title: PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma.
abstract: We have previously proposed that intravascular thrombosis and subsequent vasoocclusion contribute to the development of pseudopalisading necrosis, a pathologic hallmark that distinguishes glioblastoma (WHO grade 4) from lower grade astrocytomas. To better understand the potential prothrombotic mechanisms underlying the formation of these structures that drive tumor angiogenesis, we investigated tissue factor (TF), a potent procoagulant protein known to be overexpressed in astrocytomas. We hypothesized that PTEN loss and tumor hypoxia, which characterize glioblastoma but not lower grade astrocytomas, could up-regulate TF expression and cause intravascular thrombotic occlusion. We examined the effect of PTEN restoration and hypoxia on TF expression and plasma coagulation using a human glioma cell line containing an inducible wt-PTEN cDNA. Cell exposure to hypoxia (1% O(2)) markedly increased TF expression, whereas restoration of wt-PTEN caused decreased cellular TF. The latter effect was at least partially dependent on PTEN's protein phosphatase activity. Hypoxic cells accelerated plasma clotting in tilt tube assays and this effect was prevented by both inhibitory antibodies to TF and plasma lacking factor VII, implicating TF-dependent mechanisms. To further examine the genetic events leading to TF up-regulation during progression of astrocytomas, we investigated its expression in a series of human astrocytes sequentially infected with E6/E7/human telomerase, Ras, and Akt. Cells transformed with Akt showed the greatest incremental increase in hypoxia-induced TF expression and secretion. Together, our results show that PTEN loss and hypoxia up-regulate TF expression and promote plasma clotting by glioma cells, suggesting that these mechanisms may underlie intravascular thrombosis and pseudopalisading necrosis in glioblastoma.
authors.affiliation: Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Rong
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Post
authors.forename: Russell O
authors.initials: RO
authors.lastname: Pieper
authors.forename: Donald L
authors.initials: DL
authors.lastname: Durden
authors.forename: Erwin G
authors.initials: EG
authors.lastname: Van Meir
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Brat
mesh_terms: D001777:Blood Coagulation / Q000502:physiology*; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D005909:Glioblastoma / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051059:PTEN Phosphohydrolase; D010711:Phosphatidate Phosphatase / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D013925:Thromboplastin / Q000096:biosynthesis* / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D018631:ras Proteins / Q000378:metabolism
chemical_list: D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D013925:Thromboplastin; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C112948:lipid phosphate phosphatase; D010744:Phosphoric Monoester Hydrolases; D010711:Phosphatidate Phosphatase; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins