Cancer and Metastasis Reviews

, Volume 2, Issue 1, pp 41–73

Fibrin as a component of the tumor stroma: origins and biological significance

  • Harold F. Dvorak
  • Donald R. Senger
  • Ann M. Dvorak
Article

Summary

An association between cancer and the coagulation system was suggested by Trousseau more than a century ago and initial reports of fibrin deposition in the stroma of solid tumors date back some 25 years. However, the validity and generality of these observations have only quite recently been established, and their implications for an understanding of tumor biology, metastasis, and therapy are only now coming to be appreciated by investigators in the mainstream of cancer research. This article reviews the current status of fibrin's role in the biology of tumor growth, considering in turn: (1) the evidence that fibrin is present in tumors, the nature of such fibrin, and its relation to plasma fibronectin; (2) the mechanisms by which fibrin may come to be deposited in tumors; and (3) the potential biological and medical significance of tumorassociated fibrin deposition and degradation. Among the last are such important possiblities as a barrier function to the immune response and possible roles in angiogenesis, desmoplasia, and metastasis.

Keywords

fibrin fibronectin vascular permeability coagulation angiogenesis desmoplasia 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Folkman J: Tumor angiogenesis. Adv Cancer Res (19): 331–358, 1974.Google Scholar
  2. 2.
    O'Meara RAQ, Jackson RD: Cytological observations on carcinoma. Irish J Med Sci (6): 327–328, 1958.Google Scholar
  3. 3.
    O'Meara RAQ: Coagulative properties of cancers. Irish J Med Sci (6): 474–479, 1958.Google Scholar
  4. 4.
    Fischer A: Beitrag zur Biologie der Gewebezellen. Eine vergleichendbiologische Studie der normalen und malignen Gewebezellen in vitro. Arch Entwicklungsmech Org (104): 210, 1925.Google Scholar
  5. 5.
    Christman JK, Silverstein SC, Acs G: Plasminogen activators. In: Barret AS (ed) Mammalian cells and tissue. New York, North Holland, 1977, pp 91–149.Google Scholar
  6. 6.
    Trosseau A: Phlegmasia alba dolens. Clinique médicale de l'Hôtel-Dieu de Paris. London New Sydenham Soc (3): 94, 1865.Google Scholar
  7. 7.
    Peck SD, Reiquam CW: Disseminated intravascular coagulation in cancer patients: supportive evidence. Cancer (31): 1114–1119, 1973.Google Scholar
  8. 8.
    Ambrus JL, Ambrus CM, Pickern J, Soldes S, Bross I: Hematologic changes and thromboembolic complications in neoplastic disease and their relationship to metastasis. J Med (6): 433–458, 1975.Google Scholar
  9. 9.
    Sack GH, Levin J, Bell WR: Trousseau's syndrome and other manifestations of chronic disseminated coagulopathy in patients with neoplasms: clinical, patho-physiologic, and therapeutic features. Medicine (56): 1–37, 1977.Google Scholar
  10. 10.
    Rasche H, Dietrich M: Hemostatic abnormalities associated with malignant diseases. Eur J Cancer (13): 1053–1064, 1977.Google Scholar
  11. 11.
    Lyman GH, Bettigole RE, Robson E, Ambrus JL, Urban H: Fibrinogen kinetics in patients with neoplastic disease. Cancer (41): 1113–1122, 1978.Google Scholar
  12. 12.
    Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ, Forcier RJ, Harrower HW, Johnson RO: Rationale and experimental design for the VA cooperative study of anti-coagulation (Warfarin) in the treatment of cancer. Cancer (44): 732–741, 1979.Google Scholar
  13. 13.
    Donati MB, Poggi A: Malignancy and haemostasis. Br J Haematol (44): 173–182, 1980.Google Scholar
  14. 14.
    Wajima T: Thrombophlebitis in cancer patients. Ann NY Acad Sci (370): 138–144, 1981.Google Scholar
  15. 15.
    Edwards RL, Rickles FR, Cronlund M: Abnormalities of blood coagulation in patients with cancer. J Lab Clin Med (98): 917–928, 1981.Google Scholar
  16. 16.
    Edwards RL, Rickles FR, Bobrove AM: Monoculear cell tissue factor: cell of origin and requirements for activation. Blood (54): 359–370, 1979.Google Scholar
  17. 17.
    Gore JM, Appelbaum JS, Greene HL, Dexter L, Dalen JE: Occult cancer in patients with acute pulmonary embolism. Ann Intern Med (96): 556–560, 1982.Google Scholar
  18. 18.
    Gitlin D, Craig JM: Variations in the staining characteristics of human fibrin. Am J Pathol (33): 267–283, 1957.Google Scholar
  19. 19.
    Day ED, Planinsek JA, Pressman D: Localization in vivo of radioiodinated anti-rat-fibrin antibodies and radioiodinated rat fibrinogen in the Murphy rat lymphosarcoma and in other transplantable rat tumors. J Natl Cancer Inst (22): 413–426, 1959.Google Scholar
  20. 20.
