Download PDF
Semin Thromb Hemost 2004; 30(1): 31-44
DOI: 10.1055/s-2004-822969
Copyright © 2004 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Tissue Factor and Fibrin in Tumor Angiogenesis

Patricia M. Fernandez1 , 2 , Steven R. Patierno1 , 2 , Frederick R. Rickles3
  • 1Department of Pharmacology, George Washington University Medical Center, Washington, DC, U.S.
  • 2Department of Urology, George Washington University Medical Center, Washington, DC, U.S.
  • 3Professor, Departments of Medicine and Pediatrics, George Washington University Medical Center, Washington, DC, U.S.
Further Information

Publication History

Publication Date:
22 March 2004 (online)

    Permissions and Reprints

The hypercoagulability exhibited by most cancer patients leads to serious complications such as venous thromboembolism and contributes to the pathogenesis of tumor growth and metastasis by promoting angiogenesis. The key player in this vicious cycle is tissue factor (TF), the initiator of blood coagulation. Although TF normally safeguards vascular integrity by inducing hemostasis upon injury, abnormal expression of TF in different tumors and related vascular endothelial cells contributes to unnecessary clot formation in cancer patients. Clotting-dependent induction of tumor angiogenesis is primarily mediated by TF-induced generation of thrombin and subsequent deposition of cross-linked fibrin. A cross-linked fibrin network provides a provisional proangiogenic matrix that facilitates blood vessel infiltration. Clotting-independent mechanisms of TF-induced tumor angiogenesis have also been described, mediated primarily by the cytoplasmic tail of the TF receptor. TF activation could contribute to the venous thromboembolism that has been reported as a complication of the use of novel antiangiogenic agents in combination with chemotherapy. Anticoagulants, such as low-molecular-weight heparin, may act to prevent these complications both by interfering with TF-mediated activation of clotting and by directly down-regulating angiogenesis. Thus, TF may prove to be a novel target for cancer therapy.

KEYWORDS

Tissue factor - fibrin - angiogenesis - low-molecular-weight heparin - clot

REFERENCES

  • 1 Trousseau A. Phlegmasia alba dolens. In: Clinique Médicale de l'Hôtel-Dieu de Paris Paris; JB Balliere et Fils 1865 3: 654-712
    Google Scholar
  • 2 Rickles F R, Levine M N, Dvorak H F. Abnormalities of hemostasis in malignancy. In: Colman RW, Hirsh J, Marder VJ, Clower AW, George JN Hemostasis and Thrombosis. Philadelphia, PA; Lippincott Williams & Wilkins 2001: 1131-1152
    Google Scholar
  • 3 Hillen H F. Thrombosis in cancer patients.  Ann Oncol. 2000;  11 273-276
    Google Scholar
  • 4 Nemerson Y, Repke D. Tissue factor accelerates the activation of coagulation factor VII: the role of a bifunctional coagulation cofactor.  Thomb Res. 1985;  40 351-358
    Google Scholar
  • 5 Morrissey J H, Macik B G, Neuenschwander P F, Comp P C. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation.  Blood. 1993;  81 734-744
    Google Scholar
  • 6 Morrissey J H. Tissue factor: an enzyme cofactor and a true receptor.  Thromb Haemost. 2001;  86 66-74
    PubMedGoogle Scholar
  • 7 Bajaj M S, Birktoft J J, Steer S A, Bajaj S P. Structure and biology of tissue factor pathway inhibitor.  Thromb Haemost. 2001;  86 959-972
    Google Scholar
  • 8 Carmeliet P, Mackman N, Moons L et al.. Role of tissue factor in embryonic blood vessel development.  Nature. 1996;  383 73-75
    CrossrefPubMedGoogle Scholar
  • 9 Bugge T H, Xiao Q, Kombrinck K W. Fatal embryonic bleeding events in mice lacking tissue factor, the cell-associated initiator of coagulation.  Proc Natl Acad Sci USA. 1996;  93 6258-6263
    CrossrefPubMedGoogle Scholar
  • 10 Toomey J R, Kratzer K E, Lasky N M, Stanton J J, Broze Jr G J. Targeted disruption of the murine tissue factor gene results in embryonic lethality.  Blood. 1996;  88 1583-1587
    PubMedGoogle Scholar
  • 11 Carmeliet P, Ferreira V, Breier G et al.. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele.  Nature. 1996;  380 435-439
    CrossrefPubMedGoogle Scholar
  • 12 Ferrara N, Carver-Moore K, Chen H et al.. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene.  Nature. 1996;  380 439-442
