Summary
This review studies interactions of tumor cells with a particular host system which is normally responsible for hemostasis and the physiological integrity of the blood vessel luminal surface. With malignancy components of this system are frequently activated, producing abnormalities of blood coagulation, increased platelet responses, and conditions favoring tumor growth and metastasis. Activation of the clotting cascade is mediated by tumor and macrophage procoagulants, acting via Factor X or VII. Thrombin and fibrin are formed. Thrombin also interacts with platelets and the endothelium, potentiating or decreasing coagulation. Generation of thrombin or other tumor mechanisms activate platelets, leading to direct aggregation or secretion of ADP, serotonin, and/or intermediates of the arachidonate metabolism. Vascular lesions caused by tumor attack, platelet secretion, or exogenous agents promoting metastasis may also activate the hemostatic system. It is not yet fully understood how activation of the clotting system, including platelets, contributes to metastasis. Secretion of platelet products appears, however, to be heavily involved. Based on putative mechanisms of action, anticoagulants, platelet inhibitors, thrombocytopenic or vascular repairing agents have been used to control tumor spread. Results depended on the agent and experimental model of metastasis used. Except for coumarin, which was beneficial even against spontaneous metastases, other anticoagulants and platelet inhibitors, excluding perhaps Nafazatrom, gave equivocal results. Thrombocytopenic agents, However, were effective in every tumor system and with any experimental model of metastasis, indicating that platelets play a role in this process. Also consistent were the inhibitory effects of leech salivary gland extract (probably a vascular repairing agent) against lung tumor colonization promoted by ionizing radiation, cyclophosphamide, and cortisone.
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References
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. Raven Press, New York, 1981, pp 65–82.
Slichter SJ, Weiden PL, O'Donnell MR, Storb R: Interruption of tumor-associated platelet consumption with platelet enzyme inhibitors. Blood 59: 1252–1258, 1982.
Rickles FR, Edwards RL, Barb C, Cronlund M: Abnormalities of blood coagulation in patients with cancer. Cancer 51: 301–307, 1983.
Edwards RL, Rickles FR, Cronlund M: Abnormalities of blood coagulation in patients with cancer: mononuclear cell tissue factor generation. J Lab Clin Med 98: 917–928, 1981.
Lyberg T, Hetland O, Prydz H: Synthesis of thromboplastin protein by a murine macrophage-like cell line. Thromb Haemostas 47: 154–156, 1982.
Tracy PB, Rohrbach MS, Mann KG: Functional prothrombinase complex assembly on isolated monocytes and lymphocytes. J Biol Chem 258: 7264–7267, 1983.
O'Meara RAQ, Jackson RD: Cytological observations on carcinoma. Ir J Med Sci 391: 327–328, 1958.
Gordon SG, Franks JJ, Lewis BJ: Comparison of the procoagulant activities in extracts of normal and malignant human tissue. J Natl Cancer Inst 62: 773–776, 1979.
Boggust WA, O'Brien DJ, O'Meara RAQ, Thornes RD: The coagulative factors of normal human and human cancer tissue. Ir J Med Sci 477: 131–144, 1963.
Gordon SG, Franks JJ, Lewis B: Cancer procoagulant A: a factor X activating procoagulant from malignant tissue. Thrombosis Res 6: 127–137, 1975.
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.
Hilgard P, Whur P: Factor X-activating activity from Lewis lung carcinoma. Br J Cancer 41: 642–643, 1980.
Gordon SG, Cross BA: A factor X-activating cysteine protease from malignant tissue. Clin Invest 67: 1665–1671, 1981.
Gralnick HR: Cancer cell procoagulant activity. Thromb Haemostas 42: 352, 1979.
Gralnick HR, Abrell E: Studies of the procoagulant and fibrinolytic activity of promyelocytes in acute promyelocytic leukaemia. Br J Hematol 24: 89–99, 1973.
Khato J, Suzuki M, Sato H: Quantitative study of thromboplastin in various strains of Yoshida ascites hepatoma cells of rat. Gann 65: 289–294, 1974.
