THROMBOMODULIN MODULATES GROWTH OF TUMOR-CELLS INDEPENDENT OF ITS ANTICOAGULANT ACTIVITY

Thrombomodulin (TM), recognized as an essential vessel wall cofactor o f the antithrombotic mechanism, is also expressed by a wide range of t umor cells. Tumor cell lines subcloned from four patients with maligna nt melanoma displayed a negative correlation between TM expression and cell proliferation in vitro and in vivo. Overexpression of wild-type TM decreased cell proliferation in vitro and tumor growth in vivo. TM mutants with altered protein C activation capacity lead to a similar e ffect. In contrast, transfection of melanoma cells with mutant TM cons tructs, in which a portion of the cytoplasmic or lectin domain was del eted, abrogated the antiproliferative effect associated with overexpre ssion of wild-type TM. Experiments performed with either peptide agoni sts/antagonists of the thrombin receptor, with hirudin, or with inhibi tors of thrombin-TM interaction did not alter the growth inhibitory ef fect of TM overexpression, These data suggest that TM exerts an effect on cell proliferation independent of thrombin and the thrombin recept or, possibly related to the binding of novel ligands to determinants i n the lectin domain which might trigger signal transduction pathways d ependent on the cytoplasmic domain.