THROMBOMODULIN, A RECEPTOR FOR THE SERINE-PROTEASE THROMBIN, IS DECREASED IN PRIMARY TUMORS AND METASTASES BUT INCREASED IN ASCITIC FLUIDS OF PATIENTS WITH ADVANCED OVARIAN-CANCER FIGO-IIIC

The human ovarian cancer cell line OV-MZ-19). established from a patie nt with cystadenocarcinoma of the ovary, expressing thrombomodulin (TM ). a cell surface receptor for the serine protease thrombin, interacts with monoclonal and polyclonal antibodies having different specificit y for TM. These antibodies detect TM. antigen by means of flow cytoflu orometry, laser scanning microscopy, immunocytochemistry, and ELISA. T herefore a highly sensitive ELISA for TM antigen was established using two different monoclonal antibodies to quantify TM in tissue extracts and biological fluids, e.g. peritoneal malignant ascites. Primary mal ignant ovarian tumors and metastases of the omentum and intestine cont ain TM antigen as determined by ELISA but in significantly lower conce ntrations than benign ovarian tumors (p=0.0056). In contrast, malignan t ascitic fluid of patients with advanced ovarian cancer (FIGO IIIc:) contain significantly elevated concentrations of soluble TM than benig n peritoneal exudates (p=0.0003). Immunoaffinity purified ascites-deri ved TM efficiently activates protein C. Protein C activation of ascite s-derived TM as well as TM expressed by the tumor cells is inhibited b y the monoclonal antibodies. TM abrogates the procoagulant activity of thrombin, reduces pericellular thrombin via internalization. accelera tes the thrombin-mediated inactivation of pro-uPA, and the EGF domains of TM exhibit mitogenic activity towards fibroblasts and tumor cells. Both, thrombin and pro-uPA play important roles in tumor invasion and metastasis. Therefore, downregulation and/or release of TM into ascit ic fluid may play an important role in the malignant behavior of tumor cells.