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Thromb Haemost 2001; 86(06): 1416-1420
DOI: 10.1055/s-0037-1616744
Review Article
Schattauer GmbH

Localization of Blood Coagulation Factors In Situ in Pancreatic Carcinoma

Marek Z. Wojtukiewicz
1   Departments of Oncology
,
Monika Rucinska
1   Departments of Oncology
,
Leo R. Zacharski
4   Dartmouth Medical School and the Department of Veterans Affairs Medical and Regional Office Center, White River Junction, Vermont, USA
,
Leszek Kozlowski
1   Departments of Oncology
,
Lech Zimnoch
2   Pathological Anatomy
,
Zdzislaw Piotrowski
3   Gastroenterologic Surgery, Medical Academy, Bialystok, Poland
,
Bohdan J. Kudryk
5   Laboratory of Blood Coagulation Biochemistry, New York Blood Center, New York, USA
,
Walter Kisiel
6   Department of Pathology, University of New Mexico, School of Medicine, Albuquerque, New Mexico, USA
› Author Affiliations
Supported, in part, by the Department of Veterans Affairs Medical Research Service.
Further Information

Publication History

Received 14 May 2001

Accepted after revision 02 July 2001

Publication Date:
12 December 2017 (online)

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Summary

Blood coagulation is activated commonly in pancreatic carcinoma but the role of the tumor cell in this activation is undefined. Immunohistochemical procedures were applied to fixed sections of 22 cases of resected adenocarcinoma of the pancreas to determine the presence of components of coagulation and fibrinolysis pathways in situ. Tumor cell bodies stained for tissue factor; prothrombin; and factors VII, VIIIc, IX, X, XII, and subunit “a” of factor XIII. Fibrinogen existed throughout the tumor stroma, and tumor cells were surrounded by fibrin. Staining for tissue factor pathway inhibitor, and plasminogen activators was minimal and inconsistent. Plasminogen activator inhibitors -1, -2, and -3 were present in the tumor stroma, and on tumor cells and vascular endothelium. Extravascular coagulation activation exists associated with pancreatic carcinoma cells in situ that is apparently unopposed by naturally occurring inhibitors or the plasminogen activator-plasmin system. We postulate that such local coagulation activation may regulate growth of this malignancy. These findings provide a rationale for testing agents that modulate the blood coagulation/fibrinolytic system (that inhibit tumor growth in other settings) in pancreatic carcinoma.

