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Thromb Haemost 1998; 80(03): 407-412
DOI: 10.1055/s-0037-1615221
Rapid Communications
Schattauer GmbH

Prothrombin and Its Derivatives Stimulate Motility of Melanoma Cells

Hong Zhou
1   From the Department of Molecular Pathobiology, Tsu-city, Mie Japan
,
Esteban C. Gabazza
1   From the Department of Molecular Pathobiology, Tsu-city, Mie Japan
2   From the Third Department of Internal Medicine, Mie University School of Medicine, Tsu-city, Mie Japan
,
Hiroyuki Takeya
1   From the Department of Molecular Pathobiology, Tsu-city, Mie Japan
,
Hiroshi Deguchi
1   From the Department of Molecular Pathobiology, Tsu-city, Mie Japan
,
Hajime Urano
1   From the Department of Molecular Pathobiology, Tsu-city, Mie Japan
,
Yukihiko Adachi
2   From the Third Department of Internal Medicine, Mie University School of Medicine, Tsu-city, Mie Japan
,
Koji Suzuki
1   From the Department of Molecular Pathobiology, Tsu-city, Mie Japan
› Author Affiliations
Further Information

Publication History

Received 06 October 1997

Accepted after resubmission 29 May 1998

Publication Date:
08 December 2017 (online)

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Summary

Several studies indicated that activation of the clotting system may promote the growth and the invasive behavior of tumor cells. In the present study, we evaluated the migratory response of various melanoma cell lines to several clotting factors and prothrombin derivatives (thrombin, fragment 1, fragment 2 and kringle 1 fragment). Prothrombin, thrombin and fragment 1 stimulated chemotaxis of the murine (K-1735 M2, X21) and human A375 (SM) melanoma cell lines. Prothrombin and prothrombin fragment 1 showed their maximal chemo-tactic activity at 0.5~1 μM. Chemotaxis induced by thrombin was inhibited by hirudin, but not that induced by prothrombin or fragment 1. Other clotting proteins and the fragment 2 and kringle 1 fragment of prothrombin did not elicit chemotactic activity. Checkerboard analysis indicated that motility was directional with a significant chemokinetic component. The K-1735 M2 cells also migrated in a concentration-dependent manner to substratum-bound insoluble prothrombin, thrombin or fragment 1. Ligand binding assays showed that both prothrombin and fragment 1 bound to K-1735 M2 cells with apparent Kds of 0.5 μM. This binding was inhibited by an excess concentration of unlabeled prothrombin and fragment 1 but not by similar concentrations of other prothrombin fragments. These findings suggest that prothrombin and its fragment 1 exert chemotactic activity on melanoma cells by different mechanisms and different binding sites from that induced by thrombin.

 

