Download PDF
Thromb Haemost 2001; 85(03): 494-501
DOI: 10.1055/s-0037-1615611
Review Article
Schattauer GmbH

Elevated Plasma Levels of Crosslinked Fibrinogen Gamma-chain Dimer Indicate Cancer-related Fibrin Deposition and Fibrinolysis

Christopher Gerner
1   Institute of Cancer Research, University of Vienna, Vienna, Austria
,
Werner Steinkellner
2   Otto-Warburg Society for Research in Immunology and Oncology, Grünburg, Austria
,
Klaus Holzmann
1   Institute of Cancer Research, University of Vienna, Vienna, Austria
,
Andrea Gsur
1   Institute of Cancer Research, University of Vienna, Vienna, Austria
,
Rudolf Grimm
3   Hewlett Packard, Chemical Analytical Division, Waldbronn, Germany
,
Christian Ensinger
4   Institute of Pathology, University of Innsbruck, Innsbruck, Austria
,
Peter Obrist
4   Institute of Pathology, University of Innsbruck, Innsbruck, Austria
,
Georg Sauermann
1   Institute of Cancer Research, University of Vienna, Vienna, Austria
› Author Affiliations
Further Information

Publication History

Received 14 December 1999

Accepted after resubmission 24 October 2000

Publication Date:
08 December 2017 (online)

    Permissions and Reprints

Summary

Cancer-related fibrin deposition and fibrinolysis were investigated by two-dimensional gel electrophoresis of human solid tumor and effusion specimen in addition to plasma samples. Fibrinogen gamma-chain dimer indicating fibrin deposition and plasmin-generated fibrinogen beta-chain fragments were identified in various solid tumor types by amino acid sequencing, mass spectrometry analysis and Western blotting. In tumor-associated effusions, these techniques allowed to observe plasmin-generated fragments of fibrinogen alpha, beta and gamma-chains in addition to elevated levels of acute-phase proteins. Similar observations were made in case of inflammation-associated effusions. No fibrin degradation product was observed in plasma samples, however, high amounts of fibrinogen gamma-chain dimer crosslinked by transglutaminase were detected in plasma from tumor patients, but not in plasma from controls and patients suffering acute infections and/or inflammations. This finding demonstrated that high transglutaminase activity may be associated with cancer. The presented data indicate that the amount of crosslinked fibrinogen gamma-chain dimer in plasma may correlate with tumor-associated fibrin deposition. The tumor-biological relevance of this potential marker protein is discussed.

Keywords

Cancer - fibrin deposition - fibrinolysis - plasma proteins - two-dimensional gel electrophoresis
 

