Thrombomodulin suppresses invasiveness of HT1080 tumor cells by reducing plasminogen activation on the cell surface through activation of thrombin-activatable fibrinolysis inhibitor.
Cell malignancy is negatively correlated with the expression of thrombomodulin (TM), a thrombin receptor expressed on the surface of various cells, including tumor cells. TM accelerates thrombin-activatable fibrinolysis inhibitor (TAFI) activation catalyzed by thrombin. The active form of TAFI (TAFIa) contributes to inhibition of plasmin formation through its carboxypeptidase B (CPB)-like activity. Here, we examined whether TM- and tumor cell-dependent TAFI activation participates in controlling pericellular fibrinolysis and cell invasion. Human fibrosarcoma HT1080 cells retained the ability to activate both prothrombin and plasminogen, but did not express TM. HT1080 cells mediated activation of TAFI in plasma in the presence of soluble-type TM (sTM) through cell-dependent prothrombin activation. HT1080 cells stably expressing TM (TM-HT1080) mediated plasma TAFI activation without added sTM, but HT1080 (wild-type) and Mock-transfected HT1080 cells (Mock) did not. Production of TAFIa suppressed cell-mediated plasminogen activation. Matrigel invasion by wild-type and Mock cells was enhanced two-fold by diluted plasma (10%), whereas the plasma-induced invasion of TM-HT1080 cells (65% of wild-type invasion) was lower than those of wild-type and Mock cells. Cell invasion by TM-HT1080 was partially enhanced by addition of a TAFIa/CPB inhibitor. These results suggest that TM suppresses pericellular fibrinolysis and plasma-induced tumor cell invasion, and that it is mediated, at least in part, by plasma TAFI activation.
Higuchi
Toshiyuki
T
Department of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, Tokyo, Japan. higuchi@nichiyaku.ac.jp
Nakamura
Takashi
T
Kakutani
Hideki
H
Ishii
Hidemi
H
D017306:Annexin A2 / Q000378:metabolism; D000970:Antineoplastic Agents; D025901:Carboxypeptidase B2 / Q000187:drug effects / Q000378:metabolism*; D045744:Cell Line, Tumor; D006801:Humans; D009361:Neoplasm Invasiveness; D010960:Plasminogen Activators / Q000037:antagonists & inhibitors*; D011516:Prothrombin / Q000378:metabolism; D011956:Receptors, Cell Surface; D013917:Thrombin / Q000494:pharmacology*; D018180:Thrombomodulin / Q000502:physiology*
D017306:Annexin A2; D000970:Antineoplastic Agents; D011956:Receptors, Cell Surface; D018180:Thrombomodulin; D011516:Prothrombin; D025901:Carboxypeptidase B2; D010960:Plasminogen Activators; D013917:Thrombin