    CrossrefPubMedGoogle Scholar
  • 13 Peppelenbosch M P, Versteeg H H. Cell biology of tissue factor, an unusual member of the cytokine receptor family.  Trends Cardiovasc Med. 2001;  11 335-339
    CrossrefPubMedGoogle Scholar
  • 14 Contrino J, Hair G, Kreutzer D L, Rickles F R. In situ detection of tissue factor in vascular endothelial cells: correlation with the malignant phenotype of human breast disease.  Nat Med. 1996;  2 209-215
    CrossrefPubMedGoogle Scholar
  • 15 Ueno T, Toi M, Koike M, Nakamura S, Tominaga T. Tissue factor expression in breast cancer tissues: its correlation with prognosis and plasma concentration.  Br J Cancer. 2000;  83 164-170
    Google Scholar
  • 16 Hair G A, Padula S, Zeff R et al.. Tissue factor expression in human leukemic cells.  Leuk Res. 1996;  20 1-11
    CrossrefPubMedGoogle Scholar
  • 17 Guan M, Jin J, Su B, Liu W W, Lu Y. Tissue factor expression and angiogenesis in human glioma.  Clin Biochem. 2002;  35 321-325
    Google Scholar
  • 18 Guan M, Su B, Lu Y. Quantitative reverse transcription-PCR measurement of tissue factor mRNA in glioma.  Mol Biotechnol. 2002;  20 123-129
    CrossrefPubMedGoogle Scholar
  • 19 Koomagi R, Volm M. Tissue factor expression in human non-small-cell lung carcinoma measured by immunohistochemistry: correlation between tissue factor and angiogenesis.  Int J Cancer. 1998;  79 19-22
    CrossrefPubMedGoogle Scholar
  • 20 Sawada M, Miyake S, Ohdama S et al.. Expression of tissue factor in non-small-cell lung cancers and its relationship to metastasis.  Br J Cancer. 1999;  79 472-477
    Google Scholar
  • 21 Seto S, Onodera H, Kaido T et al.. Tissue factor expression in human colorectal carcinoma: correlation with hepatic metastasis and impact on prognosis.  Cancer. 2000;  88 295-301
    CrossrefPubMedGoogle Scholar
  • 22 Shigemori C, Wada H, Matsumoto K, Shiku H, Nakamura S, Suzuki H. Tissue factor expression and metastatic potential of colorectal cancer.  Thromb Haemost. 1998;  80 894-898
    PubMedGoogle Scholar
  • 23 Nakasaki T, Wada H, Shigemori C et al.. Expression of tissue factor and vascular endothelial growth factor is associated with angiogenesis in colorectal cancer.  Am J Hematol. 2002;  69 247-254
    Google Scholar
  • 24 Ueda C, Hirohata Y, Kihara Y et al.. Pancreatic cancer complicated by disseminated intravascular coagulation associated with production of tissue factor.  J Gastroenterol. 2001;  36 848-850
    Google Scholar
  • 25 Lwaleed B A, Cooper A J. Tissue factor expression and multidrug resistance in cancer: two aspects of a common cellular response to a hostile milieu.  Med Hypotheses. 2000;  55 470-473
    PubMedGoogle Scholar
  • 26 Abe K, Shoji M, Chen J et al.. Regulation of vascular endothelial growth factor production and angiogenesis by the cytoplasmic tail of tissue factor.  Proc Natl Acad Sci USA. 1999;  96 8663-8668
    Google Scholar
  • 27 Zhang Y, Deng Y, Luther T et al.. Tissue factor controls the balance of angiogenic and antiangiogenic properties of tumor cells in mice.  J Clin Invest. 1994;  94 1320-1327
    Google Scholar
  • 28 Shoji M, Hancock W W, Abe K et al.. Activation of coagulation and angiogenesis in cancer. Immunohistochemical localization in situ of clotting proteins and vascular endothelial growth factor in human cancer.  Am J Pathol. 1998;  152 399-411
    PubMedGoogle Scholar
  • 29 Mechtcheriakova D, Wlachos A, Holzmüller H, Binder B R, Hofer E. Vascular endothelial cell growth factor-induced tissue factor expression in endothelial cells is mediated by EGR-1.  Blood. 1999;  93 3811-3823
    PubMedGoogle Scholar
  • 30 Blum S, Issbruker K, Willuweit A et al.. An inhibitory role of the phosphatidylinositol 3-kinase signaling pathway in vascular endothelial growth factor-induced tissue factor expression.  J Biol Chem. 2001;  276 33428-33434
    CrossrefPubMedGoogle Scholar
  • 31 Kim I, Oh J-L, Ryu Y S et al.. Angiopoietin-1 negatively regulates expression and activity of tissue factor in endothelial cells.  FASEB J. 2002;  16 126-128
    PubMedGoogle Scholar
  • 32 Bach R. Mechanism of tissue factor activation on cells.  Blood Coagul Fibrinolysis. 1998;  9 S37-S43
    PubMedGoogle Scholar
