Semin Thromb Hemost 2003; 29(3): 291-300
DOI: 10.1055/s-2003-40967
Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Tissue Factor-Dependent Coagulation Activation and Impaired Fibrinolysis in Situ in Gastric Cancer

Marek Z. Wojtukiewicz1 , Ewa Sierko2 , Leo R. Zacharski3 , Lech Zimnoch4 , Bohdan Kudryk5 , Walter Kisiel6
  • 1Professor of Medicine and Oncology, Department of Oncology, Medical Academy
  • 2Department of Oncology, Medical Academy, Bialystok, Poland
  • 3Department of Medicine, Dartmouth Medical Center, Hanover, New Hampshire and the Department of Veterans Affairs Medical and Regional Office Center, White River Junction, Vermont
  • 4Department of Pathomorphology, Medical Academy, Bialystok, Poland
  • 5Laboratory of Blood Coagulation Biochemistry, New York Blood Center, New York, New York
  • 6Department of Pathology, University of New Mexico, School of Medicine, Albuquerque, New Mexico
Weitere Informationen

Publikationsverlauf

Publikationsdatum:
30. Juli 2003 (online)

ABSTRACT

Thromboembolism frequently complicates gastric cancer. This study examined the solid phase interaction between gastric cancer and coagulation proteins in situ that may explain coagulation activation and that may contribute to tumor progression and angiogenesis in this tumor type. Immunohistochemical techniques were applied to tissues from 37 cases of adenocarcinoma of the stomach obtained at surgical resection. Fibrinogen was present throughout the tumor stroma. Fibrin and its D-dimer cross-link sites occurred at the host-tumor interface. Subunit "a" of factor (F) XIII and F VII, IX, X, and XII were observed on cancer cells. Prothrombin and prothrombin fragment F1+2 (F1+2) were demonstrated in the tumor stroma on cancer cells and on small blood vessels. Tissue factor (TF) was present on cancer cells and tumor-associated macrophages. Protein C was observed on cancer cells and small blood vessels, whereas protein S was present only in the vascular bed. There was no staining for tissue factor pathway inhibitor (TFPI). High-molecular-weight (HMW) urokinase plasminogen activator (u-PA) antigen was not detected, but weak and inconsistent staining for low-molecular-weight (LMW) u-PA was demonstrated on cancer cells. Weak staining for tissue plasminogen activator (t-PA) occurred on cancer cells and in the tumor stroma. In contrast, plasminogen activator inhibitor-1 (PAI-1) expression was strong in the tumor stroma, along with PAI-2 and PAI-3. The endothelium of small stromal blood vessels, particularly near the host-tumor interface, demonstrated von Willebrand factor antigen (vWF Ag). Vascular endothelial growth factor (VEGF) was present on cancer cells and stromal macrophages. These results demonstrate tumor cell-associated TF-dependent extravascular coagulation activation in situ in gastric cancer that does not appear to be counterbalanced by TFPI or sufficient fibrinolytic activity. Colocalization of VEGF with hemostatic proteins suggests that they may cooperate in the pathogenesis of gastric cancer.