  • References

  • 1 Nagy JA, Brown LF, Senger DR, Lanir N, Van-de-Water L, Dvorak AM, Dvorak HF. Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition. Biochim Biophys Acta 1989; 948: 305-26.
    PubMedGoogle Scholar
  • 2 Nakstad B, Lyberg T. Immunohistochemical localization of coagulation, fibrinolytic and antifibrinolytic markers in adenocarcinoma of the lung. APMIS 1991; 99: 981-8.
    CrossrefPubMedGoogle Scholar
  • 3 Dvorak HF. Abnormalities of Hemostasis in Malignant Disease. In: Hemostasis and Thrombosis. Basic Principles and Clinical Practice.. Colman RW, Hirsh J, Marder VJ, Salzmann EW. eds. Philadelphia: J. B. Lippincott; 1994: 1238-54.
    Google Scholar
  • 4 Semeraro N, Colucci M. Tissue factor in health and disease. Thromb Haemost 1997; 78: 759-64.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Contrino J, Hair G, Kreutzer DL, Rickles FR. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant pheno-type of human breast disease. Nat Med 1996; 2: 209-15.
    CrossrefPubMedGoogle Scholar
  • 6 Reich E. Activation of plasminogen: a widespread mechanism for generating localized extracellular proteolysis. In Biological Markers of Neoplasia: basic and Applied Aspects. Edited by Ruddon EW. New York: Elsevier; 1978: 491-500.
    Google Scholar
  • 7 Dano K, Behrendt N, Brünner N, Ellis V, Ploug M, Pyke C. The Urokinase Receptor. Protein Structure and Role in Plasminogen Activation and Cancer Invasion. Fibrinolysis 1994; 8 (Suppl. 01) 189-203.
    PubMedGoogle Scholar
  • 8 Vasalli JD, Sappino AP, Belin D. The plasminogen activator/plasmin system. J Clin Invest 1991; 88: 1067-72.
    CrossrefPubMedGoogle Scholar
  • 9 Pöllänen J, Stephens R, Vaheri A. Directed plasminogen activation at the surface of normal and malignant cells. Adv Cancer Res 1991; 57: 273-328.
    PubMedGoogle Scholar
  • 10 Dvorak RF. Thrombosis and cancer. Hum Pathol 1987; 18: 275-84.
    CrossrefPubMedGoogle Scholar
  • 11 Mitter CG, Zielinski CC. Plasma levels of D dimer: a crosslinked fibrin degradation product in female breast cancer. J Cancer Res Clin Oncol 1991; 117: 259-62.
    CrossrefPubMedGoogle Scholar
  • 12 Blackwell K, Haroon Z, Broadwater G, Berry D, Harris L, Iglehart JD, Dewhirst M, Greenberg C. Plasma D-dimer levels in operable breast cancer patients correlate with clinical stage and axillary lymph node status. J Clin Oncol 2000; 18: 600-8.
    CrossrefPubMedGoogle Scholar
  • 13 Bini A, Mesa Tejada R, Fenoglio Jr JJ, Kudryk B, Kaplan KL. Imunohisto-chemical characterization of fibrin(ogen)-related antigens in human tissues using monoclonal antibodies. Lab Invest 1989; 60: 814-21.
    PubMedGoogle Scholar
  • 14 Mannucci PM. Markers of Hypercoagulability in Cancer Patients. Haemostasis 1997; 27 (Suppl. 01) 25-31.
    PubMedGoogle Scholar
  • 15 Bottasso M, Mari D, Coppola R, Santoro N, Vaglini M, Manucci PM. Hypercoagulability and hyperfibrinolysis in patients with melanoma. Throm Res 1996; 81: 345-52.
    CrossrefPubMedGoogle Scholar
  • 16 Gotzmann J, Gerner C. 2000; A method to produce Ponceau-replicas from blots: Applications for Western analysis. Electrophoresis 21: 523-5.
    CrossrefPubMedGoogle Scholar
  • 17 Selmayr E, Mahn I, Muller-Berghaus G. Crosslinking of soluble fibrin and fibrinogen. Thromb Res 1985; 39: 467-74.
    CrossrefPubMedGoogle Scholar
  • 18 Jass JR, and Sobin LH. International Histological Classification of Tumors, WHO. New York: Springer Verlag New York, Inc.; 1989
    Google Scholar
  • 19 Union Internationale Contre le Cancer.. TNM Classification of Malignant Tumors. New York: Wiley-Liss, Inc.; 1997
    Google Scholar
  • 20 Gerner C, Holzmann K, Grimm R, Sauermann G. Similarity between nuclear matrix proteins of various cells revealed by an improved isolation method. J Cell Biochem 1998; 71: 363-74.
    CrossrefPubMedGoogle Scholar
  • 21 Hochstrasser DF, Harrington MG, Hochstrasser AC, Miller MJ, Merill CR. Methods for increasing the resolution of two-dimensional protein electrophoresis. Anal Biochem 1988; 173: 424-35.
    CrossrefPubMedGoogle Scholar
  • 22 Wray W, Boulikas T, Wray V, Hancock R. Silver staining of proteins in polyacrylamide gels. Anal Biochem 1981; 118: 197-203.
    CrossrefPubMedGoogle Scholar
