cells become hypersensitive to TF/PAR-mediated signaling and produce ample angiogenic factors (vascular endothelial growth factor and interleukin-8) on exposure to FVIIa and PAR1- or PAR2-activating peptides. Thus, oncogenes may cause complex changes in the ability of GBM cancer cells to interact with the coagulation system, thereby exacerbating its influence on angiogenesis and disease progression.
Magnus
Nathalie
N
Montreal Children's Hospital, McGill University, Montreal, QC.
Garnier
Delphine
D
Rak
Janusz
J
D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor / Q000378:metabolism; D066246:ErbB Receptors / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D018773:Genes, erbB-1; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D009857:Oncogenes; D044463:Receptor, PAR-1 / Q000096:biosynthesis / Q000235:genetics; D044464:Receptor, PAR-2 / Q000096:biosynthesis / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D013925:Thromboplastin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000235:genetics*
D009363:Neoplasm Proteins; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D013925:Thromboplastin; C512478:EGFR protein, human; D066246:ErbB Receptors