Niewiarowski S, Rao AK: Contribution of thrombogenic factors to the pathogenesis of atherosclerosis. Progress in Cardiovascular Diseases 26: 197–222, 1983.
Tuszynski GP, Walsh PN, Piperno JR, Koshy A: Association of coagulation factor V with the platelet cytoskeleton. J Biol Chem 257: 4557–4563, 1982.
Miletich JP, Jackson CM, Majerus PW: Properties of the factor Xa binding site on human platelets. J Biol Chem 253: 6908–6916, 1978.
Detwiler TC: Hypothetical model for the thrombin-platelet interaction. Ann NY Acad Sci 370: 67–71, 1981.
Pearlstein E, Ambrogio C, Gasic G, Karpatkin S: Inhibition of the platelet-aggregating activity of two human adenocarcinomas of the colon and an anaplastic murine tumor with a specific thrombin inhibitor, Dansylarginine N-(3-ethyl-1, 5-pentanediyl)amide. Cancer Res 41: 4535–4539, 1981.
Lollar P, Owen WG: Clearance of thrombin from circulation in rabbits by high-affinity binding sites on endothelium: possible roles in the inactivation of thrombin by antithrombin III. J Clin Invest 66: 1222–1230, 1980.
Lollar P, MacIntosh S, Owen WG: Interaction of thrombin with the vascular endothelium in a recirculating Langendorff rabbit heart preparation. Ann NY Acad Sci 401: 234–240, 1982.
Esmon CT, Owen WG: Identification of an endothelial cell cofactor for thrombin-catalyzed activation of protein C. Proc Natl Acad Sci 78: 2249–2252, 1981.
Comp PC, Esmon CT: Activated protein C inhibits platelet prothrombin-converting activity. Blood 54: 1272–1281, 1979.
Dahlback B, Stenflo J: Inhibitor effect of activated protein C on activation of prothrombin by platelet-bound factor Xa. J Biochem 107: 331–335, 1980.
Gospodarowicz D, Brown KD, Birdwell Cr, Zetter BR: Control of proliferation of human vascular endothelial cells. J Cell Biol 77: 774–788, 1978.
Donati MB, Poggi A: Malignancy and haemostasis. Brit J Haemat 44: 173–182, 1980.
Hansson GK, Schwartz SM: Evidence for cell death in the vascular endothelium in vivo and in vitro. AJP 112: 278–286, 1983.
Gasic GJ, Gasic TB: Plasma membrane vesicles as mediators of interactions between tumor cells and components of the hemostatic and immune systems. In: Interaction of platelets and tumor cells. Alan R Liss, New York, 1982, pp 429–444.
Holmsen H, Kaplan KL, Dangelmaier CA: Differential energy requirements for platelet responses. Biochem J 208: 9–18, 1982.
Paschen W, Patscheke H, Worner P: Aggregation of activated platelets with Walker 256 carcinoma cells. Blut 38: 17–24, 1979.
Sloane BF: Lysosomal cathepsin B: correlation with metastatic potential. Science 212: 1151–1153, 1981.
Gasic GJ, Koch PAG, Hsk B, Gasic TB, Niewiarowski: Thrombogenic activity of mouse and human tumors: effects on platelets, coagulation, and fibrinolysis, and possible significance for metastases. Z Krebsforsch 86: 263–277, 1976.
Gasic GJ, Gasic TB, Jimenez SA: Effects of trypsin on the platelet-aggregating activity of mouse tumor cells. Thromb Res 10: 33–45, 1977.
Holme R, Oftebro R, Hovig T: In vitro interaction between cultured cells and human blood platelets. Thromb Haemost 40: 89–102, 1978.
Jamieson GA, Bastida E, Ordinas A: Mechanisms of platelet aggregation by human tumor cells. In: Jamieson GA (ed) Interaction of platelets and tumor cells. Alan R Liss, New York, 1982, pp 405–413.
Hara Y, Steiner M, Baldini MG: Characterization of the platelet-aggregating activity of tumor cells. Cancer Res 40: 1217–1222, 1980.