  • 33 Nemerson Y, Giesen P L. Some thoughts about localization and expression of tissue factor.  Blood Coagul Fibrinolysis. 1998;  9 S45-S47
    PubMedGoogle Scholar
  • 34 Rao L V, Pendurthi U R. Tissue factor on cells.  Blood Coagul Fibrinolysis. 1998;  9 S27-S35
    PubMedGoogle Scholar
  • 35 Wolberg A S, Monroe D M, Roberts H R, Hoffman M R. Tissue factor deencryption: ionophore treatment induces changes in tissue factor activity by phosphatidylserine-dependent and -independent mechanisms.  Blood Coagul Fibrinolysis. 1999;  10 201-210
    PubMedGoogle Scholar
  • 36 Carson S D, Bromberg M E. Tissue factor encryption/de-encryption is not altered in the absence of the cytoplasmic domain.  Thromb Haemost. 2000;  84 657-663
    PubMedGoogle Scholar
  • 37 Sevinsky J R, Rao L V, Ruf W. Ligand-induced protease receptor translocation into caveolae: a mechanism for regulating cell surface proteolysis of the tissue factor-dependent coagulation pathway.  J Cell Biol. 1996;  133 293-304
    Google Scholar
  • 38 Shin J-S, Abraham S N. Caveolae-not just craters in the cellular landscape.  Science. 2001;  293 1447-1448
    CrossrefPubMedGoogle Scholar
  • 39 Carson S D. Manifestation of cryptic fibroblast tissue factor occurs at detergent concentrations which dissolve the plasma membrane.  Blood Coagul Fibrinolysis. 1996;  7 303-313
    PubMedGoogle Scholar
  • 40 Camera M, Giesen P LA, Fallon J et al.. Cooperation between VEGF and TNF-alpha is necessary for exposure of active tissue factor on the surface of human endothelial cells.  Arterioscler Thromb Vasc Biol. 1999;  19 531-537
    PubMedGoogle Scholar
  • 41 Rickles F R, Shoji M, Abe K. The role of the hemostatic system in tumor growth, metastasis, and angiogenesis: tissue factor is a bifunctional molecule capable of inducing both fibrin deposition and angiogenesis in cancer.  Int J Hematol. 2001;  73 145-150
    CrossrefPubMedGoogle Scholar
  • 42 Fernandez P M, Rickles F R. Tissue factor and angiogenesis in cancer.  Curr Opin Hematol. 2002;  9 401-406
    CrossrefPubMedGoogle Scholar
  • 43 Carmeliet P. Biomedicine. Clotting factors build blood vessels.  Science. 2001;  293 1602-1604
    CrossrefPubMedGoogle Scholar
  • 44 Coughlin S R. Protease-activated receptors in vascular biology.  Thromb Haemost. 2001;  86 298-307
    PubMedGoogle Scholar
  • 45 Rottingen J A, Enden T, Camerer E, Iversen J G, Prydz H. Binding of human factor VIIa to tissue factor induces cytosolic Ca2+ signals in J82 cells, transfected COS-1 cells, Madin-Darby canine kidney cells and in human endothelial cells induced to synthesize tissue factor.  J Biol Chem. 1995;  270 4650-4660
    CrossrefPubMedGoogle Scholar
  • 46 Poulsen L K, Jacobsen N, Sorensen B B et al.. Signal transduction via the mitogen-activated protein kinase pathway induced by binding of coagulation factor VIIa to tissue factor.  J Biol Chem. 1998;  273 6228-6232
    CrossrefPubMedGoogle Scholar
  • 47 Camerer E, Rottingen J A, Gjernes E et al.. Coagulation factors VIIa and Xa induce cell signaling leading to upregulation of the egr-1 gene.  J Biol Chem. 1999;  274 32225-32233
    CrossrefPubMedGoogle Scholar
  • 48 Sorensen B B, Freskgard P O, Nielsen L S, Rao L V, Ezban M, Petersen L C. Factor VIIa-induced p44/42 mitogen-activated protein kinase activation requires the proteolytic activity of factor VIIa and is independent of the tissue factor cytoplasmic domain.  J Biol Chem. 1999;  274 21349-21354
    CrossrefPubMedGoogle Scholar
  • 49 Chen J, Bierhaus A, Schiekofer S et al.. Tissue factor-a receptor involved in the control of cellular properties, including angiogenesis.  Thromb Haemost. 2001;  86 334-345
    PubMedGoogle Scholar
  • 50 Ollivier V, Bentolila S, Chabbat J, Hakim J, de Prost D. Tissue factor-dependent vascular endothelial growth factor production by human fibroblasts in response to activated factor VII.  Blood. 1998;  91 2698-2703
    PubMedGoogle Scholar
  • 51 Ollivier V, Chabbat J, Herbert J M, Hakim J, de Prost D. Vascular endothelial growth factor production by fibroblasts in response to factor VIIa binding to tissue factor involves thrombin and factor Xa.  Arterioscler Thromb Vasc Biol. 2000;  20 1374-1381
    PubMedGoogle Scholar