    Marrack D, Kubala M, Corry P, Leavens M, Howze J, Dewey W, Bale WF, Spar IL: Localization of intracranial tumors: comparative study with 131I-labeled antibody to human fibrinogen and neohydrin-203Hg. Cancer (20): 751–755, 1967.Google Scholar
  21. 21.
    Spar IL, Bale WF, Marrack D, Dewey WC, McCardle RJ, Harper PV: 131I-Labeled antibodies to human fibrinogen: diagnostic studies and therapeutic trials. Cancer (20): 865–870, 1967.Google Scholar
  22. 22.
    Hiramoto R, Yagi Y, Pressman D: Immunohistochemical studies of antibodies in anti-Murphy lymphosarcoma sera. Cancer Res (19): 874–879, 1959.Google Scholar
  23. 23.
    Hiramoto R, Bernecky J, Jurandowski J, Pressman D: Fibrin in human tumors. Cancer Res (20): 592–593, 1960.Google Scholar
  24. 24.
    Kodama Y, Tanaka K: Thromboplastic and fibrinolytic activities of V2 and V7 carcinomas of rabbit, with special reference to fibrin deposition and thrombus formation in the tumors. Acta Pathol Jap (28): 279–286, 1978.Google Scholar
  25. 25.
    Chew EC, Wallace AC: Demonstration of fibrin in early stages of experimental metastases. Cancer Res (36): 1904–1909, 1976.Google Scholar
  26. 26.
    Wood S, Holyoke ED, Yardly JH: Mechanisms of metastasis production by blood-borne cancer cells. Can Cancer Conf (4): 167–221, 1961.Google Scholar
  27. 27.
    Kinjo M: Lodgement and extravasation of tumour cells in blood-borne metastasis: an electron microscope study. Br J Cancer (38): 293–300, 1978.Google Scholar
  28. 28.
    Dvorak HF, Galli SJ, Dvorak AM: Expression of cell-mediated hypersensitivity in vivo—recent advances. Int Rev Exp Pathol (21): 119–194, 1980.Google Scholar
  29. 29.
    Harris NL, Dvorak AM, Smith J, Dvorak HF: Fibrin deposits in Hodgkin's disease. Am J Pathol (108): 119–129, 1982.Google Scholar
  30. 30.
    Grinnell F: Cellular adhesiveness and extracellular substrata. Int Rev Cytol (53): 65–144, 1978.Google Scholar
  31. 31.
    Hynes RO: Relationship between fibronectin and the cytoskeleton. In: Poste G, Nicolson GL (eds) Cytoskeletal elements and plasma membrane organization. Cell surface reviews, Vol 7. New York, Elsevier/North Holland, 1981.Google Scholar
  32. 32.
    Mosher DF: Fibronectin. Prog Hemostasis Thromb (5): 111–151, 1980.Google Scholar
  33. 33.
    Vaheri A, Mosher DF: High molecular weight, cell surface-associated glycoprotein (fibronectin) lost in malignant transformation. Biochem Biophys Acta (516): 1–25, 1978.Google Scholar
  34. 34.
    Yamada K, Olden K: Fibronectins: adhesive glycoproteins of cell surface and blood. Nature (275): 179–184, 1978.Google Scholar
  35. 35.
    Doolittle RF, Bouma H, Cottrell BA, Strong D, Watt KWK: The covalent structure of human fibrinogen. In: Bing DH (ed) The chemistry and physiology of the human plasma proteins. New York, Pergamon Press, 1979, pp. 77–95.Google Scholar
  36. 36.
    Nossel HL: Radioimmunoassay of fibrinopeptides in relation to intravascular coagulation and thrombosis. New Engl J Med (295): 428–432, 1981.Google Scholar
  37. 37.
    Davie EW, Fujikawa K, Kurachi K, Kisiel W: The role of serine proteases in the blood coagulation cascade. Adv Enzymol (48): 277–318, 1979.Google Scholar
  38. 38.
    Zimmerman TS, Fierer J, Rothberger H: Blood coagulation and the inflammatory response. Semin Hematol (14): 391–408, 1977.Google Scholar
  39. 39.
    Folk JE, Finlayson JS: The ε-(γ-glutamyl) lysine crosslink and the catalytic role of transglutaminases. Adv Protein Chem (31): 1–133, 1977.Google Scholar
  40. 40.
    Hermans J, McDonagh J: Fibrin: structure and interactions. Semin Thromb Hemostas (8): 11–24, 1982.Google Scholar
  41. 41.
    Lopaciuk S, McDonagh RP, McDonagh J: Comparative studies on blood coagulation factor XIII. Proc Soc Exp Biol Med (158): 68–72, 1978.Google Scholar
  42. 42.
    Robbins KC, Wohl RC, Summaria L: Plasmin and plasminogen activators: kinetics, and kinetics of plasminogen activation. Ann N Y Acad Sci (370): 588–591, 1981.Google Scholar
  43. 43.