  • 23 Sanchez JC, Appel RD, Golaz O, Pasquali C, Ravier F, Bairoch A, Hochstrasser DF. Inside SWISS-2DPAGE database. Electrophoresis 1995; 16: 1131-51.
    CrossrefPubMedGoogle Scholar
  • 24 Holzmann K, Korosec T, Gerner C, Grimm R, Sauermann G. Identification of human common nuclear-matrix proteins as heterogeneous nuclear ribonucleoproteins H and H’ by sequencing and mass spectrometry. Eur J Biochem 1997; 244: 479-86.
    CrossrefPubMedGoogle Scholar
  • 25 Fountoulakis M, Langen H. Identification of proteins by matrix-assisted laser desorption-mass spectrometry following in-gel digestion in low-salt, nonvolatile buffer and simplified peptide recovery. Anal. Biochem. 1997; 250: 153-6.
    CrossrefPubMedGoogle Scholar
  • 26 Wilkins MR, Williams KL. Cross-species identification using amino acid composition : a theoretical evaluation. J Theor Biol 1997; 186: 7-15.
    CrossrefPubMedGoogle Scholar
  • 27 Bjellqvist B, Hughes GJ, Pasquali Ch, Paquet N, Ravier F, Sanchez JCh, Frutiger S, and Hochstrasser DF. The focusing positions of polypeptides in immobilized pH gradients can be predicted from their amino acid sequences. Electrophoresis 1993; 14: 1023-31.
    CrossrefPubMedGoogle Scholar
  • 28 Gerner C, Holzmann K, Meissner M, Gotzmann J, Grimm R, Sauermann G. Reassembling proteins and chaperones in human nuclear matrix protein fractions. J Cell Biochem 1999; 74: 145-51.
    CrossrefPubMedGoogle Scholar
  • 29 Gerner C, Sauermann G. Nuclear matrix proteins specific for subtypes of human hematopoietic cells. J Cell Biochem 1999; 72: 470-82.
    CrossrefPubMedGoogle Scholar
  • 30 Francis CW, Marder VJ, Martin SE. Plasmic degradation of crosslinked fibrin. I. Structural analysis of the particulate clot and identification of new macromolecular-soluble complexes. Blood 1980; 56: 456-64.
    PubMedGoogle Scholar
  • 31 Spraggon G, Everse SJ, Doolittle RF. Crystal structures of fragment D from human fibrinogen and its crosslinked counterpart from fibrin. Nature 1997; 389: 455-62.
    CrossrefPubMedGoogle Scholar
  • 32 Dvorak HF, Nagy JA, Berse B, Brown LF, Yeo KT, Yeo TK, Dvorak AM, van de Water L, Sioussat TM, Senger DR. Vascular permeability factor, fibrin and the pathogenesis of tumor stroma formation. Ann N, Y Acad Sci 1992; 667: 101-11.
    CrossrefPubMedGoogle Scholar
  • 33 Wilhelm O, Hafter R, Henschen A, Schmitt M, Graeff H. Role of Plasmin in the Degradation of Stroma-Derived Fibrin in Human Ovarian Carcinoma. Blood 1990; 75: 1673-8.
    PubMedGoogle Scholar
  • 34 Wildenauer DB, Körschenhausen D, Hoechtlen W, Ackenheil M, Kehl M, Lottspeich F. Analysis of cerebrospinal fluid from patients with psychiatric and neurological disorders by two-dimensional electrophoresis: Identification of disease-associated polypeptides as fibrin fragments. Electrophoresis 1991; 12: 487-92.
    CrossrefPubMedGoogle Scholar
  • 35 Felcher A, Commichau C, Cao Q, Brown MJ, Torres A, Francis CW. Disseminated intravascular coagulation and status epilepticus. Neurology 1998; 51: 629-31.
    CrossrefPubMedGoogle Scholar
  • 36 Laudano AP, Doolittle RF. Studies on synthetic peptides that bind to fibrinogen and prevent fibrin polymerization. Structural requirements, number of binding sites, and species differences. Biochemistry 1980; 19: 1013-9.
    CrossrefPubMedGoogle Scholar
  • 37 Südhoff T, Schneider W. Fibrinolytic mechanisms in tumor growth and spreading. Clin Investig 1992; 70: 631-6.
    PubMedGoogle Scholar
  • 38 Donati MB. Cancer and thrombosis: from Phlegmasia alba dolens to transgenic mice. Thromb Haemost 1995; 74: 278-81.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 Nieswandt B, Hafner M, Echtenacher B, Mannel DN. Lysis of tumor cells by natural killer cells in mice is impeded by platelets. Cancer Res 1999; 59: 1295-3300.
    PubMedGoogle Scholar
  • 40 Chapman HA. Plasminogen activators, integrins and the coordinated regulation of cell adhesion and migration. Curr Op Cell Biol 1997; 9: 714-24.
    CrossrefPubMedGoogle Scholar
  • 41 Grand RJA, Turnell AS, Grabham PW. Cellular consequences of thrombin-receptor activation. Biochem J 1996; 313: 353-68.
    CrossrefPubMedGoogle Scholar
  • 42 Hoogland C, Sanchez J-C, Tonella L, Binz P-A, Bairoch A, Hochstrasser DF, Appel RD. The 1999 SWISS-2DPAGE database update. Nucleic Acids Res, 2000; 28: 286-8.
    CrossrefPubMedGoogle Scholar