  • References

  • 1 Gasic G, Tuszynski GP, Gorelik E. Interaction of the hemostatic and immune system in the metastatic spread of tumor cells. Inter Review of Exp Pathol 1986; 29: 173-212.
    PubMedSearch in Google Scholar
  • 2 Dvorak HF. Thrombosis and cancer. Human Pathol 1987; 18: 275-84.
    CrossrefPubMedSearch in Google Scholar
  • 3 Gordon SG. Cancer cell procoagulants and their role in malignant disease. Semin Thromb Hemost 1992; 18: 424-33.
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Esumi N, Fan D, Fidler IJ. Inhibition of murine melanoma experimental metastasis by recombinant desulfatohirudin, a highly specific thrombin inhibitor. Cancer Res 1991; 51: 4549-56.
    PubMedSearch in Google Scholar
  • 5 Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell Jr CJ, Forcier RJ, Edwards R, Headley E, Kim SH, O’Donnell JR, O’Dell R, Tornyos K, Kwaan HC. Effect of warfarin on survival in small cell carcinoma of the lung. JAMA 1981; 245: 831-5.
    CrossrefPubMedSearch in Google Scholar
  • 6 Wojtukiewicz MZ, Zacharski LR, Moritz TE, Hur K, Edward RL, Rickles FR. Prognostic significance of blood coagulation tests in carcinoma of the lung and colon. Blood Coagul Fibrinol 1992; 3: 429-37.
    CrossrefPubMedSearch in Google Scholar
  • 7 Mann KG. Prothrombin and thrombin. In: Hemostasis and Thrombosis. Basic Principles and Clinical Practice. Colman RW, Hirsh J, Marder VJ, Salzman EW. eds. Philadelphia: J B Lippincott; 1994: 184-99.
    Search in Google Scholar
  • 8 Bruhn HD, Zorborn KH. Influences of clotting factors (thrombin, factor XIII) and of fibronectin on the growth of tumor cells and leukemic cells in vitro. Blut. 1983; 46: 85-8.
    CrossrefPubMedSearch in Google Scholar
  • 9 Medrano EE, Cafferata EGA, Cancher F. Role of thrombin in the proliferative response of T-47D mammary tumor cells. Exp. Cell Res 1987; 172: 354-64.
    CrossrefPubMedSearch in Google Scholar
  • 10 Wojtukiewicz MZ, Tang DG, Ciarelli JJ, Nelson KK, Walz DA, Diglio CA, Mammen EF, Honn KV. Thrombin increases the metastatic potential of tumor cells. Int J Cancer 1993; 54: 793-806.
    CrossrefPubMedSearch in Google Scholar
  • 11 Shavit RB, Kahn A, Fenton II JW, Wilner GD. Chemotactic response of monocytes to thrombin. J Cell Biol 1983; 96: 282-5.
    CrossrefPubMedSearch in Google Scholar
  • 12 Dawes KE, Gray AJ, Laurent GJ. Thrombin stimulates fibroblast chemo-taxis and replication. Europ J Cell Biol 1993; 61: 126-30.
    PubMedSearch in Google Scholar
  • 13 Noda HH, Sobel BE. Vascular smooth muscle cell migration mediated by thrombin and urokinase receptor. American J Physiol 1995; 268 Cell Physiol. (37) C1195-1201.
    PubMedSearch in Google Scholar
  • 14 Suzuki K, Stenflo J, Dahlback B, Teodorsson B. Inactivation of human coagulation factor V by activated protein C. J Biol Chem 1983; 258: 1914-20.
    PubMedSearch in Google Scholar
  • 15 Miletich JP, Broze GJ, Majerus PW. The synthesis of sulfated dextran beads for isolation of human plasma coagulation factors II, IX, and X. Anal Biochem 1980; 105: 304-10.
    CrossrefPubMedSearch in Google Scholar
  • 16 DiScipio RG, Hermodson MA, Davie EW. Activation of human factor X (Stuart factor) by a protease from Russells viper venom. Biochemistry 1977; 16: 5253-60.
    CrossrefPubMedSearch in Google Scholar
  • 17 Suzuki K, Dahlback B, Stenflo J. Thrombin-catalyzed activation of human coagulation factor V. J Biol Chem 1982; 257: 6556-64.
    PubMedSearch in Google Scholar
  • 18 Deguchi H, Takeya H, Gabazza EC, Nishioka J, Suzuki K. Prothrombin kringle 1 domain interacts with factor Va during the assembly of prothrombinase complex. Biochem J 1997; 321: 729-35.
    CrossrefPubMedSearch in Google Scholar
  • 19 Sullivan SJ, Zigmond SH. Chemotactic peptide receptor modulation in polymorphonuclear leukocytes. J Cell Biol 1980; 85: 703-11.
    CrossrefPubMedSearch in Google Scholar
  • 20 Mc Carthy JB, Palm SL, Furcht LT. Migration by haptotaxis of a Schwann cell tumor line to the basement membrane glycoprotein laminin. J Cell Biol 1983; 97: 772-7.
    CrossrefPubMedSearch in Google Scholar
  • 21 Rickles FR, Edwards R. Activation of blood coagulation in cancer: Trousseau’s syndrome revisited. Blood 1983; 62: 14-31.
    PubMedSearch in Google Scholar
  • 22 Zacharski LR, Wojtukiewicz MZ, Costantini V, Ornstein DL, and Memoli VA. Pathways of coagulation / fibrinolysis activation in malignancy. Semin Thromb Hemost 1992; 18: 104-16.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Weiss L, Orr FW, Honn KV. Interactions of cancer cells with the micro-vasculature during metastasis. FASEB J 1987; 2: 12-21.
    PubMedSearch in Google Scholar
  • 24 Dvorak HF, Harvey VS, Estrella P, Brown LF, Mcdonagh J, Dvorak AM. Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing. Lab Invest 1987; 57: 673-86.
    PubMedSearch in Google Scholar
  • 25 Olander JV, Bremer ME, Marasa JC, Feder J. Fibrin enhanced endothelial cell organization. J Cell Physiol 1985; 125: 1-9.
    CrossrefPubMedSearch in Google Scholar
  • 26 Rickles FR, Edward RL, Barb C, Cronlund M. Abnormalities of blood coagulation in patients with cancer. Cancer 1983; 15: 301-7.
    PubMedSearch in Google Scholar
  • 27 Ambrosin G, Plescia J, Chu KC, High KA, Altieri DC. Activation-dependent exposure of the inter-EGF sequence Leu83-Leu88 in factor Xa mediates ligand binding to effector cell protease receptor-1. J Biol Chem 1997; 272: 8340-5.
    CrossrefPubMedSearch in Google Scholar
  • 28 Krishnaswamy S. Prothrombinase complex assembly. Contributions of protein-protein and protein-membrane interactions toward complex formation. J Biol Chem 1990; 265: 3708-18.
    PubMedSearch in Google Scholar
  • 29 Kotkow KJ, Furie B, Furie BC. The interaction of prothrombin with phospholipid membranes is independent of either kringle domain. J Biol Chem 1993; 268: 15633-9.
    PubMedSearch in Google Scholar
  • 30 Byzova TV, Plow EF. Networking in the hemostatic system. Integrin αIIβ3 binds prothrombin and influences its activation. J Biol Chem 1997; 272: 27183-8.
    CrossrefPubMedSearch in Google Scholar