  • 52 Bromberg M E, Sundaram R, Homer R J, Garen A, Königsberg W H. Role of tissue factor in metastasis: functions of the cytoplasmic and extracellular domains of the molecule.  Thromb Haemost. 1999;  82 88-92
    PubMedGoogle Scholar
  • 53 Tsopanoglou N E, Pipili-Synetos E, Maragoudakis M E. Thrombin promotes angiogenesis by a mechanism independent of fibrin formation.  Am J Physiol. 1993;  264 C1302-C1307
    PubMedGoogle Scholar
  • 54 Richard D E, Vouret-Craviari V, Pouyssegur J. Angiogenesis and G-protein-coupled receptors: signals that bridge the gap.  Oncogene. 2001;  20 1556-1562
    CrossrefPubMedGoogle Scholar
  • 55 Tsopanoglou N E, Maragoudakis M E. On the mechanism of thrombin-induced angiogenesis. Potentiation of vascular endothelial growth factor activity on endothelial cells by up-regulation of its receptors.  J Biol Chem. 1999;  274 23969-23976
    CrossrefPubMedGoogle Scholar
  • 56 Wojtukiewicz M Z, Sierko E, Klement P, Rak J. The hemostatic system and angiogenesis in malignancy.  Neoplasia. 2001;  3 371-384
    Google Scholar
  • 57 Nagy J A, Brown L F, Senger D R et al.. Pathogenesis of tumor stroma generation: a critical role for leaky blood vessels and fibrin deposition.  Biochim Biophys Acta. 1989;  948 305-326
    PubMedGoogle Scholar
  • 58 Mosesson M W, Siebenlist K R, Meh D A. The structure and biological features of fibrinogen and fibrin.  Ann N Y Acad Sci. 2001;  936 11-30
    PubMedGoogle Scholar
  • 59 Medved L, Tsurupa G, Yakovlev S. Conformational changes upon conversion of fibrinogen into fibrin. The mechanisms of exposure of cryptic sites.  Ann N Y Acad Sci. 2001;  936 185-204
    PubMedGoogle Scholar
  • 60 Hantgan R P, Simpson-Haidaris P J, Francis C W, Marder V J. Fibrinogen structure and physiology. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN Hemostasis and Thrombosis. Basic Principles and Clinical Practice Philadelphia, PA; Lippincott Williams & Wilkins 2001: 203-232
    Google Scholar
  • 61 Doolittle R F. Fibrinogen and fibrin.  Sci Am. 1981;  245 126-135
    PubMedGoogle Scholar
  • 62 Bootle-Wilbraham C A, Tazzyman S, Marshall J M, Lewis C E. Fibrinogen E-fragment inhibits the migration and tubule formation of human dermal microvascular endothelial cells in vitro.  Cancer Res. 2000;  60 4719-4724
    PubMedGoogle Scholar
  • 63 Degen J L, Drew A F, Palumbo J S et al.. Genetic manipulation of fibrinogen and fibrinolysis in mice.  Ann N Y Acad Sci. 2001;  936 276-290
    PubMedGoogle Scholar
  • 64 Virchow R. Gesammelte Abhandlungen zur wissenschaftliden Medizin. Frankfurt, Germany; Meidinger Sohn 1856
    Google Scholar
  • 65 Altieri D C, Mannucci P M, Capitanio A M. Binding of fibrinogen to human monocytes.  J Clin Invest. 1986;  78 968-976
    PubMedGoogle Scholar
  • 66 Felding-Habermann B, Ruggeri Z M, Cheresh D A. Distinct biological consequences of integrin alpha v beta 3-mediated melanoma cell adhesion to fibrinogen and its plasmic fragments.  J Biol Chem. 1992;  267 5070-5077
    PubMedGoogle Scholar
  • 67 Dejana E, Languino L R, Polentarutti N et al.. Interaction between fibrinogen and cultured endothelial cells. Induction of migration and specific binding.  J Clin Invest. 1985;  75 11-18
    PubMedGoogle Scholar
  • 68 Donaldson D J, Mahan J T, Amrani D L, Farrell D H, Sobel J H. Further studies on the interaction of migrating keratinocytes with fibrinogen.  Cell Adhes Commun. 1994;  2 299-308
    PubMedGoogle Scholar
  • 69 Brown L F, Lanir N, McDonagh J, Tognazzi K, Dvorak A M, Dvorak H F. Fibroblast migration in fibrin gel matrices.  Am J Pathol. 1993;  142 273-283
    PubMedGoogle Scholar
  • 70 Naito M, Funaki C, Hayashi T et al.. Substrate-bound fibrinogen, fibrin and other cell attachment-promoting proteins as a scaffold for cultured vascular smooth muscle cells.  Atherosclerosis. 1992;  96 227-234
    CrossrefPubMedGoogle Scholar
  • 71 Henschen A, Lottspeich F, Kehl M, Southan C. Covalent structure of fibrinogen.  Ann N Y Acad Sci. 1983;  408 28-43
    PubMedGoogle Scholar
  • 72 Odrljin T M, Shainoff J R, Lawrence S O, Simpson-Haidaris P J. Thrombin cleavage enhances exposure of a heparin binding domain in the N-terminus of the fibrin beta chain.  Blood. 1996;  88 2050-2061
    PubMedGoogle Scholar