    Reich E: Plasminogen activator: secretion by neoplastic cells and macrophages. In: Reich E, Rifkin DB, Shaw E (eds) Proteases and biological control. New York, Cold Spring Harbor, 1975.Google Scholar
  44. 44.
    Wiman B, Collen D: Molecular mechanism of physiological fibrinolysis. Nature (272): 549–550, 1978.Google Scholar
  45. 45.
    Marder VJ, Budzynski AZ: Data for defining fibrinogen and its plasmic degradation products. Thromb Diathes Haemorrh (Stuttgart (33): 199–207, 1975.Google Scholar
  46. 46.
    Osbabr AJ, Gladner JA, Laki K: Studies on the physiological activity of the peptide released during the fibrinogen-fibrin conversion. Biochim Biophys Acta (86): 535–542, 1964.Google Scholar
  47. 47.
    Stecher VJ, Sorkin E: The chemotactic activity of fibrin lysis products. Int Arch Allergy (43): 879–886, 1972.Google Scholar
  48. 48.
    Kay AB, Pepper DS, Ewart MR: Generation of chemotactic activity for leukocytes by the action of thrombin on human fibrinogen. Nat New Biol (243): 56–57, 1973.Google Scholar
  49. 49.
    Girmann G, Pees H, Schwarze G, Scheurlen PG: Immunosuppression by micromolecular fibrinogen degradation products in cancer. Nature (259): 399–401, 1976.Google Scholar
  50. 50.
    Richardson DL, Pepper DS, Kay AB: Chemotaxis for human monocytes by fibrinogen-derived peptides. Br J Haematol (32): 507–513, 1976.Google Scholar
  51. 51.
    Belew M, Gerdin B, Porath J, Saldeen T: Isolation of vasoactive peptides from human fibrin and fibrinogen degraded by plasmin. Thromb Res (13): 983–994, 1978.Google Scholar
  52. 52.
    Gerdin B, Saldeen T: Effect of fibrin degradation products on microvascular permeability. Thromb Res (13): 995–1006, 1978.Google Scholar
  53. 53.
    Krzystyniak K, Stachurska J, Ryzewski J, Bykowska K, Kopec M: Suppressive effect of low molecular weight fibrinogen degradation products on human and rat lymphocytes. Thromb Res (12): 523–530, 1978.Google Scholar
  54. 54.
    Belew M, Gerdin B, Lindeberg G, Porath J, Saldeen T, Wallin R: Structure-activity relationships of vasoactive peptides derived from fibrin or fibrinogen degraded by plasmin. Biochim Biophys Acta (621): 169–178, 1980.Google Scholar
  55. 55.
    Plow EF, Freaney D, Edgington TS: Inhibition of lymphocyte protein synthesis by fibrinogen-derived peptides. J Immunol (128): 1595–1599, 1982.Google Scholar
  56. 56.
    Francis CW, Marder VJ, Barlow GH: Plasmic degradation of crosslinked fibrin: characterization of new macromolecular soluble complexes and a model of their structure. J Clin Invest (66): 1033–1043, 1980.Google Scholar
  57. 57.
    Colvin RB, Dvorak HF: Role of the clotting system in cell-mediated hypersensitivity. J Immunol (114): 377–387, 1975.Google Scholar
  58. 58.
    Dvorak HF, Mihm MCJr: Basophilic leukocytes in allergic contact dermatitis. J Exp Med (135): 235–254, 1972.Google Scholar
  59. 59.
    Colvin RB, Johnson RA, Mihm MCJr, Dvorak HF: Role of the clotting system in cell-mediated hypersensitivity. I. Fibrin deposition in delayed skin reactions in man. J Exp Med (138): 686–698, 1973.Google Scholar
  60. 60.
    Kashgarian M, Hayslett JP, Spargo BH: Renal Disease. Am J Pathol (89): 187–272, 1977.Google Scholar
  61. 61.
    Dvorak HF, Dickersin GR, Dvorak AM, Manseau EJ, Pyne K: Human breast carcinoma. Fibrin deposits and desmoplasia. Inflammatory cell type and distribution. Microvasculature and infarction. J Natl Cancer Inst (67): 335–345, 1981.Google Scholar
  62. 62.
    Rosas-Uribe A, Variakojis D, Rappaport H: Proteinacious precipitate in nodular (follicular) lymphomas. Cancer (31): 534–542, 1973.Google Scholar
  63. 63.
    Talerman A, Platenburg HPJM: Follicular lymphoma with deposits of amorphous hyaline material. J Pathol (112): 27–31, 1974.Google Scholar
  64. 64.
    Cooper JH, Haq BM, Bagnell H: Intrafollicular hyalinosis and arterial hyalinosis of the spleen: histochemical and immunofluorescence studies. J Pathol (98): 193–199, 1969.Google Scholar
  65. 65.
    Resnick GD, Nachman RL: Reed-Sternberg cells in Hodgkin's disease contain fibronectin. Blood (57): 339–342, 1981.Google Scholar
  66. 66.
