TUMOR-CELL PROCOAGULANT AND UROKINASE EXPRESSION IN CARCINOMA OF THE OVARY

Background: An association between cancer and increased blood coagulat ion has been observed for many years. Generally, there is an equilibri um between the coagulation system (fibrin deposition) and the fibrinol ytic system (degradation of fibrin by enzymes). However, in malignant disease such as ovarian carcinoma, this equilibrium is disrupted, resu lting in the abnormal activation of coagulation or hypercoagulability. Also, evidence indicates that various components of these pathways ma y contribute to the disorderly characteristics of malignancy, such as proliferation, invasion, and metastasis. Purpose: Our purpose was to d efine the mode of interaction of tumor cells in ovarian carcinoma with both the coagulation (procoagulant-initiated) and fibrinolysis (uroki nase-type plasminogen activator-initiated) (u-PA) pathways. Methods: S tudies were performed on acetone-methylbenzoate-xylene-fixed tissue pr epared from fresh resected primary tumor specimens from 15 patients wi th cystic epithelial ovarian carcinoma. None of the patients had recei ved prior treatment. Antibodies were tested on control and tumor tissu es in concentrations that provided maximum staining intensity with min imum background staining. Laboratory immunohistochemical techniques us ed purified, monospecific antibodies to detect coagulant antigens. Tes ts were performed utilizing antibodies to recombinant human tissue fac tor; factor VII; factor X; factor XIIIA; high-molecular-weight and low -molecular-weight forms of u-PA; tissue-type plasminogen activator; pl asminogen; and the plasminogen activator inhibitors 1, 2, and 3. Monoc lonal antibodies used for specific antigen detection included 1-8C6 (f ibrinogen), T2G1 (fibrin), and EBM-11 (macrophage-specific). Results: The ovarian tumor cells expressed urokinase-type plasminogen activator in a pattern that was variable in intensity and distribution. Tumor c ell plasminogen was not detected. Tumor cells also expressed tissue fa ctor and coagulation pathway intermediates that resulted in local thro mbin generation as evidenced by the conversion of fibrinogen (present in tumor connective tissue) to fibrin that was found to hug the surfac es of tumor nodules and individual tumor cells. Detected fibrin could not be accounted for on the basis of necrosis or a local inflammatory cell infiltrate. Conclusions: These results are consistent with the ex istence of a dominant tumor cell-associated procoagulant pathway that leads to thrombin generation and hypercoagulability in carcinoma of th e ovary. Implications: In ovarian carcinoma the procoagulant pathway m ay contribute to tumor progression. Clinical trials of therapeutic dru gs capable of limiting local coagulability (anticoagulants, protease i nhibitors) are indicated in this tumor type.