  • 73 Odrljin T M, Francis C W, Sporn L A, Bunce L A, Marder V J, Simpson-Haidaris P J. Heparin binding domain of fibrin mediates its binding to endothelial cells.  Arterioscler Thromb Vasc Biol. 1996;  16 1544-1551
    PubMedGoogle Scholar
  • 74 Altieri D C, Duperray A, Plescia J, Thronton G B, Languino L R. Structural recognition of a novel fibrinogen gamma chain sequence (117-133) by intercellular adhesion molecule-1 mediates leukocyte-endothelial interaction.  J Biol Chem. 1995;  270 696-699
    CrossrefPubMedGoogle Scholar
  • 75 Phillips D R, Charo I F, Parise L V, Fitzgerald L A. The platelet membrane glycoprotein IIb-IIIa complex.  Blood. 1988;  71 831-843
    PubMedGoogle Scholar
  • 76 Bennett J S, Vilaire G. Exposure of platelet fibrinogen receptors by ADP and epinephrine.  J Clin Invest. 1979;  64 1393-1401
    CrossrefPubMedGoogle Scholar
  • 77 Shattil S J, Kashiwagi H, Pampori N. Integrin signaling: the platelet function.  Blood. 1998;  91 2645-2657
    PubMedGoogle Scholar
  • 78 Martinez J, Ferber A, Bach T L, Yaen C H. Interaction of fibrin with VE-cadherin.  Ann N Y Acad Sci. 2001;  936 386-405
    PubMedGoogle Scholar
  • 79 van Hinsbergh V WM, Collen A, Koolwijk P. Role of fibrin in angiogenesis.  Ann N Y Acad Sci. 2001;  936 426-437
    CrossrefPubMedGoogle Scholar
  • 80 Brooks P C, Clark R A, Cheresh D A. Requirement of vascular integrin alpha v beta 3 for angiogenesis.  Science. 1994;  264 569-571
    CrossrefPubMedGoogle Scholar
  • 81 Okada Y, Copeland B R, Hamann G F, Koziol J A, Cheresh D A, del Zoppo G J. Integrin alpha v beta 3 is expressed in selected microvessels after focal cerebral ischemia.  Am J Pathol. 1996;  149 37-44
    PubMedGoogle Scholar
  • 82 Clark R AF, Tonnesen M G, Gailit J, Cheresh D A. Transient functional expression of alpha v beta 3 on vascular cells during wound repair.  Am J Pathol. 1996;  148 1407-1421
    PubMedGoogle Scholar
  • 83 Brooks P C, Montgomery A M, Rosenfeld M et al.. Integrin alpha v beta 3 antagonists promote tumor regression by inducing apoptosis of angiogenic blood vessels.  Cell. 1994;  79 1157-1164
    CrossrefPubMedGoogle Scholar
  • 84 Friedlander M, Brooks P C, Shaffer R W, Kincaid C M, Varner J A, Cheresh D A. Definition of two angiogenic pathways by distinct alpha v integrins.  Science. 1995;  270 1500-1502
    PubMedGoogle Scholar
  • 85 Brooks P C, Stromblad S, Klemke R, Visscher D, Sarkar F H, Cheresh D A. Antiintegrin alpha v beta 3 blocks human breast cancer growth and angiogenesis in human skin.  J Clin Invest. 1995;  96 1815-1822
    CrossrefPubMedGoogle Scholar
  • 86 Reynolds L E, Wyder L, Lively J C et al.. Enhanced pathological angiogenesis in mice lacking beta 3 integrin or beta 3 and beta 5 integrin.  Nat Med. 2002;  8 27-34
    CrossrefPubMedGoogle Scholar
  • 87 Bader B L, Rayburn H, Crowley D, Hynes R O. Extensive vasculogenesis, angiogenesis, and organogenesis precede lethality in mice lacking all alpha v integrins.  Cell. 1998;  95 507-519
    CrossrefPubMedGoogle Scholar
  • 88 Hodivala-Dilke K M, McHugh K P, Tsakiris D A et al.. Beta3-integrin-deficient mice are a model for Glanzmann thrombasthenia showing placental defects and reduced survival.  J Clin Invest. 1999;  103 229-238
    CrossrefPubMedGoogle Scholar
  • 89 Carmeliet P. Integrin indecision.  Nat Med. 2002;  8 14-16
    PubMedGoogle Scholar
  • 90 Cheresh D A, Stupack D G. Integrin-mediated death: an explanation of the integrin-knockout phenotype?.  Nat Med. 2002;  8 193-194
    PubMedGoogle Scholar
  • 91 Hynes R O. A reevaluation of integrins as regulators of angiogenesis.  Nat Med. 2002;  8 918-921
    CrossrefPubMedGoogle Scholar
  • 92 Dallabrida S M, De Sousa M A, Farrell D H. Expression of antisense to integrin subunit beta 3 inhibits microvascular endothelial cell capillary tube formation in fibrin.  J Biol Chem. 2000;  275 32281-32288
    CrossrefPubMedGoogle Scholar
  • 93 Kleinman H K, McGarvey M L, Liotta L A, Robey P G, Tryggvason K, Martin G R. Isolation and characterization of type IV procollagen, laminin and heparan sulfate proteoglycan from the EHS sarcoma.  Biochemistry. 1982;  21 6188-6193
    CrossrefPubMedGoogle Scholar