    Dvorak HF, Orenstein NS, Carvalho AC, Churchill WH, Dvorak AM, Galli SJ, Feder J, Bitzer AM, Rypsyc J, Giovinco P: Induction of a fibrin-gel investment: an early event in line 10 hepatocarcinoma growth mediated by tumor-secreted products. J Immunol (122): 166–174, 1979.Google Scholar
  67. 67.
    Dvorak HF, Dvorak AM, Manseau EJ, Wiberg L, Churchill WH: Fibrin-gel investment associated with line 1 and line 10 solid tumor growth, angiogenesis, and fibroplasia in guinea pigs. Role of cellular immunity, myofibroblasts, microvascular damage, and infarction in line 1 tumor regression. J Natl Cancer Inst (62): 1459–1472, 1979.Google Scholar
  68. 68.
    Churchill WHJr, Rapp HJ, Kronman BS, Borsos T: Detection of antigens of a new diethylnitrosamine-induced transplantable hepatoma by delayed hypersensitivity. J Natl Cancer Inst (41): 13–29, 1968.Google Scholar
  69. 69.
    Asch BB, Dvorak HF, Senger DR: A major phospho-protein marker for neoplastic transformation of fibroblastic and epithelial cells. Cold Spring Harbor Conferences on Cell Proliferation, vol 9, 1982, 365–369.Google Scholar
  70. 70.
    Dvorak HF, Quay SC, Orenstein NS, Dvorak AM, Hahn P, Bitzer AM, Carvalho AC: Tumor shedding and coagulation. Science (212): 923–924, 1981.Google Scholar
  71. 71.
    Dvorak HF, Mihm MCJr, Dvorak AM, Barnes BA, Manseau EJ, Galli SJ: Rejection of first-set skin allografts in man. The microvasculature is the critical target of the immune reponse. J Exp Med (150): 322–337, 1979.Google Scholar
  72. 72.
    Dvorak HF, Dvorak AM, Churchill WHJr: Immunologic rejection of diethylnitrosamine-induced hepatomas in strain 2 guinea pigs. Participation of basophilic leukocytes and macrophage aggregates. J Exp Med (137): 751–775, 1973.Google Scholar
  73. 73.
    Dvorak HF, Orenstein NS, Dvorak AM: Tumor-secreted mediators and the tumor microenvironment: relationship to immunological surveillance. Lymphokines (2): 203–233, 1981.Google Scholar
  74. 74.
    Adelman NE, Hammond ME, Cohen S, Dvorak HF: Lymphokines as inflammatory mediators. In: Pick E, Oppenheim J, Cohen S (eds) The biology of lymphokines. New York, Academic Press, 1979, pp. 13–58.Google Scholar
  75. 75.
    DeWeck AL, Kristensen F, Landy M: Biochemical characterization of lymphokines. Academic Press, New York, 1980, pp 1–622.Google Scholar
  76. 76.
    Dvorak HF, Dvorak AM: Immunohistologic characterization of inflammatory cells that infiltrate tumors. In: Haskill JS (ed) Tumor immunity in prognosis: the role of mononuclear cell infiltration. New York, Marcel Dekker, Inc, 1982, 279–307.Google Scholar
  77. 77.
    Johnston MM, Greenbaum LM: Leukokinin-forming system in the ascitic fluid of a murine mastocytoma. Biochem Pharmacol (22): 1386–1389, 1973.Google Scholar
  78. 78.
    Greenbaum LM, Semente G, Prakash A, Roffman S: Leukokinins; their pharmacological properties and role in the pathology of fluid (ascites) accumulation. Agents Actions (8): 80–84, 1978.Google Scholar
  79. 79.
    Grebow P, Prakash A, Greenbaum L: Leukokinin-H generated from human ascites fluid: its isolation and pharmacology. Agents Actions (9): 265–274, 1979.Google Scholar
  80. 80.
    Greenbaum LM: Kininogenases of blood cells (alternate kinin generating systems). In: Erdos EG (ed) Handbook of experimental pharmacology, vol 25, Suppl, 1979, pp. 91–102.Google Scholar
  81. 81.
    Roffman S, Greenbaum L: Properties of leukokininogen isolated from human neoplastic ascites. Biochem Pharmacol (28): 1043–1050, 1979.Google Scholar
  82. 82.
    Greenbaum LM, Grebow P, Johnston M, Prakash A, Semente G: Pepstatin, an inhibitor of leukokinin formation and ascitic fluid accumulation. Cancer Res (35): 706–710, 1975.Google Scholar
  83. 83.
    Greenbaum LM: Pepstatin, an inhibitor of acid kininogenases and ascites retardant in neoplastic disease. Fed Proc (38): 2788–2791, 1979.Google Scholar
  84. 84.
    Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF: Vascular permeability factor (VPF): a protein secreted by tumors that causes ascites fluid accumulation. Fed Proc (41): 964, 1982 (abstract).Google Scholar
  85. 85.
    Senger DR, Galli SJ, Dvorak AM, Perruzzi CA, Harvey VS, Dvorak HF: Tumor cells secrete a vascular permeability factor that promotes ascites fluid accumulation Science, 1983 (in press).Google Scholar
  86. 86.