REFERENCES

  • 1 Trousseau A. Phlegmasia alba dolens. In: Clinique Medicale de l'Hotel-Dieu de Paris, 2nd ed., Vol 3. Paris: J.B. Balliere et Fils 1865: 654-712
  • 2 Bick R L. Coagulation abnormalities in malignancy: a review.  Semin Thromb Hemost . 1992;  18 353-372
  • 3 Schillaci F, Stagnitti F, Iurato C. et al . Deep vein thrombosis and neoplastic pathology: our experience in emergencies.  G Chir . 1998;  19 293-300
  • 4 Zyrianow B N, Tsisik R M, Udut V V, Karpow A B. Venous thromboses of lower extremities in stomach cancer patients.  Vopr Onkol . 1990;  36 872-875
  • 5 Ishikawa M, Koyama S, Ikagami T. et al . Venous tumor thrombosis and cavernous transformation of the portal vein in a patient with gastric carcinoma.  J Gastroenterol . 1995;  30 529-533
  • 6 Kakeji Y, Hashi Zume M, Kitano S, Hasuo K, Sugimachi K. Successful treatment of Budd-Chiari syndrome with early gastric cancer.  Int Surg . 1991;  76 55-57
  • 7 Sequiera J F, Gomes R M, Gonzales M A, Sarmento J L. Neoplastic hypercoagulability. Apropos of 2 cases with Trousseau syndrome.  Acta Med Port . 1990;  3 179-183
  • 8 Patel N, Krasnow A Z, Collier B D, Hellman R S, Isitman A T. Pulmonary embolism as an indicator of occult malignancy.  Clin Nucl Med . 1990;  15 841-842
  • 9 Kuraki T, Kobayashi H, Nagata N, Kawai T. Pulmonary tumor embolism caused by asymptomatic gastric cancer.  Nihon Kyobu Shikkan Gakkai Zasshi . 1997;  35 641-644
  • 10 Pasquini E, Gianni L, Aitini E. et al . Acute disseminated intravascular coagulation syndrome in cancer patients.  Oncology . 1995;  52 505-508
  • 11 Yeh K H, Cheng A L. Gastric cancer associated with acute disseminated intravascular coagulation: successful initial treatment with weekly 24-infusion of high-dose 5-fluorouracil and leucovorin.  Br J Haematol . 1998;  100 769-772
  • 12 Carr D J, Kramer B S, Dragonetti D E. Thrombotic thrombocytopenic purpura associated with metastatic gastric adenocarcinoma: successful management with plasmapheresis.  South Med J . 1986;  79 476-479
  • 13 Tsuchiya Y, Ishibashi H, Ohtsuka T. et al . Mucin-producing signet ring carcinoma of stomach accompanied by microangiopathic hemolytic anemia and disseminated intravascular coagulation: a case report.  Fukuoka Igaku Zasshi . 1989;  80 477-481
  • 14 Morimatsu M, Shirouzu K, Irie K, Tokunaga O, Sasaguri Y. Gross and microscopic characteristics of stomach cancer with microangiopathic hemolytic anemia and/or disseminated intravascular coagulopathy.  Acta Pathol Jpn . 1985;  35 809-822
  • 15 Kressel B R, Ryan K P, Duong A T, Berenberg J, Schein P S. Microangiopathic hemolytic anemia, thrombocytopenia, and renal failure in patients treated for adenocarcinoma.  Cancer . 1981;  48 1738-1745
  • 16 Korte W, Flury R. Acquired factor X deficiency and disseminated intravascular coagulation in a case of metastasizing carcinoma of the stomach and its course under chemotherapy.  Ann Hematol . 1992;  64 152-154
  • 17 Ludmerer K M, Kissane J M. Anemia and thrombocytopenia in a 63-year-old man.  Am J Med . 1983;  74 502-506
  • 18 Morgan A D. The pathology of subacute cor pulmonale in diffuse carcinomatosis of the lungs.  J Pathol Bacteriol . 1949;  61 75-84
  • 19 Bresciani C, Borges P C, Gama-Rodriguez J J. et al . Fatal pulmonary thromboembolism in gastrectomy intraoperative procedures by gastric adenocarcinoma: case report.  Rev Hosp Clin Fac Med Sao Paulo . 1999;  54 115-120
