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 patient 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 specificity for TM. These antibodies detect TM antigen by means of flow cytofluorometry, laser scanning microscopy, immunocytochemistry, and ELISA. Therefore 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 malignant ovarian tumors and metastases of the omentum and intestine contain TM antigen as determined by ELISA but in significantly lower concentrations than benign ovarian tumors (p=0.0056). In contrast, malignant ascitic fluid of patients with advanced ovarian cancer (FIGO IIIc) contain significantly elevated concentrations of soluble TM than benign peritoneal exudates (p=0.0003). Immunoaffinity purified ascites-derived TM efficiently activates protein C. Protein C activation of ascites-derived TM as well as TM expressed by the tumor cells is inhibited by the monoclonal antibodies. TM abrogates the procoagulant activity of thrombin, reduces pericellular thrombin via internalization, accelerates 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 ascitic fluid may play an important role in the malignant behavior of tumor cells.
Wilhelm
S
S
Frauenklinik der Technischen Universitat Munchen, Klinikum rechts der Isar, D-81675 Munchen, Germany.
Schmitt
M
M
Parkinson
J
J
Kuhn
W
W
Graeff
H
H
Wilhelm
O G
OG
D000911:Antibodies, Monoclonal / Q000276:immunology; D000937:Antigen-Antibody Reactions / Q000276:immunology; D001202:Ascitic Fluid / Q000737:chemistry / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000737:chemistry / Q000378:metabolism / Q000556:secondary*; D011956:Receptors, Cell Surface / Q000378:metabolism; D018179:Receptors, Thrombin / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism; D018180:Thrombomodulin / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; D018180:Thrombomodulin; D012697:Serine Endopeptidases