    Aukland K, Nicolaysen G: Interstitial fluid volume: local regulatory mechanisms. Physiol Rev (61): 556–643, 1981.Google Scholar
  87. 87.
    Butler TP, Grantham FH, Gullino PM: Bulk transfer of fluid in the interstitial compartment of mammary tumors. Cancer Res (35): 3084–3088, 1975.Google Scholar
  88. 88.
    Maillard JL, Pick E, Turk JL: Interaction between ‘sensitized lymphocytes’ and antigen in vitro. V. Vascular permeability induced by skin-reactive factor. Int Arch Allergy (42): 50–68, 1972.Google Scholar
  89. 89.
    Willoughby DA, Boughton B, Schild HO: A factor capable of increasing vascular permeability present in lymph node cells. A possible mediator of the delayed reaction. Immunol (6): 484–498, 1963.Google Scholar
  90. 90.
    Sobel A, LaGrue G: Role of a vascular permeability-increasing factor released by lymphocytes in renal pathology. Lymphokine Rep (1): 211–230, 1980.Google Scholar
  91. 91.
    Semeraro N, Donati MB: Pathways of blood clotting initiation by cancer cells. In: Donati MB, Davidson JF, Garattini S (eds) Malignancy and the hemostatic system. New York, Raven Press, 1981, pp. 65–81.Google Scholar
  92. 92.
    Boggust WA, O'Meara RAQ, Fullerton WW: Diffusible thromboplastins of human cancer and chorion tissue. Eur J Cancer (3): 467–473, 1968.Google Scholar
  93. 93.
    Frank AL, Holyoke ED: Tumor fluid thromboplastin activity. J Cancer (3): 677–682, 1968.Google Scholar
  94. 94.
    Gasic GJ, Koch PAG, Hsui B, Gasic TB, Niewiarowski S: Thrombogenic activity of mouse and human tumors: effect on platelets, coagulation, and fibrinolysis, and possible significance for metastasis. Z Krebforsch (86): 263–277, 1967.Google Scholar
  95. 95.
    Gordon SG, Cross BA: A factor X-activating cysteine protease from malignant tissue. J Clin Invest (67): 1665–1671, 1981.Google Scholar
  96. 96.
    Holyoke ED, Ichihashi H: The C3H/St/Ha mammary tumor. I. Stabilizing enzymes from the mouse tumor YPC-1. Biochem Biophys Res Com (24): 776–781, 1966.Google Scholar
  97. 97.
    Khato J, Suzuki M, Sato H: Quantitative study on thromboplastin in various strains of Yoshida ascites hepatoma cells of rat. Gann (65): 289–294, 1974.Google Scholar
  98. 98.
    Kinjo M, Oka K, Naito S, Kohga S, Tanaka K, Oboshi S, Yahata Y, Yasumoto K: Thromboplastic and fibrinolytic activities of cultured human cancer cell lines. Br J Cancer (39): 15–23, 1979.Google Scholar
  99. 99.
    Laki K, Tyler HM, Yancey ST: Clot forming and clot stabilizing enzymes from the mouse tumor YPC-1. Biochem Biophys Res Com (24): 776–781, 1966.Google Scholar
  100. 100.
    Peterson HI, Zettertren L: Thromboplastic and fibrinolytic properties of three transplantable rat tumors. Acta Chir Scand (136): 365–368, 1970.Google Scholar
  101. 101.
    Sakuragawa N, Takahashi K, Hoshiyama M, Jimbo C, Ashizawa K, Matsuoka M, Ohnishi Y: The extract from the tissue of gastric cancer as procoagulant in disseminated intravascular coagulation syndrome. Thromb Res (10): 457–463, 1977.Google Scholar
  102. 102.
    Svanberg L: Thromboplastic activity of human ovarian tumors. Thromb Res (6): 307–313, 1975.Google Scholar
  103. 103.
    Zacharski LR, McIntyre OR: Tissue factor (thromboplastin, factor III) synthesis by cultured cells. J Med (4): 118–131, 1973.Google Scholar
  104. 104.
    Green D, Ryan C, Malandruccolo N, Nadler HL: Characterization of the coagulant activity of cultured human fibroblasts. Blood (37): 47–51, 1971.Google Scholar
  105. 105.
    Maynard JR, Fintel DJ, Pitlick FA, Nemerson Y: Tissue factor in cultured cells. Metabolic control. Lab Invest (35): 542–549, 1976.Google Scholar
  106. 106.
    Cattan A, Bresson ML: Murine tumor cell activity on in vitro hemostasis. Biomedicine (25): 252–254, 1976.Google Scholar
  107. 107.
    Curatolo L, Colucci M, Cambini AL, Poggi A, Morasca L, Donati MB, Semeraro N: Evidence that cells from experimental tumours can activate coagulation factor X. Br J Cancer (40): 228–233, 1979.Google Scholar
  108. 108.