  • 20 Rickles F R, Levine M, Edwards R L. Hemostatic alterations in cancer patients.  Cancer Metastasis Rev . 1992;  11 237-248
  • 21 Kambayashi J, Sakon M, Yokota M. et al . Activation of coagulation and fibrinolysis during surgery, analyzed for by molecular markers.  Thromb Res . 1990;  60 157-167
  • 22 Rahr H B, Sørensen J V, Larsen J F, Svendsen Jensen F, Bredahl C. Markers of coagulation and fibrinolysis in portal blood from patients with and without gastric malignancy.  Scand J Gastroenterol . 1994;  29 516-521
  • 23 Gouin-Thibault I, Samama M M. Laboratory diagnosis of the thrombophilic state in cancer patients.  Semin Thromb Hemost . 1999;  25 167-172
  • 24 Hillen H FP. Thrombosis in cancer patients.  Ann Oncol . 2000;  11(Suppl 3) 273-276
  • 25 Wojtukiewicz M Z, Rucinska M, Kloczko J, Dib A, Galar M. Profiles of plasma serpins in patients with advanced malignant melanoma, gastric cancer and breast cancer.  Haemostasis . 1998;  28 7-13
  • 26 Ho C H, Chao Y, Lee S D. et al . Diagnostic and prognostic values of plasma levels of fibrinolytic markers in gastric cancer.  Thromb Res . 1998;  91 23-27
  • 27 Wojtukiewicz M Z, Rucinska M, Zimnoch L. et al . Expression of prothrombin fragment 1+2 in cancer tissue as an indicator of local activation of blood coagulation.  Thromb Res . 2000;  97 335-342
  • 28 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
  • 29 Wojtukiewicz M Z, Zacharski L R, Memoli V A. et al . Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung.  Cancer . 1990;  65 481-485
  • 30 Wojtukiewicz M Z, Zacharski L R, Memoli V A. et al . Malignant melanoma. Interaction with coagulation and fibrinolysis pathways in situ.  Am J Clin Pathol . 1990;  93 516-521
  • 31 Wojtukiewicz M Z, Zacharski L R, Memoli V A. et al . Fibrinogen-fibrin transformation in situ in renal cell carcinoma.  Anticancer Res . 1990;  10 579-582
  • 32 Wojtukiewicz M Z, Zacharski L R, Rucinska M. et al . Expression of tissue factor and tissue factor pathway inhibitor in situ in laryngeal carcinoma.  Thromb Haemost . 1999;  82 1659-1662
  • 33 Wojtukiewicz M Z, Rucinska M, Zacharski L R. et al . Localization of blood coagulation factors in situ in pancreatic carcinoma.  Thromb Haemost . 2001;  86 1416-1420
  • 34 Zacharski L R, Wojtukiewicz M Z, Costantini V, Ornstein D L, Memoli V A. Pathways of coagulation/fibrinolysis activation in malignancy.  Semin Thromb Hemost . 1992;  18 104-116
  • 35 Rickles F R, Falanga A. Molecular basis for the relationship between thrombosis and cancer.  Thromb Res . 2001;  102 V215-V224
  • 36 Wojtukiewicz M Z, Tang T G, Ben-Josef E. et al . Solid tumor cells express functional "tethered ligand" thrombin receptor.  Cancer Res . 1995;  55 698-704
  • 37 Wojtukiewicz M Z, Tang T G, Ciarelli J J. et al . Thrombin increases the metastatic potential of tumor cell.  Int J Cancer . 1993;  54 793-806
  • 38 Wojtukiewicz M Z, Tang T G, Nelson K K. et al . Thrombin enhances tumor cell adhesive and metastatic properties via increased alpha IIb beta 3 expression on the cell surface.  Thromb Res . 1992;  68 233-245
  • 39 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
  • 40 Folkman J. Tumor angiogenesis: therapeutic implications.  N Engl J Med . 1971;  285 1182-1186