  • 94 Bayless K J, Salazar R, Davis G E. RGD-dependent vacuolation and lumen formation observed during endothelial cell morphogenesis in three-dimensional fibrin matrices involves the alpha(v)beta(3) and alpha(5)beta(1) integrins.  Am J Pathol. 2000;  156 1673-1683
    PubMedGoogle Scholar
  • 95 Feng X, Clark R AF, Galanakis D, Tonnesen M G. Fibrin and collagen differentially regulate human dermal microvascular endothelial cell integrins: stabilization of alphav/beta3 mRNA by fibrin1.  J Invest Dermatol. 1999;  113 913-919
    CrossrefPubMedGoogle Scholar
  • 96 Dvorak H F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing.  N Engl J Med. 1986;  315 1650-1659
    CrossrefPubMedGoogle Scholar
  • 97 Dvorak H F, Harvey V S, Estrella P, Brown L F, McDonagh J, Dvorak A M. Fibrin containing gels induce angiogenesis. Implications for tumor stroma generation and wound healing.  Lab Invest. 1987;  57 673-686
    PubMedGoogle Scholar
  • 98 Dvorak H F, Brown L F, Detmar M, Dvorak A M. Vascular permeability factor/vascular endothelial growth factor, microvascular hyperpermeability, and angiogenesis.  Am J Pathol. 1995;  146 1029-1039
    PubMedGoogle Scholar
  • 99 Bach T L, Barsigian C, Yaen C H, Martinez J. Endothelial cell VE-cadherin functions as a receptor for the beta15-42 sequence of fibrin.  J Biol Chem. 1998;  273 30719-30728
    CrossrefPubMedGoogle Scholar
  • 100 Gorlatov S, Medved L. Interaction of fibrin(ogen) with the endothelial cell receptor VE-cadherin: mapping of the receptor binding site in the NH2-terminal portion of the fibrin beta chains.  Biochemistry. 2002;  41 4107-4116
    CrossrefPubMedGoogle Scholar
  • 101 Sahni A, Baker C A, Sporn L A, Francis C W. Fibrinogen and fibrin protect fibroblast growth factor-2 from proteolytic degradation.  Thromb Haemost. 2000;  83 736-741
    PubMedGoogle Scholar
  • 102 Sahni A, Francis C W. Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation.  Blood. 2000;  96 3772-3778
    PubMedGoogle Scholar
  • 103 Sahni A, Sporn L A, Francis C W. Potentiation of endothelial cell proliferation by fibrin(ogen)-bound fibroblast growth factor-2.  J Biol Chem. 1999;  274 14936-14941
    CrossrefPubMedGoogle Scholar
  • 104 Lalla R V, Goralnick S J, Tanzer M L, Kreutzer D L. Fibrin induces IL-8 expression from human oral squamous cell carcinoma cells.  Oral Oncol. 2001;  37 234-242
    CrossrefPubMedGoogle Scholar
  • 105 Collen A, Maas A, Kooistra T et al.. Aberrant fibrin formation and cross-linking of fibrinogen Nieuwegein, a variant with a shortened Aalpha-chain, alters endothelial capillary tube formation.  Blood. 2001;  97 973-980
    CrossrefPubMedGoogle Scholar
  • 106 Thompson W D, Smith E B, Stirk C M, Marshall F I, Stout A J, Kocchar A. Angiogenic activity of fibrin degradation products is located in fibrin fragment E.  J Pathol. 1992;  168 47-53
    PubMedGoogle Scholar
  • 107 Schlager S I, Dray S. Complete local tumor regression with antibody to fibrin fragment E.  J Immunol. 1975;  115 976-981
    PubMedGoogle Scholar
  • 108 Taguchi O, Gabazza E C, Yasui H, Kobayashi T, Yoshida M, Kobayashi H. Prognostic significance of plasma D-dimer levels in lung cancer.  Thorax. 1997;  52 563-565
    PubMedGoogle Scholar
  • 109 Oya M, Akiyamaz Y, Yanagida T, Akoa S, Ishikawa H. Plasma D-dimer level in patients with colorectal cancer: its role as a tumor marker.  Surg Today. 1998;  28 373-378
    CrossrefPubMedGoogle Scholar
  • 110 Blackwell K, Haroon Z, Broadwater G et al.. Plasma D-dimer levels in operable breast cancer patients correlate with clinical stage and axillary lymph node status.  J Clin Oncol. 2000;  18 600-608
    PubMedGoogle Scholar
  • 111 Dirix L Y, Salgado R, Weytjens R et al.. Plasma fibrin D-dimer levels correlate with tumour volume, progression rate and survival in patients with metastatic breast cancer.  Br J Cancer. 2002;  86 389-395
    CrossrefPubMedGoogle Scholar
  • 112 Myers T J, Rickles F R, Barb C, Cronlund M. Fibrinopeptide A in acute leukemia: relationship of activation of blood coagulation to disease activity.  Blood. 1981;  57 518-525
    CrossrefPubMedGoogle Scholar
  • 113 Edwards R L, Rickles F R, Cronlund M. Abnormalities of blood coagulation in patients with cancer.  J Lab Clin Med. 1981;  98 917-928
    PubMedGoogle Scholar