Pearlstein E, Cooper LB, Karpatkin S: Extraction and characterization of a platelet-aggregating material from SV40-transformed mouse 3T3 fibroblasts. J Lab Clin Med 93: 332–344, 1979.
Karpatkin S, Pearlstein E: Role of platelets in tumor cell metastases. Ann Int Med 95: 636–641, 1981.
Lerner WA, Pearlstein E, Ambrogio C, Karpatkin S: New mechanism for tumor-induced platelet aggregation. Comparison with mechanisms shared by other tumors with possible pharmacologic strategy toward prevention of metastases. Int J Cancer 31: 463–469, 1983.
Bastida E, Ordinas A, Giardina SL, Jamieson GA: Differentiation of platelet-aggregating effects of human tumor cell lines based on inhibition studies with apyrase, hirudin, and phospholipase. Cancer Res 42: 4348–4352, 1982.
Gasic GJ, Boettiger D, Catalfamo JL, Gasic TB, Stewart GJ: Aggregation of platelets and cell membrane vesiculartion by rat cells transformed in vitro by Rous sarcoma virus. Cancer Res 38: 2950–2955, 1978.
Gasic GJ, Catalfamo JL, Gasic TB, Avdalovic N: In vitro mechanism of platelet aggregation by purified plasma membrane vesicles shed by mouse 15091A tumor cells. In: Donati MB (ed) Malignancy and the hemostatic system. Raven Press, New York, 1981, pp 27–35.
Cavanaugh PG, Sloane BF, Bajkowski A, Gasic GJ, Gasic TB, Honn KV: Involvement of a cathepsin B-like cysteine proteinase in platelet aggregation induced by tumor cells and their shed membrane vesicles. Clin Exp Metastasis 1: 297–307, 1983.
Dvorak HF, Quay SC, Orenstein NS, Dvorak AM, Hahn P, Bitzer AM: Tumor shedding and coagulation. Science 212: 923–924, 1981.
Gasic GJ, Gasic TB, Jimenez SA: Platelet aggregating material in mouse tumor cells: removal and regeneration. Lab Invest 36: 413–419, 1977.
Gasic GJ, Gasic TB, Stewart GJ: Mechanisms of platelet aggregation by murine tumor cell sheddings. In: Honn KV, Sloane BF (eds) Hemostatic mechanisms and metastasis. Martinus Nijhoff, Boston, 1984 (in press).
Kinlough-Rathbone RL, Packham MA, Reimers HJ, Cazenave JP, Mustard JF: Mechanisms of platelet shape change, aggregation, and release induced by collagen, thrombin, or A23, 187. J Lab Clin Med 90: 707–719, 1977.
Feinman RD, Lubowsky J, Charo I, Zabinski MP: The lumiaggregometer: a new instrument for simultaneous messurement of secretion and aggregation by platelets. J Lab Clin Med 90: 125–129, 1977.
Warren BA: Platelet-tumor cell interactions: morphological studies. In: de Gaetano G, Garattini S (eds) Platelets: a multidisciplinary approach. Raven Press, New York, 1978, pp 427–446.
Ivarsson L: Pulmonary metastasis formation after trauma: an experimental study on the relevance of rheological disturbances of blood. Acta chirurgica scandanavia. Almqvist & Wiksell, Stockholm, Göteborg, 1976.
Milas L, Peters LJ: Conditioning of tissues for metastasis formation by radiation and cytotoxic drugs. In: Nicolson GL, Milas L (eds) Cancer invasion and metastasis: biologic and therapeutic aspects. Raven Press, New York, 1984, pp 321–336.
Van Putten LM, Kram LKJ, van Dierendenck HHC, Smink T, Fuzy M: Enhancement of drugs of metastatic lung nodule formation after intravenous tumor cell injection. Int J Cancer 15: 588–595, 1975.
De Brabander M, Aerts F, Borgers M: The influence of a glucocorticoid on the lodgement and development in the lungs of intravenously injected tumor cells. Eur J Cancer 10: 751–755, 1974.
Nicolson GL: Cancer metastasis: organ colonization and the cell-surface properties of malignant cells. Biochimica et Biophysica Acta 695: 113–176, 1982.
