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PTEN and hypoxia regulate tissue factor expression and
plasma coagulation by glioblastoma
Rong Y, Post DE, Pieper RO, Durden DL, Van Meir EG, Brat DJ
Department of Pathology and Laboratory Medicine, Winship Cancer Institute,
Emory University School of Medicine, Atlanta, Georgia, USA.
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.
PMID: 15735028 [PubMed - in process]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15735028
HTML Full Text: http://cancerres.aacrjournals.org/cgi/content/full/65/4/1406
PDF Full Text: http://cancerres.aacrjournals.org/cgi/reprint/65/4/1406
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