    Dvorak HF, Van De Water L, Dvorak AM, Harvey VS, Anderson D, De Wolf W, Bach R: Human tumor cells and guinea pig macrophages shed plasma membrane derived vesicles with procoagulant activity. Fed Proc (41): 8, 1982 (abstract).Google Scholar
  109. 109.
    Gordon SG, Lewis BJ: Comparison of procoagulant activity in tissue culture medium from normal and transformed fibroblasts. Cancer Res (38): 2467–2472, 1978.Google Scholar
  110. 110.
    Nemerson Y, Zur M, Bach R, Gentry R: The mechanism of action of tissue factor: a provisional model. In: Mann KG, Taylor FB (eds) The regulation of coagulation. New York. Elsevier/North Holland, 1980, pp 193–202.Google Scholar
  111. 111.
    Bach R, Nemerson Y, Konigsberg W: Purification and characterization of bovine tissue factor. J Biol Chem (256): 8324–8331, 1981.Google Scholar
  112. 112.
    Gralnick HR, Abrell E: Studies on the procoagulant and fibrinolytic activity of promyelocytes in acute promyelocytic leukaemia. Br J Haematol (24): 89–99, 1973.Google Scholar
  113. 113.
    Gralnick HR, Tan HK: Acute promyelocytic leukemia. A model for understanding the role of the malignant cell in hemostasis. Hum Pathol (5): 661–673, 1974.Google Scholar
  114. 114.
    Green D, Ryan C, Malandrucculo N, Nadler HL: Characterization of the coagulant activity of cultured human fibroblasts. Blood (37): 47–51, 1971.Google Scholar
  115. 115.
    Zacharski LR, McIntyre OR: Physical stability of cell culture procoagulants detectable in first-stage coagulation factor assays. Proc Soc Exp Biol Med (139): 713–715, 1972.Google Scholar
  116. 116.
    Maynard JR, Heckman CA, Pitlick FA, Nemerson Y: Association of tissue factor activity with the surface of cultured cells. J Clin Invest (55): 814–824, 1975.Google Scholar
  117. 117.
    Maynard JR, Dreyer BE, Stemerman MB, Pitlick FA: Tissue-factor coagulant activity of cultured human endothelial and smooth muscle cells and fibroblasts. Blood (50): 387–396, 1977.Google Scholar
  118. 118.
    Kadish JL, Wenc KM, Dvorak HF: Tissue factor activity of normal and neoplastic cells: quantitation and species specificity. J Natl Cancer Inst, 1983 (in press).Google Scholar
  119. 119.
    Stormorken H: Species differences of clotting factors in ox, dog, horse, and man. Theomboblastin and proconvertin. Acta Physiol Scand (41): 301–324, 1957.Google Scholar
  120. 120.
    Lyberg T, Hetland O, Prydz H: Synthesis of thromboplastin protein by a murine macrophage-like cell line. Thromb Haemostas (47): 154–156, 1982.Google Scholar
  121. 121.
    Pineo GF, Regoeczi E, Hatton MWC, Brain MC: The activation of coagulation by extracts of mucus: a possible pathway of intravascular coagulation accompanying adenocarcinomas. J Lab Clin Med (82): 255–266, 1973.Google Scholar
  122. 122.
    Pineo GF, Brain MC, Gallus AS, Hirsh J, Hatton MWC, Regoeczi E: Tumors, mucus production, and hypercoagulability. Ann N Y Acad Sci (230): 262–270, 1974.Google Scholar
  123. 123.
    Gordon SG, Franks JJ, Lewis B: Cancer procoagulant A: a factor X activating procoagulant from malignant tissue. Thromb Res (6): 127–137, 1975.Google Scholar
  124. 124.
    Gordon SG, Franks JJ, Lewis BJ: Comparison of procoagulant activities in extracts of normal and malignant human tissue. J Natl Cancer Inst (62): 773–776, 1979.Google Scholar
  125. 125.
    Gordon SG: A proteolytic procoagulant associated with malignant transformation. J Histochem Cytochem (29): 457–463, 1981.Google Scholar
  126. 126.
    Colucci M, Curatolo L, Donati MB, Semeraro N: Cancer cell procoagulant activity: evaluation by an amidolytic assay. Thromb Res (18): 589–595, 1980.Google Scholar
  127. 127.
    Black PH: Shedding from the cell surface of normal and cancer cells. Adv Cancer Res (32): 75–199, 1980.Google Scholar
  128. 128.
    Doljanski F, Kapeller M. Cell surface shedding — the phenomenon and its possible significance. J Theor Biol (62): 253–270, 1976.Google Scholar
  129. 129.
    Calafat J, Hilgers J, Van Blitterswijk WJ, Verbeet M, Hageman PC: Antibody-induced modulation and shedding of mammary tumor virus antigens on the surfaces of GR ascites leukemia cells as compared with normal antigens. J Natl Cancer Inst (56): 1019–1029, 1976.Google Scholar
  130. 130.
    Bystryn J-C: Release of cell-surface tumor-associated antigens by viable melanoma cells from humans. J Natl Cancer Inst (59): 325–328, 1977.Google Scholar
  131. 131.