Warren BA: Cancer cell-endothelial reactions: the microinjury hypothesis and localized thrombosis in the formation of micrometastases. In: Donati MB, Davidson JE, Garanttini S (eds) Malignancy and the hemostasis system. Raven Press, New York, 1981, pp 5–26.
Gasic GJ, Viner ED, Budzynski AZ, Gasic GP: Inhibition of lung tumor colonization by leech salivary gland extracts from Haementeria ghilianii. Cancer Res 43: 1633–1636, 1983.
Murer EH, James HL, Budzynski AZ, Malinconico SM, Gasic GJ: Protease inhibitors in Haementeria leech species. Thrombosis and Haemostasis 51: 24–26, 1984.
Gasic GJ, Iwakawa I, Viner C, Viner ED, Milas L: Inhibition of metastasis promotion by cyclophosphamide (CY), cortisone (E) & local thorax irradiation (LTI) by leech salivary gland extract (SGE) from Haementeria officinalis. Proc Am Assoc Cancer Res 25: 58, 1984.
Maat B, Hilgard P: Anticoagulants and experimental metastases—evaluation of antimetastatic effects in different model systems. J Cancer Res Clin Oncol 101: 275–283, 1981.
Gralnick HR: Cancer cell procoagulant activity. In: Donati MB, Davidson JF, Garattini S (eds) Malignancy and the hemostatic system. Raven Press, New York, 1981, pp 57–64.
Gorelik E, Wiltrout RH, Okumura K, Habu S, Herberman RB: Role of NK cells in the control of metastatic spread and growth of tumor cells in mice. Int J Cancer 30: 107–112, 1982.
Colucci M, Giavazzi R, Alessandri G, Semeraro N, Mantovani A, Donati MB: Procoagulant activity of sarcoma sublines with different metastatic potential. Blood 57: 733–735, 1981.
Zacharski LR: Anticoagulation in the treatment of cancer in man. In: Donati MB, Davidson JF, Garattini S (eds) Malignancy and the hemostatic system. Raven Press, New York, 1981, pp 113–128.
Hilgard P, Maat B: Mechanism of lung tumour colony reduction caused by coumarin anticoagulation. Europ J Cancer 15: 183–187, 1979.
Stenflo J: A new vitamin K-dependent protein: purification from bovine plasma and preliminary characterization. J Biol Chem 251: 355–363, 1976.
Hilgard P: Experimental vitamin K deficiency and spontaneous metastases. Br J Cancer 35: 891–893, 1977.
Maat B: Selective macrophage inhibition abolishes warfarin-induced reduction of metastases. Br J Cancer 41: 313–316, 1981.
Ossowski L, Reich E: Antibodies to plasminogen activator inhibit human tumor metastasis. Cell 35: 611–619, 1983.
Gasic GJ, Gasic TB, Galanti N, Johnson T, Murphy S: Platelet-tumor-cell interactions in mice: the role of platelets in the spread of malignant disease. Int J Cancer 11: 704–718, 1973.
Boucek RJ, Alvarez TR: Increase in survival of subcultured fibroblasts mediated by serotonin. Nature New Biology 229: 61–62, 1971.
Marguerie GA, Plow EF: The fibrinogen-dependent pathway of platelet aggregation. Ann NY Acad Sci 408: 556–566, 1983.
Nachman RL, Weksler B, Ferris B: Characterization of human platelet vascular permeability-enhancing activity. J Clin Invest 51: 549–555, 1972.
Wood S: Pathenogenesis of metastasis formation observed in vivo in the rabbit ear chamber. AMA Archives of Pathology 66: 550–568, 1958.
Niewiarowski S: Proteins secreted by the platelet. Thrombos Haemostas 38: 924–938, 1977.
Capitianio AM, Niewiaroswki S, Tuszynski CP, Kornecki E, Rao K: The interaction platelet factor X with human platelets and its association with the platelet tritium X-100 insoluble cytoskeleton (Abstract). Blood 60 (suppl): 709, 1982.
