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Co-localization of Protein Z, Protein Z-Dependent protease inhibitor and coagulation factor X in human colon cancer tissue: implications for coagulation regulation on tumor cells
Authors:Sierko Ewa  Wojtukiewicz Marek Z  Zimnoch Lech  Tokajuk Piotr  Ostrowska-Cichocka Krystyna  Kisiel Walter
Affiliation:
  • a Department of Oncology, Medical University, Bialystok, Poland
  • b Comprehensive Cancer Center, Bialystok, Poland
  • c Department of Clinical Pathomorphology, Medical University, Bialystok, Poland
  • d Department of Pathology, University of New Mexico, School of Medicine, Albuquerque, New Mexico, USA
    		•
    Abstract:

    Introduction

    Several hemostatic system components, including factor X (FX), contribute to cancer progression. The Protein Z (PZ)/protein Z-dependent protease inhibitor (ZPI) complex directly inhibits factor Xa proteolytic activity. The aim of this study was to determine the antigenic distribution of ZPI and PZ, in relation to FX, as well as indicators of blood coagulation activation (F1+2 and fibrin) in human colon cancer tissue.

    Materials & methods

    Studies were performed on human colon cancer fragments. Immunohistochemical (IHC) ABC procedures and double staining method employed polyclonal antibodies against PZ, FX, F1+2 and monoclonal antibodies against ZPI and fibrin. In-situ hybridization (ISH) methods employed biotin-labeled 25-nucleotide single-stranded DNA probes directed to either FX, PZ or ZPI mRNAs.

    Results

    Expression of FX, PZ and ZPI in association with colon cancer cells was observed by IHC. Moreover, the presence of both F1+2 and fibrin in association with colon cancer cells was found, which indicates that blood coagulation activation proceeds extravascularly at the tumor site. Furthermore, expression of FX and PZ was visualized in association with endothelial cells. In turn, colon cancer-associated macrophages were characterized by FX , PZ and ZPI presence. The double staining studies revealed strong FX/PZ, FX/ZPI, as well as PZ/ZPI co-localization on colon cancer cells. ISH studies revealed the presence of FX mRNA, PZ mRNA and ZPI mRNA in colon cancer cells indicating induced synthesis of these proteins.

    Conclusions

    The localization of PZ/ZPI and FX in colon cancer cells indicates that PZ/ZPI may contribute to anticoagulant events at the tumor site. Strong co-localization of PZ/ZPI and FX in cancer cells, and the presence of the mRNAs encoding the proteins, suggests their role in the tumor's biology. However, the presence of F1+2 and fibrin at the colon cancer site also suggests that the regulation of FXa by the PZ/ZPI complex at this site is incomplete.
    Keywords:ABC, avidin-biotin complex technique   T2G1, antibody directed to fibrin II (des fibrinopeptide B fibrin)   AT, antithrombin   CP, cancer procoagulant   EC(s), endothelial cell(s)   EPR-1, effector cell protease receptor-1   FX, coagulation factor X   FXa, activated form of coagulation factor X   F1+2, prothrombin fragment F1+2   G, grade of pathologic malignancy   HIS, in situ hybridization   HLA-DR, a class II antigen of major histocompatibility complex   IHC, immunohistochemistry   IgM, immunoglobulin M   MHC, main human compatibility   IRS, immunoreactive score   mRNA, messenger ribonucleic acid   N, number   PAR-1,-2, protease activated receptor-1,-2   PAA/PCA, platelet aggregating activity/procoagulant activity   PC, protein C   PS, protein S   PZ, protein Z   TAMs, tumor associated macrophages   TF, tissue factor   TFPI, tissue factor pathway inhibitor   TNM, tumor/nodes/metastases, classification of the clinical stage cancer   VEGF, vascular endothelial growth factor   ZPI, protein Z-dependent protease inhibitor
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