  • 41 Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other diseases.  Nat Med . 1995;  1 27-31
  • 42 Tanigawa N, Amaya H, Matsurmura M, Shimomatsuya T. Correlation between expression of vascular endothelial growth factor and tumor vascularity, and patient outcome in human gastric carcinoma.  J Clin Oncol . 1997;  15 826-832
  • 43 He X, Hokita S, Natsugoe S. et al . Tumor angiogenesis related to growth pattern and lymph node metastasis in early gastric cancer.  Chin Med J . 1998;  111 1090-1093
  • 44 Ferrara N. Vascular endothelial growth factor: molecular and biological aspects.  Curr Top Microbiol Immunol . 1999;  237 1-30
  • 45 Kakeji Y, Maehara Y, Sumiyoshi Y, Oda S, Emi Y. Angiogenesis as a target for gastric cancer.  Surgery . 2002;  131 S48-54
  • 46 Tao H Q, Lin Y Z, Wang R N. Significance of vascular endothelial growth factor messenger RNA expression in gastric cancer.  World J Gastroenterol . 1998;  4 10-13
  • 47 Sato Y, Mukai K, Watanabe S, Goto M, Shimosato Y. The AMeX method. The simplified technique of tissue processing and paraffin embedding with improved preservation of antigens for immunostaining.  Am J Pathol . 1986;  125 431-435
  • 48 Hsu S, Raine L, Fanger H. Use of avidin-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: a comparison between ABC and unlabeled antibody (PAP) procedures.  J Histochem Cytochem . 1981;  29 577-580
  • 49 Kudryk B, Rohoza A, Ahadi M, Chin J, Wiebe M E. A monoclonal antibody for the NH2-terminal fragments derived from fibrinogen and fibrin.  Mol Immunol . 1984;  20 1191-1200
  • 50 Kudryk B. Specificity of a monoclonal antibody for the NH2-terminal region of fibrin.  Mol Immunol . 1984;  21 89-94
  • 51 Kudryk B, Grossman Z D, McAfee J G, Rosebrough S F. Monoclonal antibodies as probes for fibrin(ogen) proteolysis. In: Chatal JF, ed. Monoclonal Antibodies in Immunoscintigraphy Boca Raton, FL: CRS Press 1988: 365-398
  • 52 Mombelli G, Roux A, Haeberli A, Straub P W. Comparison of 125I-fibrinogen kinetics and fibrinopeptide A in patients with disseminated neoplasias.  Blood . 1982;  60 381-388
  • 53 Zacharski L R, Costantini V, Wojtukiewicz M Z, Memoli V A, Kudryk B J. Anticoagulants as cancer therapy.  Semin Oncol . 1990;  17 217-227
  • 54 Di Micco P, Romano M, Niglio A. et al . Alteration of haemostasis in non-metastatic gastric cancer.  Dig Liver Dis . 2001;  33 546-550
  • 55 Abbasciano V, Tassinari D, Sartori S. et al . Usefulness of coagulation markers in staging of gastric cancer.  Cancer Detect Prev . 1995;  19 331-334
  • 56 Wojtukiewicz M Z, Sierko E, Klement P, Rak J. The hemostatic system and angiogenesis in neoplasms.  Neoplasia . 2001;  3 371-384
  • 57 Ellis C A, Tiruppathi C, Sandoval R, Niles W D, Malik A B. Time course of recovery of endothelial cell surface thrombin receptor (PAR-1) expression.  Am J Physiol . 1999;  276 C38-C45
  • 58 Tsopanoglou N E, Pipili-Synetos E, Maragoudakis M E. Thrombin promotes angiogenesis by a mechanism independent of fibrin formation.  Am J Physiol . 1993;  264 1302-1307
  • 59 Tsopanoglou N E, Maragoudakis M E. On the mechanism of thrombin-induced angiogenesis.  J Biol Chem . 1999;  274 23969-23976
  • 60 Zucker S, Conner C, DiMassmo B I. et al . Thrombin induces the activation of progelatinase A in vascular endothelial cells.  J Biol Chem . 1995;  270 23730-23738