Rucinski B, Niewiarowski S, James P, Walz DA, Budzynski AZ: Antiheparin proteins secreted by human platelets: purification, characterization, and radioimmunoassay. Blood 53: 47–62, 1979.
Ross R, Vogel A: The platelet-derived growth factor. Cell 14: 203–210, 1978.
Cowan DH, Graham J: Stimulation of human tumor colony formation by platelet lysate. J Lab Clin Med 102: 973–986, 1983.
Stiles CD: The molecular biology of platelet-derived growth factor. Cell 33: 653–655, 1983.
Turner WA, Menter DG, Honn KV, Taylor JD: Tumor cell-induced fibronectin release. (Abstract) Proc Am Assoc Cancer Res 23: 97, 1983.
McKeown-Longo PJ, Hanning R, Mosher DF: Binding and degradation of platelet thrombospondin by cultured fibroblasts. J Cell Biol 98: 22–28, 1984.
Meyer D, Baumgartner HR: Role of von Willebrand factor in platelet adhesion to the subendothelium. Br J Haematol 54: 1–9, 1983.
Fujimotu T, O'Hara S, Hawiger J: Thrombin-induced exposure and prostacyclin inhibition of the receptor for factor VIII/von Willebrand factor on human platelets. J Clin Invest 69: 1212–1222, 1982.
Ruan C, Tobolem G, McMichael AJ, Drouet L, Legrand Y, Degos L, Kieffer N, Lee H, Caen JP: Monoclonal antibody to human platelet glycoprotein I: II. Effects of human platelet function. Br J Haematol 49: 511–519, 1981.
Tuszynski GP, Niewiarowski S, Lawley J, Srivastava S: Thrombospondin as a potential fibrin receptor on platelets identified by affinity chromatography. (Abstract) Circulation 68 (suppl III): 317, 1983.
Gogstad GO, Hagen I, Korsmo R, Solum NO: Evidence for a separate location of platelet glycoprotein II and III in the alpha granule membrane. (Abstract) Thromb Haemost 46: 109, 1981.
Wasteson A, Glimelius B, Busch D, Westermark B, Heldin C-H, Norling B: Effect of a platelet endoglycosidase on cell surface associated heparan sulphate of human cultured endothelial and glial cells. Thromb Res 11: 309–321, 1977.
Nakajima M, Irimura T, di Ferrante D, di Ferrante N, Nicolson G: Heparan sulfate degradation: relation to tumor invasive and metastatic properties of mouse B16 melanoma sublines. Science 220: 611–612, 1983.
Seamon KB, Padgett W, Daly JW: Forskolin: unique diterpene activator of adenylate cyclase in membranes and in intact cells. Proc Natl Acad Sci 78: 3363–3367, 1981.
Mussoni L, Poggi A, de Gaetano G, Donati MB: Effect of Ditazole, an inhibitor of platelet aggregation, on a metastasizing tumour in mice. Brit J Cancer 37: 126–129, 1978.
Jaffe BM, Santoro MG: Prostaglandins and cancer. Environ. Sci Res 29: 313–319, 1983.
Gasic G, Gasic T: Removal of sialic acid from the cell coat in tumor cells and vascular endothelium and its effects on metastasis. Proc Natl Acad Sci (USA) 48: 1172–1177, 1962.
Choi S-I, Simone JV, Journey LJ: Neuraminidase-induced thrombocytopenia in rats. Br J Haematol 22: 93–101, 1972.
Grottum KA, Jeremic M: Neuraminidase injections in rabbits: reduced platelet surface change, aggregation and thrombocytopenia. Thrombos Diathes Haemorrh 29: 461–469, 1973.
Greenburg J, Packham MA, Cazenave J-P, Reimers H-J, Mustard JF: Effects on platelet function of removal of platelet sialic acid by neuraminidase. Lab Invest 32: 476–484, 1975.
Gasic G, Gasic T, Stewart CC: Anti-metastatic effects associated with platelet reduction. Proc Natl Acad Sci (USA) 61: 46–52, 1968.
Morrison FS, Baldini MG: Antigenic relationship between blood platelets and vascular endothelium. Blood 33: 46–56, 1969.