    Koch GLE, Smith MJ: An association between actin and the major histocompatibility antigen H-2. Nature (273): 274–277, 1978.Google Scholar
  132. 132.
    Raz A, Goldman R, Yuli I, Inbar M: Isolation of plasma membrane fragments and vesicles from ascites fluid of lymphoma-bearing mice and their possible role in the escape mechanism of tumors from host immune rejection. Cancer Immunol Immunother (4): 53–59, 1978.Google Scholar
  133. 133.
    Gasic GJ, Boettiger D, Catalfamo JL, Gasic TB, Steward GJ: Aggregation of platelets and cell membrane vesiculation by rat cells transformed in vitro by Rous sarcoma virus. Cancer Res (38): 2950–2955, 1978.Google Scholar
  134. 134.
    Bitzer AM, Carvalho ACA, Davis GL, Dvorak HF: PCA10 Procoagulant released by line 10 tumor cells in culture. Fed Proc (41): 780, 1981 (abstract).Google Scholar
  135. 135.
    Dvorak HF, Van de Water L, Bitzer AM, Dvorak AM, Anderson D, Harvey VS, Bach R, DeWolf W, Carvalho ACA: Tumor cells shed plasma membrane vesicles with procoagulant activity in short term tissue culture (submitted for publication).Google Scholar
  136. 136.
    Dunkel VC, Bast RC, Gerwin BI, Heine V, Cotter-Fox M, Borsos T: Presence of A-type and absence of C-type virus particles in a chemically induced guinea pig hepatoma. J Natl Cancer Inst (53): 591–593, 1974.Google Scholar
  137. 137.
    Pitlick FA, Nemerson Y: Purification and characterization of tissue factor apoprotein. Meth Enzymol (40): 37–48, 1976.Google Scholar
  138. 138.
    Jordan RE, Oosta GM, Gardner WT, Rosenberg RD: The kinetics of hemostatic enzyme-antithrombin interactions in the presence of low molecular weight heparin. J Biol Chem (255): 10081–10090, 1980.Google Scholar
  139. 139.
    Laki K, Tyler HM, Yancey ST: Clot forming and clot stabilizing enzymes from the mouse tumor YPC-1. Biochem Biophys Res Comm (24): 776–781, 1966.Google Scholar
  140. 140.
    Colvin RB, Mosesson MW, Dvorak HF: Delayed-type hypersensitivity skin reactions in congenital afibrinogenemia lack fibrin deposition and induration. J Clin Invest (63): 1302–1306, 1979.Google Scholar
  141. 141.
    Rickles FR, Hardin JA, Pitlick FA, Hoyer LW, Conrad ME: Tissue factor activity in lymphocyte cultures from normal individuals and patients with hemophilia A. J Clin Invest (52): 1427–1434, 1973.Google Scholar
  142. 142.
    Rothberger H, Zimmerman S, Spiegelberg HL, Vaughan JH: Leukocyte procoagulant activity. Enhancement of production in vitro by IgG and antigen-antibody complexes. J Clin Invest (59): 549–557, 1977.Google Scholar
  143. 143.
    Edwards RL, Rickles FR: Delayed hypersensitivity in man: effects of systemic anticoagulation. Science (200): 541–543, 1978.Google Scholar
  144. 144.
    Gezy CL, Hopper KE: A mechanism of migration inhibition in delayed-type hypersensitivity reactions. II. Lymphokines promote procoagulant activity of macrophages in vitro. J Immunol (126): 1059–1065, 1981.Google Scholar
  145. 145.
    Levy GA, Schwartz BS, Edgington TS: The kinetics and metabolic requirements for direct lymphocyte induction of human procoagulant monokines by bacterial lipopolysaccharide. J Immunol (127): 357–363, 1981.Google Scholar
  146. 146.
    Rothberger H, Zimmerman TS, Vaughan JH: Increased production and expression of tissue thromboplastin-like procoagulant activity in vitro by allogeneically stimulated human leukocytes. J Clin Invest (62): 649–655, 1978.Google Scholar
  147. 147.
    Genco P, Bettigole R, Yoshida T, Cohen S: A factor with procoagulant activity produced by stimulated human leukocyte cultures. Clin Immunol Immunopathol (17): 363–371, 1980.Google Scholar
  148. 148.
    Edwards RL, Rickles FR, Bobrove AM: Mononuclear cell tissue factor: cell of origin and requirements for activation. Blood (54): 359–370, 1979.Google Scholar
  149. 149.
    Edwards RL, Rickles FR: The role of human T cells (and T cell products) for monocyte tissue factor generation. J Immunol (125): 606–609, 1980.Google Scholar
  150. 150.
    Edwards RL, Rickles FR: The role of monocyte tissue factor in the immune response. Lymphokine Rep (1): 181–210, 1980.Google Scholar
  151. 151.
    Schwartz BS, Edgington TS: Immune complex-induced human monocyte procoagulant activity. I. A Rapid unidirectional lymphocyte-instructed pathway. J Exp Med (154): 892–906, 1981.Google Scholar
  152. 152.