  • 114 Rickles F R, Edwards R L, Barb C, Cronlund M. Abnormalities of blood coagulation in patients with cancer.  Cancer. 1983;  51 301-307
    PubMedGoogle Scholar
  • 115 Edwards R L, Rickles F R, Moritz T E et al.. Abnormalities of blood coagulation tests in patients with cancer.  Am J Clin Pathol. 1987;  88 596-602
    PubMedGoogle Scholar
  • 116 Edwards R L, Klaus M, McCullen C, Bona R D, Rickles F R. Heparin abolishes the chemotherapy-induced increase in plasma fibrinopeptide A levels.  Am J Med. 1990;  89 25-28
    CrossrefPubMedGoogle Scholar
  • 117 Yoda Y, Abe T. Fibrinopeptide A (FPA) level and fibrinogen kinetics in patients with malignant disease.  Thromb Haemost. 1981;  46 706-709
    PubMedGoogle Scholar
  • 118 Dvorak H F, Senger D R, Dvorak A M. Fibrin as a component of the tumor stroma: origins and biological significance.  Cancer Metastasis Rev. 1983;  2 41-73
    CrossrefPubMedGoogle Scholar
  • 119 Bardos H, Molnar P, Csecsei G, Adany R. Fibrin deposition in primary and metastatic human brain tumours.  Blood Coagul Fibrinolysis. 1996;  7 536-548
    PubMedGoogle Scholar
  • 120 Wojtukiewicz M Z, Zacharski L R, Memoli V A et al.. Fibrin formation on vessel walls in hyperplastic and malignant prostate tissue.  Cancer. 1991;  67 1377-1383
    PubMedGoogle Scholar
  • 121 Costantini V, Zacharski L R, Memoli V A, Kisiel W, Kudryk B J, Rousseau S M. Fibrinogen deposition without thrombin generation in primary human breast cancer tissue.  Cancer Res. 1991;  51 349-353
    PubMedGoogle Scholar
  • 122 Wojtukiewicz M Z, Zacharski L R, Memoli V A et al.. Indirect activation of blood coagulation in colon cancer.  Thromb Haemost. 1989;  62 1062-1066
    PubMedGoogle Scholar
  • 123 Costantini V, Zacharski L R, Memoli V A et al.. Fibrinogen deposition and macrophage-associated fibrin formation in malignant and non-malignant lymphoid tissue.  J Lab Clin Med. 1992;  119 124-131
    PubMedGoogle Scholar
  • 124 Wojtukiewicz M Z, Zacharski L R, Memoli V A et al.. Absence of components of coagulation and fibrinolysis pathways in situ in mesothelioma.  Thromb Res. 1989;  55 279-284
    CrossrefPubMedGoogle Scholar
  • 125 Simpson-Haidaris P J, Rybarczyk B. Tumors and fibrinogen. The role of fibrinogen as an extracellular matrix protein.  Ann N Y Acad Sci. 2001;  936 406-425
    PubMedGoogle Scholar
  • 126 Lee S Y, Lee K P, Lim J W. Identification and biosynthesis of fibrinogen in human uterine cervix carcinoma cells.  Thromb Haemost. 1996;  75 466-470
    PubMedGoogle Scholar
  • 127 Simpson-Haidaris P J, Courtney M A, Wright T W, Goss R, Harmsen A, Gigliotti F. Induction of fibrinogen expression in the lung epithelium during Pneumocystis carinii pneumonia.  Infect Immun. 1998;  66 4431-4439
    PubMedGoogle Scholar
  • 128 Palumbo J S, Kombrinck K W, Drew A F et al.. Fibrinogen is an important determinant of the metastatic potential of circulating tumor cells.  Blood. 2000;  96 3302-3309
    Google Scholar
  • 129 Palumbo J S, Degen J L. Fibrinogen and tumor cell metastasis.  Haemostasis. 2001;  31 11-15
    PubMedGoogle Scholar
  • 130 Contrino J, Goralnick S, Qi J, Hair G, Rickles F R, Kreutzer D L. Fibrin induction of tissue factor expression in human vascular endothelial cells.  Circulation. 1997;  96 605-613
    PubMedGoogle Scholar
  • 131 Zhang Y, Deng Y, Werndt T et al.. Intravenous somatic gene transfer with antisense tissue factor restores blood flow by reducing tumor necrosis-induced tissue factor expression and fibrin deposition in mouse meth A sarcomas.  J Clin Invest. 1996;  97 2213-2224
    PubMedGoogle Scholar
  • 132 Huang X, Molema G, King S, Watkins L, Edgington T S, Thorpe P E. Tumor infarction in mice by antibody-directed targeting of tissue factor to tumor vasculature.  Science. 1997;  275 547-555
    CrossrefPubMedGoogle Scholar
  • 133 Hu Z, Sun Y, Garen A. Targeting tumor vasculature endothelial cells and tumor cells for immunotherapy of human melanoma in a mouse xenograft model.  Proc Natl Acad Sci USA. 1999;  96 8161-8166
    CrossrefPubMedGoogle Scholar
  • 134 Hu Z, Garen A. Targeting tissue factor on tumor vasculature endothelial cells and tumor cells for immunotherapy in mouse models of prostatic cancer.  Proc Natl Acad Sci USA. 2001;  98 12180-12185
    CrossrefPubMedGoogle Scholar