Pearlstein E, Abrogio C, Karpatkin S: Lack of effect of PGI2 on the development of pulmonary metastases in mice following the intravenous injection of three syngeneic tumors; inhibition of metastases with anti-platelet antibody. (Abstract) Proceedings of the American Federation of Clinical Research, Washington DC, May 4–7, 1984.
Awouters F, Leysen JE, De Clerck F, van Nueten JM: General pharmacological profile of ketanserin (R41468), a selective 5-HT2 receptor antagonist. In: De Clerck F, Vanhoutte PM (eds) 5-Hydroxytryptamine in peripheral reactions. Raven Press, New York, 1982, pp 193–198.
Skolnik G, Ericsson LE, Bagge U: The effect of thrombocytopenia and anti-serotonin treatment on the lodgement of circulating tumor cells. J Cancer Res Clin Oncol 105: 30–37, 1983.
George JN, Thoi LL, McManus LM, Reimann TA: Isolation of human platelet membrane microparticles from plasma and serum. Blood 60: 834–840, 1982.
Gorelik E, Wiltrout RH, Brunda MJ, Holden HT, Herberman RB: Augmentation of metastasis formation by thyoglycollate-elicited macrophages. Int J Cancer 29: 575–581, 1982.
Gasic GJ, Gasic TB, Murphy S: Anti-metastatic effect of aspirin. Lancet 2: 713, 1972.
Wood S, Hilgard P: Aspirin and tumour metastasis. Lancet 2: 1416–1417, 1972.
Hilgard P, Schmidt CG: The influence of platelet aggregation inhibitors on metastasis formation in mice (3LL). Z Krebsforsch 86: 243–250, 1976.
Honn KV, Cicone B, Skoff A: Prostacyclin: a potent antimetastatic agent. Science 212: 1270–1272, 1981.
Menter DG, Onoda JM, Taylor JD, Honn KV: Effects of prostacyclin on tumor cell-induced platelet aggregation. Cancer Res 44: 450–456, 1984.
Kohga S, Kinjo M, Tanaka K, Ogawa H, Ishihara M, Tanaka N: Effects of 5-(2-chlorobenzyl)-4,5,6,7-tetrahydrothieno[3,2-C]pyridine hydrocloride (ticlopidine), a platelet aggregation inhibitor, on blood-borne metastasis. Cancer Res 41: 4710–4714, 1981.
Agarwal KC, Parks RE: Forskolin: a potential antimetastatic agent. Int J Cancer 32: 801–804, 1983.
Honn KV: Inhibition of tumor cell metastasis by modulation of the vascular prostacyclin/thromboxane A2 system. Clin Expl Metastasis 1: 103–114, 1983.
Honn KV, Busse WD, Sloane BF: Prostacyclin and thromboxanes: implications for their role in tumor cell metastasis. Biochemical Pharmacology 32: 1–11, 1983.
Honn KV, Menter DG, Onoda JM, Taylor JD, Sloane BF: Role of prostacyclin as a natural deterrent to hematogenous tumor metastasis. In: Nicolson GL, Milas L (eds) Tumor invasion and metastasis. Raven Press, New York, 1984, pp 361–388.
Kolenich JJ, Mansour EG, Flynn A: Haematological effects of aspirin. Lancet 2: 714, 1972.
Atherton A, Busfield D, Hellmann K: The effects of an antimetastatic agent, (=)-1,2-Bis(3,5-dioxopiperazin-1-yl)propane (ICRF 159), on platelet behavior. Cancer Res 35: 953–957, 1975.
Gordon S, Witul M, Cohen H, Sciandra J, Williams P, Gastpar H, Murphy GP, Ambrus JL: Studies of platelet aggregation inhibitors in vivo VIII; effect of pentoxifylline on spontaneous metastases. J Med 10: 435–441, 1979.
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Gasic, G.J. Role of plasma, platelets, and endothelial cells in tumor metastasis. Cancer Metast Rev 3, 99–114 (1984). https://doi.org/10.1007/BF00047657
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DOI: https://doi.org/10.1007/BF00047657