Keywords

Pancreatic cancer - blood coagulation - fibrin
 

  • References

  • 1 Rickles FR, Levine M, Edwards RL. Hemostatic alterations in cancer patients. Cancer Metastasis Rev 1992; 11: 237-48.
    CrossrefPubMedSearch in Google Scholar
  • 2 Nand S. Hemostasis and cancer. Cancer J 1993; 6: 54-8.
    PubMedSearch in Google Scholar
  • 3 Donati MB. Cancer and thrombosis: from plegmasia alba dolens to transgenic mice. Thromb Haemost 1995; 74: 278-81.
    Thieme ConnectPubMedSearch in Google Scholar
  • 4 Naschitz JE, Yeshurun D, Lev LM. Thromboembolism in cancer. Cancer 1993; 71: 1384-90.
    CrossrefPubMedSearch in Google Scholar
  • 5 Trousseau A. Phlegmasia alba dolens. Clinique Medicale de I’Hotel-Dieu. Paris: Bailliere JB 1865; 3: 654-712.
    PubMedSearch in Google Scholar
  • 6 Mao C, Domenico DR, Kim K, Hanson DJ, Howard JM. Observations on the developmental patterns and the consequences of pancreatic exocrine adenocarcinoma. Findings of 154 autopsies. Arch Surg 1995; 130: 125-34.
    CrossrefPubMedSearch in Google Scholar
  • 7 Sproul EE. Carcinoma and venous thrombosis: the frequency of association of carcinoma in the body or tail of the pancreas with multiple venous thrombosis. Amer J Cancer 1938; 34: 566-85.
    PubMedSearch in Google Scholar
  • 8 Lindahl AK, Odegaard OR, Sandset PM, Harbitz TB. Coagulation inhibition and activation in pancreatic cancer. Cancer 1992; 70: 2067-72.
    CrossrefPubMedSearch in Google Scholar
  • 9 Sorensen HT, Mellemkjaer L, Steffensen FH, Olsen JH, Neilsen GL. The risk of a diagnosis of cancer after primary deep venous thrombosis or pulmonary embolism. N Engl J Med 1998; 388: 1169-73.
    PubMedSearch in Google Scholar
  • 10 Hu T, Bach RR, Horton R, Konigsberg WH, Todd MB. Procoagulant activity in cancer cells is dependent on tissue factor expression. Oncology Res 1994; 6: 321-7.
    PubMedSearch in Google Scholar
  • 11 Zacharski LR, Wojtukiewicz MZ, Constantini V, Ornstein DL, Memoli VA. Pathways of coagulation/fibrinolysis activation in malignancy. Semin Thromb Hemost 1992; 18: 104-16.
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Ruf W, Mueller BM. Tissue factor in cancer angiogenesis and metastasis. Curr Opin Hematol 1996; 3: 379-84.
    CrossrefPubMedSearch in Google Scholar
  • 13 Sato Y, Mukai K, Watanabe S, Goto M, Shimosato Y. The AMeX method. A simplified technique of tissue processing and paraffin embedding with improved preservation of antigens for immunostaining. Am J Pathol 1986; 125: 431-5.
    PubMedSearch in Google Scholar
  • 14 Wojtukiewicz MZ, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Rousseau SM, Stump DC. Fibrinogen-fibrin transformation in situ in renal cell carcinoma. Anticancer Res 1990; 10: 579-82.
    PubMedSearch in Google Scholar
  • 15 Wojtukiewicz MZ, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Rousseau SM, Stump DC. Malignant melanoma. Interaction with coagulation and fibrinolysis pathways in situ . Am J Clin Pathol 1990; 93: 516-21.
    CrossrefPubMedSearch in Google Scholar
  • 16 Kudryk B, Rohoza A, Ahadi M, Chin J, Wiebe ME. Monoclonal antibodies with ability to distinguish between NH2-terminal fragments derived from fibrinogen and fibrin. Molec Immunol 1983; 20: 1191-200.
    CrossrefPubMedSearch in Google Scholar
  • 17 Kudryk B. Specificity of a monoclonal antibody for the NH2-terminal region of fibrin. Molec Immunol 1984; 21: 89-94.
    CrossrefPubMedSearch in Google Scholar
  • 18 Kudryk B, Grossman ZD, McAfee JG, Rosebrough SF. Monoclonal antibodies as probes for fibrin(ogen) proteolysis. W: Chatal JF. (red.) Monoclonal Antibodies in Immunoscintigraphy. Boca Raton, FL: CRS Press; 1988. pp. 365-98.
    Search in Google Scholar
  • 19 Zacharski LR, Memoli VA, Costantini V, Wojtukiewicz MZ, Ornstein DL. Clotting factors in tumour tissue: implications for cancer therapy. Blood Coag Fibrinol 1990; 1: 71-8.
    CrossrefPubMedSearch in Google Scholar
  • 20 Wojtukiewicz MZ, Zacharski LR, Memoli VA, Kisiel W, Kudryk BJ, Rousseau SM, Stump DC. Abnormal regulation of coagulation/fibrinolysis in small cell carcinoma of the lung. Cancer 1990; 65: 481-5.
    CrossrefPubMedSearch in Google Scholar
  • 21 Zacharski LR, Memoli VA, Ornstein DL, Rousseau SM, Kisiel W, Kudryk BJ. Tumor cell procoagulant and urokinase expression in carcinoma of the ovary. J Natl Cancer Inst 1993; 85: 1225-30.
    CrossrefPubMedSearch in Google Scholar
  • 22 Werling RW, Zacharski LR, Kisiel W, Bajaj SP, Memoli VA, Rousseau SA. Distribution of tissue factor pathway inhibitor in normal and malignant human tissues. Thromb Haemost 1993; 69: 366-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 23 Warshaw AL, Fernandez-del Castillo C. Pancreatic carcinoma. N Engl J Med 1992; 326: 455-65.
    CrossrefPubMedSearch in Google Scholar