  • 135 Nilsson F, Kosmehl H, Zardi L, Neri D. Targeted delivery of tissue factor to the ED-B domain of fibronectin, a marker of angiogenesis, mediates the infarction of solid tumors in mice.  Cancer Res. 2001;  61 711-716
    PubMedGoogle Scholar
  • 136 Zangari M, Anaissie E, Barlogie B et al.. Increased risk of deep-vein thrombosis in patients with multiple myeloma receiving thalidomide and chemotherapy.  Blood. 2001;  98 1614-1615
    CrossrefPubMedGoogle Scholar
  • 137 Kuenen B C, Rosen L, Smit E F et al.. Dose-finding and pharmacokinetic study of cisplatin, gemcitabine and SU5416 in patients with solid tumors.  J Clin Oncol. 2002;  20 1657-1667
    CrossrefPubMedGoogle Scholar
  • 138 Marx G M, Steer C B, Harper P, Pavlakis N, Rixe O, Khayat D. Unexpected serious toxicity with chemotherapy and antiangiogenic combinations: time to take stock!.  J Clin Oncol. 2002;  20 1446-1448
    PubMedGoogle Scholar
  • 139 Osman K, Comenzo R, Rajkumar S V. Deep vein thrombosis and thalidomide therapy for multiple myeloma.  N Engl J Med. 2001;  344 1951-1952
    CrossrefPubMedGoogle Scholar
  • 140 Zangari M, Siegel E, Barlogie B et al.. Thrombogenic activity of doxorubicin in myeloma patients receiving thalidomide: implications for therapy.  Blood. 2002;  100 1168-1171
    CrossrefPubMedGoogle Scholar
  • 141 Urbauer E, Kaufmann H, Nosslinger T, Raderer M, Drach J. Thrombotic events during treatment with thalidomide.  Blood. 2002;  99 4247-4248
    CrossrefPubMedGoogle Scholar
  • 142 Escudier B, Lassau N, Leborgne S, Angevin E, Laplanche A. Thalidomide and venous thrombosis.  Ann Intern Med. 2002;  136 711
    PubMedGoogle Scholar
  • 143 Kaushal V, Kohli M, Zangari M, Fink L, Mehta P. Endothelial dysfunction in antiangiogenesis-associated thrombosis.  J Clin Oncol. 2002;  20 3042
    PubMedGoogle Scholar
  • 144 Cavo M, Zamagni E, Cellini C et al.. Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy.  Blood. 2002;  100 2272-2273
    CrossrefPubMedGoogle Scholar
  • 145 Cosgrove R H, Zacharski L R, Racine E, Andersen J C. Improved cancer mortality with low-molecular-weight heparin treatment: a review of the evidence.  Semin Thromb Hemost. 2002;  28 79-87
    Article in Thieme ConnectPubMedGoogle Scholar
  • 146 Prandoni P, Lensing A W, Büller H R et al.. Comparison of subcutaneous low-molecular-weight heparins with intravenous standard heparin in proximal deep-vein thrombosis.  Lancet. 1992;  339 441-445
    CrossrefPubMedGoogle Scholar
  • 147 Hettiarachchi R JK, Smorenburg S M, Ginsberg J, Levine M, Prins M H, Büller H R. Do heparins do more than just treat thrombosis? The influence of heparins on cancer spread.  Thromb Haemost. 1999;  82 947-952
    PubMedGoogle Scholar
  • 148 Smorenburg S M. Inhibition of angiogenesis with heparin?.  Haemostasis. 2001;  31(suppl 1) 25-29
    PubMedGoogle Scholar
  • 149 Norrby K, Østergaard P. Basic-fibroblast-growth-factor-mediated de novo angiogenesis is more effectively suppressed by low-molecular-weight than by high-molecular-weight heparin.  Int J Microcirc Clin Exp. 1996;  16 8-15
    PubMedGoogle Scholar
  • 150 Moussa S A. Anticoagulants in thrombosis and cancer: the missing link.  Semin Thromb Hemost. 2002;  28 45-52
    Article in Thieme ConnectPubMedGoogle Scholar
  • 151 Collen A, Smorenburg S M, Peters E et al.. Unfractionated and low molecular weight heparin affect fibrin structure and angiogenesis in vitro.  Cancer Res. 2000;  60 6196-6200
    PubMedGoogle Scholar
  • 152 Varki N M, Varki A. Heparin inhibition of selectin-mediated interactions during the hematogenous phase of carcinoma metastasis: rationale for clinical studies in humans.  Semin Thromb Hemost. 2002;  28 53-66
    Article in Thieme ConnectPubMedGoogle Scholar
  • 153 Lever R, Page C P. Novel drug development opportunities for heparin.  Nat Rev Drug Discov. 2002;  1 140-148
    CrossrefPubMedGoogle Scholar
  • 154 Matsui N M, Varki A, Embury S H. Heparin inhibits the flow adhesion of sickle red blood cells to P-selectin.  Blood. 2002;  100 3790-3796
    CrossrefPubMedGoogle Scholar

Frederick R RicklesM.D. 

Federation of American Societies for Experimental Biology (FASEB)

9650 Rockville Pike, Bethesda, MD 20814

Email: frickles@faseb.org

      >