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

Marek Z. Wojtukiewicz; Ewa Sierko; Leo R. Zacharski; Lech Zimnoch; Bohdan Kudryk; Walter Kisiel

doi:10.1055/s-2003-40967

Seminars in Thrombosis and Hemostasis, Inhaltsverzeichnis

Semin Thromb Hemost 2003; 29(3): 291-300
DOI: 10.1055/s-2003-40967

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

Abstract

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.

KEYWORDS

Gastric cancer - blood coagulation - angiogenesis

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Referenzen

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