Self-production of tissue factor-coagulation factor VII complex by ovarian cancer cells.
BACKGROUND
Thromboembolic events are a major complication in ovarian cancer patients. Tissue factor (TF) is frequently overexpressed in ovarian cancer tissue and correlates with intravascular thrombosis. TF binds to coagulation factor VII (fVII), changing it to its active form, fVIIa. This leads to activation of the extrinsic coagulation cascade. fVII is produced by the liver and believed to be supplied from blood plasma at the site of coagulation. However, we recently showed that ovarian cancer cells express fVII transcripts under normoxia and that this transcription is inducible under hypoxia. These findings led us to hypothesise that ovarian cancer cells are intrinsically associated with TF-fVIIa coagulation activity, which could result in thrombosis.


METHODS
In this study, we examined whether ectopically expressed fVII could cause thrombosis by means of immunohistochemistry, RT-PCR, western blotting and flow cytometry.


RESULTS
Ectopic fVII expression occurs frequently in ovarian cancers, particularly in clear cell carcinoma. We further showed that ovarian cancer cells express TF-fVIIa on the cell surface under normoxia and that this procoagulant activity is enhanced by hypoxic stimuli. Moreover, we showed that ovarian cancer cells secrete microparticles (MPs) with TF-fVIIa activity. Production of this procoagulant secretion is enhanced under hypoxia.


CONCLUSIONS
These results raise the possibility that cancer cell-derived TF-fVIIa could cause thrombotic events in ovarian cancer patients.
Yokota
N
N
Molecular Pathology and Genetics Division, Kanagawa Cancer Center Research Institute, 1-1-2 Nakao Asahi-ku, 241-0815 Yokohama, Japan.
Koizume
S
S
Miyagi
E
E
Hirahara
F
F
Nakamura
Y
Y
Kikuchi
K
K
Ruf
W
W
Sakuma
Y
Y
Tsuchiya
E
E
Miyagi
Y
Y
D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D055252:Cell-Derived Microparticles / Q000378:metabolism; D005167:Factor VII / Q000378:metabolism*; D005260:Female; D006801:Humans; D009375:Neoplasms, Glandular and Epithelial / Q000737:chemistry; D010051:Ovarian Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D013925:Thromboplastin / Q000378:metabolism*; D054556:Venous Thromboembolism / Q000209:etiology*
D005167:Factor VII; D013925:Thromboplastin