  • 61 Bunce L A, Sporn L A, Francis C W. Endothelial cell spreading on fibrin requires fibrinopeptide B cleavage and amino acid residues 15-42 of the β chain.  J Clin Invest . 1992;  89 842-850
  • 62 Sahni A, Francis C W. Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation.  Blood . 2000;  96 3772-3778
  • 63 Sahni A, Baker C A, Sporn L A, Francis C W. Fibrinogen and fibrin protect fibroblast factor-2 from proteolytic degradation.  Thromb Haemost . 2000;  83 736-741
  • 64 Dallabrida S M, Falls L A, Farrell D H. Factor XIIIa supports microvascular endothelial cell adhesion and inhibits capillary tube formation in fibrin.  Blood . 2000;  95 2586-2582
  • 65 Rao L VM. Tissue factor as a tumor procoagulant.  Cancer Metastasis Rev . 1992;  11 249-266
  • 66 Gordon S G. Cancer cell procoagulants and their role in malignant disease.  Semin Thromb Hemost . 1992;  18 424-433
  • 67 Clauss M. Molecular biology of the VEGF and the VEGF receptor family.  Semin Thromb Hemost . 2000;  5 561-569
  • 68 Ruf W, Mueller B M. Tissue factor signaling.  Thromb Haemost . 1999;  82 175-182
  • 69 Rak J, Mitsuhashi Y, Sheehan C. et al . Oncogenes and tumor angiogenesis: differential modes of vascular endothelial growth factor up-regulation in ras-transformed epithelial cells and fibroblasts.  Cancer Res . 2000;  60 490-498
  • 70 Abe K, Shoji M, Chen J. et al . Regulation of vascular endothelial growth production and angiogenesis by the cytoplasmic tail of tissue factor.  Proc Natl Acad Sci USA . 1999;  96 8663-8668
  • 71 Bromberg M E, Capello M. Cancer and blood coagulation: molecular aspects.  Cancer J . 1999;  5 132-138
  • 72 Shigemori C, Wada H, Matsumoto K. et al . Tissue factor expression and metastatic potential of colorectal cancer.  Thromb Haemost . 1998;  80 894-898
  • 73 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
  • 74 Ott I, Fischer E G, Miyagi Y, Mueller B M, Ruf W. A role for tissue factor in cell adhesion and migration mediated by interaction with actin-binding protein 280.  J Cell Biol . 1998;  140 1241-1253
  • 75 Naito S, Inoune S, Kinjo M, Tanaka K. Thromboplastic and fibrinolytic activities of cultured human gastric cancer cell lines.  Gann . 1983;  74 240-247
  • 76 Szczepanski M, Bardadin K, Zawadzki J, Pypno W. Procoagulant activity of gastric, colorectal and renal cancer is factor VII-dependent.  J Cancer Res Clin Oncol . 1988;  114 519-522
  • 77 Zacharski L R, Memoli V A, Ornstein D L. et al . Tumor cell procoagulant and urokinase expression in carcinoma of the ovary.  J Natl Cancer Inst . 1993;  85 1225-1230
  • 78 Mizumoto R, Kawarada Y, Ogura Y. Gastrectomy in siblings with Christmas disease (hemophilia B).  Japan J Surg . 1980;  10 328-337
  • 79 Lindahl A K, Sandset P M, Abildgaard U, Adersson T R, Harbitz T B. High plasma levels of extrinsic pathway inhibitor and low levels of other coagulation inhibitors in advanced cancer.  Acta Chir Scand . 1989;  155 389-393
  • 80 Werling R W, Zacharski L R, Kisiel W. et al . Distribution of tissue factor pathway inhibitor in normal and malignant human tissues.  Thromb Haemost . 1993;  69 366-369
  • 81 Ganesh S, Sier C F, Heerding M M. Prognostic value of the plasminogen activation system in patients with gastric carcinoma.  Cancer . 1996;  77 1035-1043