  • 24 Wojtukiewicz MZ, Rucinska M, Zimnock L, Jaromin J, Piotrowski Z, Rozanska-Kudelska M, Kisiel W, Kudryk BJ. Expression of prothrombin fragment 1+2 in cancer tissue as an indicator of local activation of blood coagulation. Thromb Res 2000; 97: 335-42.
    CrossrefPubMedSearch in Google Scholar
  • 25 Lindahl AK, Sandset PM, Abildgaard U. The present status of tissue factor pathway inhibitor. Blood Coag Fibrinol 1992; 3: 439-49.
    CrossrefPubMedSearch in Google Scholar
  • 26 Lindahl AK, Abildgaard U, Stokke G. Release of extrinsic pathway inhibitor after heparin injection: increased response in cancer patients. Thromb Res 1990; 59: 651-6.
    CrossrefPubMedSearch in Google Scholar
  • 27 Kakkar AK, Chinswangwatanakul V, Tebbutt S, Lemoine NR, Williamson RCN. A characterization of the coagulant and fibrinolytic profile of human pancreatic carcinoma cells. Haemostasis 1998; 28: 1-6.
    PubMedSearch in Google Scholar
  • 28 Andren-Sandberg A, Lecander I, Martinsson G, Astedt B. Peaks in plasma plasminogen activator inhibitor-1 concentration may explain thrombotic events in cases of pancreatic carcinoma. Cancer 1992; 69: 2884-7.
    CrossrefPubMedSearch in Google Scholar
  • 29 Takeuchi Y, Nakao A, Harada A, Nonami T, Fukatsu T, Takagi H. Expression of plasminogen activators and their inhibitors in human pancreatic carcinoma: immunohistochemical study. Am J Gastroenterol 1993; 88: 1928-33.
    PubMedSearch in Google Scholar
  • 30 Kakkar AK, DeRuvo N, Chinswang-Watanakul V, Tebbutt S, Williamson RCN. Extrinsic-pathway activation in cancer with high factor VIIa and tissue factor. Lancet 1995; 346: 1004-5.
    CrossrefPubMedSearch in Google Scholar
  • 31 Silberberg JM, Gordon S, Zucker S. Identification of tissue factor in two human pancreatic cancer cell lines. Cancer Res 1989; 49: 5443-7.
    PubMedSearch in Google Scholar
  • 32 Kakkar AK, Lemoine NR, Scully MF, Tebbutt S, Williamson RCN. Tissue factor expression correlates with histological grade in human pancreatic cancer. Br J Surg 1995; 82: 1101-4.
    CrossrefPubMedSearch in Google Scholar
  • 33 Costantini V, Zacharski LR. The role of fibrin in tumor metastasis. Cancer Metast Rev 1992; 11: 283-90.
    CrossrefPubMedSearch in Google Scholar
  • 34 Wojtukiewicz MZ, Tang DG, Ciarelli JJ, Nelson KK, Walz DA, Diglio CA, Mammen EF, Honn KV. Thrombin increases the metastatic potential of tumor cells. Int J Cancer 1993; 54: 793-806.
    CrossrefPubMedSearch in Google Scholar
  • 35 Heinmoller E, Schropp T, Kisker B, Simon B, Weinel RJ. Tumor cell-induced platelet aggregation in vitro by human pancreatic cancer cell lines. Scand J Gastroenterol 1995; 30: 1008-16.
    CrossrefPubMedSearch in Google Scholar
  • 36 Pluda JM, Parkinson DR. Clinical implications of tumor-associated neovascularization and current antiangiogenic strategies for the treatment of malignancies of pancreas. Cancer 1996; 78: 680-7.
    CrossrefPubMedSearch in Google Scholar
  • 37 Wojtukiewicz MZ, Tang DG, Nelson KK, Walz DA, Diglio CA, Honn KV. Thrombin enhances tumor cell adhesive and metastic properties via increased ∂11bβ3 expression on the cell surface. Thromb Res 1992; 68: 233-45.
    CrossrefPubMedSearch in Google Scholar
  • 38 Brown LF, Chester JF, Malt RA, Dvorak HF. Fibrin deposition in autochthonous Syrian hamster pancreatic adenocarcinomas induced by the chemical carcinogen N-nitroso-bis (2-oxopropyl) amine. J Natl Cancer Inst 1987; 78: 979-86.
    PubMedSearch in Google Scholar
  • 39 Tzanakakis GN, Agarwal KC, Vezeridis MP. Inhibition of hepatic metastasis from a human pancreatic adenocarcinoma (RWP-2) in the nude mouse by prostacyclin, forskolin, and ketoconazole. Cancer 1990; 65: 446-61.
    CrossrefPubMedSearch in Google Scholar
  • 40 Waddell WR. Chemotherapy for carcinoma of the pancreas. Surgery 1973; 74: 420-9.
    PubMedSearch in Google Scholar
  • 41 Sadoff L, Latino F. Complete clinical remission in a patient with advanced pancreatic cancer using mitomycin C-based chemotherapy. The role of adjuvant heparin. Amer J Clin Oncol 1999; 22: 187-90.
    CrossrefPubMedSearch in Google Scholar
  • 42 Zarcharski LR, Ornstein DL. Heparin and Cancer. Thromb Haemost 1998; 80: 10-23.
    Thieme ConnectPubMedSearch in Google Scholar
  • 43 Hamamoto T, Kisiel W. The effect of heparin on the regulation of factor VIIa-tissue factor activity by tissue factor pathway inhibitor. Blood Coagul Fibrinol 1996; 7: 470-6.
    CrossrefPubMedSearch in Google Scholar
  • 43 Kleeff J, Ishiwata T, Kumbasar A, Friess H, Buchler MW, Lander AD, Korc M. The cell-surface heparan sulfate proteoglycan glypican-1 regulates growth factor action in pancreatic carcinoma cells and is over-expressed in human pancreatic cancer. J Clin Invest 1998; 102: 1662-73.
    CrossrefPubMedSearch in Google Scholar