    Schwartz BS, Levy GA, Edgington TS: Immune complex induced human monocyte procoagulant activity. II. Cellular kinetics and metabolic requirements. J Immunol (128): 1037–1042, 1982.Google Scholar
  153. 153.
    Geczy CL, Meyer PA: Leukocyte procoagulant activity in man: an in vitro correlate of delayed-type hypersensitivity. J Immunol (128): 331–335, 1982.Google Scholar
  154. 154.
    Chen LB, Buchanan JM: Mitogenic activity of blood components. I. Thrombin and prothrombin. Proc Nat Acad Sci (72): 131–135, 1975.Google Scholar
  155. 155.
    Glenn KC, Carney DH, Fenton JWII, Cunningham DD: Thrombin active site regions required for fibroblast receptor binding and initiation of cell division. J Biol Chem (255): 6609–6616, 1980.Google Scholar
  156. 156.
    Ratnoff OD: Some relationships among hemotasis, fibrinolytic phenomena, immunity, and the inflammatory response. Adv Immunol (10): 145–277, 1969.Google Scholar
  157. 157.
    Colman RW, Osbahr AJ, Morris RE: New vasoconstrictor, bovine peptide B, released during blood coagulation. Nature (215): 292–293, 1967.Google Scholar
  158. 158.
    Postlethwaite AE, Keski-Oja J, Balian G, Kang AH: Induction of fibroblast chemotaxis by fibronectin. Localization of the chemotactic region to a 140,000-molecular weight non-gelatin-binding fragment. J Exp Med (153): 494–499, 1981.Google Scholar
  159. 159.
    Bowerson JC, Sorgente N: Chemotactic response of vascular endothelial cells to fibronectin. J Cell Biol (87): 64a, 1980 (abstract).Google Scholar
  160. 160.
    Tsukamoto Y, Helsel WE, Wahl SM: Macrophage production of fibronectin, a chemoattractant for fibroblasts. J Immunol (127): 673–678, 1981.Google Scholar
  161. 161.
    Atherton BT, Hynes RO: A difference between plasma and cellular fibronectin located with monoclonal antibodies. Cell (25): 133–141, 1981.Google Scholar
  162. 162.
    Pierschbacher MD, Hayman EG, Ruoslahti E: Location of the cell-attachment site in fibronectin with monoclonal antibodies and proteolytic fragments of the molecule. Cell (26): 259–267, 1981.Google Scholar
  163. 163.
    Hayashi M, Yamada KM: Differences in domain structures between plasma and cellular fibronectins. J Biol Chem (256): 11292–11300, 1981.Google Scholar
  164. 164.
    Ryan JJ, Ketcham AS, Wexler H: Warfarin treatment of mice bearing autochthonous tumors: effect on spontaneous metastases. Science (162): 1493–1494, 1968.Google Scholar
  165. 165.
    Editorial. Fibrin and cancer. Br Med J (4): 641–642, 1971.Google Scholar
  166. 166.
    Brown JM: A study of the mechanism by which anticoagulation with warfarin inhibits blood-borne metastases. Cancer Res (33): 1217–1224, 1973.Google Scholar
  167. 167.
    Hilgard P, Thornes RD: Anticoagulants in the treatment of cancer. Eur J Cancer (12): 755–762, 1976.Google Scholar
  168. 168.
    Hoover HC, Ketchman AS: Techniques for inhibiting tumor metastases. Cancer (35): 5–14, 1975.Google Scholar
  169. 169.
    Zacharski LR, Henderson WG, Rickles FR, Forman WB, Cornell CJ, Forcier RJ, Edwards R, Headley E, Kim S-H, O'Donnell JR, O'Dell R, Tornyos K, Kwaan HC: Effect of warfarin on survival in small cell carcinoma of the lung. JAMA (245): 831–835, 1981.Google Scholar
  170. 170.
    Gralnick HR: Cancer cell procoagulant activity. In: Donati MB, Davidson JF, Garattini S (eds) Malignancy and the hemostatic system. New York, Raven press, 1981. pp 57–63.Google Scholar
  171. 171.
    Hilgard P: The use of one anticoagulant in tumor therapy. In: Donati MB, Davidson JF, Garattini S (eds) Malignancy and the hemostatic system. New York, Raven press, 1981, pp. 103–111.Google Scholar

Copyright information

© Martinus Nijhoff Publishers 1983

Authors and Affiliations

  • Harold F. Dvorak
    • 1
    • 2
    • 3
  • Donald R. Senger
    • 1
    • 2
    • 3
  • Ann M. Dvorak
    • 1
    • 2
    • 3
  1. 1.Department of PathologyBeth Israel HospitalBostonUSA
  2. 2.Department of PathologyHarvard Medical SchoolBostonUSA
  3. 3.the Charles A. Dana Biomedical Research InstituteBeth Israel HospitalBostonUSA
  4. 4.Department of PathologyBeth Israel HospitalBostonUSA

Personalised recommendations