  • 82 Heiss M M, Babic R, Allgayer H. The prognostic impact of the urokinase-type plasminogen activator system is associated with tumor differentiation in gastric cancer tissue.  Eur J Surg Oncol . 1996;  22 74-77
  • 83 Heiss M M, Babic R, Allgayer H. Tumor-associated proteolysis and prognosis: new functional risk factors in gastric cancer defined by the urokinase-type plasminogen activation system.  J Clin Oncol . 1995;  13 2084-2093
  • 84 Cho J Y, Chung H C, Noh S H. et al . High level of urokinase-type plasminogen activator is a new prognostic marker in patients with gastric carcinoma.  Cancer . 1997;  79 878-883
  • 85 Nekarda H, Schmitt M, Ulm K. Prognostic impact of urokinase-type plasminogen activator and its inhibitor PAI-1 in completely resected gastric cancer.  Cancer Res . 1994;  54 2900-2907
  • 86 Bajou K, Noel A, Gerard R D. et al . Absence of host plasminogen activator inhibitor 1 prevents cancer invasion and vascularization.  Nat Med . 1998;  4 923-928
  • 87 Nakamura M, Konno H, Tanaka T. et al . Possible role of plasminogen activator inhibitor 2 in the prevention of the metastasis of gastric cancer tissues.  Thromb Res . 1992;  65 709-719
  • 88 Carroll V, Binder B. The role of the plasminogen activation system in cancer.  Semin Thromb Hemost . 1999;  25 183-197
  • 89 Pepper M S. Extracellular proteolysis and angiogenesis.  Thromb Haemost . 2001;  86 346-355
  • 90 Dvorak H F, Brown L F, Detmar M, Dvorak A M. Vascular permeability factor/vascular endothelial growth factor, microvascular permeability and angiogenesis.  Am J Pathol . 1995;  146 1029-1039
  • 91 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
  • 92 Shoji M, Hancock W W, Abe K. et al . Activation of blood coagulation and angiogenesis in cancer.  Am J Pathol . 1998;  152 399-411
  • 93 Key N S, Bach R R. Tissue factor as a therapeutic target.  Thromb Haemost . 2001;  85 375-376
  • 94 Falanga A, Rickles F R. Pathophysiology of the thrombophilic state in the cancer patient.  Semin Thromb Hemost . 1999;  25 173-182
  • 95 Amirkhosravi A, Meyer T, Warnes G. et al . Pentoxyfilline inhibits hypoxia-induced upregulation of tumor cell tissue factor and vascular endothelial growth factor.  Thromb Haemost . 1998;  80 598-602
  • 96 Fenton II W J, Shen G X, Minnear F L. et al . Statins induce hypothrombotic states?.  Clin Appl Thromb Hemost . 2000;  6 18-21
  • 97 Rosen L. Antiangiogenic strategies and agents in clinical trials.  Oncologist . 2000;  5(Suppl 1) 20-27
  • 98 Zacharski L R, Ornstein D L. Heparin and cancer.  Thromb Haemost . 1998;  80 10-23
  • 99 Zacharski L R, Henderson W B. Vitamin K antagonists and cancer survival.  Thromb Haemost . 2002;  28 5-17
  • 100 Rha S Y, Noh S H, Kim T S. et al . Modulation of biological phenotypes for tumor growth and metastasis by target-specific biological inhibitors in gastric cancer.  Int J Mol Med . 1999;  4 203-212
  • 101 Hattori Y, Odagiri H, Katoh O. et al . K-sam-related gene, N-sam, encodes fibroblast growth factor receptor and is expressed in T-lymphocytic tumors.  Cancer Res . 1992;  52 3367-3371
  • 102 Hattori Y, Odagiri H, Nakatani H. et al . K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes.  Proc Natl Acad Sci USA . 1990;  87 5983-5987
  • 103 Zacharski L R, Ornstein D L, Gabazza E C. et al . Treatment of malignancy by activation of the plasminogen system.  Semin Thromb Hemost . 2002;  28 5-17