Expression of Prothrombin Fragment 1+2 in Cancer Tissue as an Indicator of Local Activation of Blood Coagulation

Wojtukiewicz, Marek Z.; Rucińska, Monika; Zimnoch, L; J, Jaromin; Piotrowski, Z; Rózańska-Kudelska, Małgorzata; Kisiel, Walter; Kudryk, Bohdan J.

doi:10.1016/s0049-3848(99)00169-3

Cited by 34 publications

(31 citation statements)

References 31 publications

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“…Because this variability has been linked to the relative tissue expression of several apoptosis survival genes, including Bcl-2-family genes and VEGF (28), the histological presence of thrombi in our study in the pancreatic tumors, but not in the surrounding normal pancreas, could be attributed to a differential expression pattern between the normal and cancerous tissue. Another contributing factor to the specificity of the thrombosis in the pancreatic tumors could be related to observations that pancreatic cancer patients tend to develop regional blood clots, reportedly due to thrombin activation (32). Indeed, our thrombus induction experiments in DSFCs support this observation but, most importantly, are the first to show that tumor vessels are particularly susceptible to thrombus formation with rapamycin treatment.…”

Section: Discussionsupporting

confidence: 67%

Rapamycin-Induced Endothelial Cell Death and Tumor Vessel Thrombosis Potentiate Cytotoxic Therapy against Pancreatic Cancer

Bruns

Koehl

Guba

et al. 2004

Clinical Cancer Research

101

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Purpose: Despite current chemotherapies, pancreatic cancer remains an uncontrollable, rapidly progressive disease. Here, we tested an approach combining a recently described antiangiogenic drug, rapamycin, with standard gemcitabine cytotoxic therapy on human pancreatic tumor growth.Experimental Design: Tumor growth was assessed in rapamycin and gemcitabine-treated nude mice orthotopically injected with metastatic L3.6pl human pancreatic cancer cells. H&E staining was performed on tumors, along with Ki67 staining for cell proliferation and immunohistochemical terminal deoxynucleotidyl transferase-mediated nick end labeling and CD31 analysis. Rapamycin-treated tumor vessels were also directly examined in dorsal skin-fold chambers for blood flow after thrombosis induction. Cell death in human umbilical vein endothelial cells was assessed by flow cytometry after annexin-V staining.Results: Rapamycin therapy alone inhibited tumor growth and metastasis more than gemcitabine, with remarkable long-term tumor control when the drugs were combined. Mechanistically, H&E analysis revealed tumor vessel endothelium damage and thrombosis with rapamycin treatment. Indeed, dorsal skin-fold chamber analysis of rapamycin-treated tumors showed an increased susceptibility of tumor-specific vessels to thrombosis. Furthermore, terminal deoxynucleotidyl transferase-mediated nick end labeling/ CD31 double staining of orthotopic tumors demonstrated apoptotic endothelial cells with rapamycin treatment, which also occurred with human umbilical vein endothelial cells in vitro. In contrast, gemcitabine was not antiangiogenic and, despite its known cytotoxicity, did not reduce proliferation in orthotopic tumors; nevertheless, rapamycin did reduce tumor proliferation.Conclusions: Our data suggest a novel mechanism whereby rapamycin targets pancreatic tumor endothelium for destruction and thrombosis. We propose that rapamycin-based vascular targeting not only reduces tumor vascularization, it decreases the number of proliferating tumor cells to be destroyed by gemcitabine, thus introducing a new, clinically feasible strategy against pancreatic cancer.

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Section: Discussionsupporting

confidence: 67%

Rapamycin-Induced Endothelial Cell Death and Tumor Vessel Thrombosis Potentiate Cytotoxic Therapy against Pancreatic Cancer

Bruns

Koehl

Guba

et al. 2004

Clinical Cancer Research

101

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“…Specific mouse monoclonal anti-human ZPI IgM (4249.2) was a generous gift from Dr. George J. Broze Jr (Division of Hematology, Barnes-Jewish Hospital, St. Louis, MO, USA) [23]. Polyclonal antibodies directed to coagulation FX and F1 + 2 were generously provided by Dr. David Stump (Genentech, South San Francisco, California) [24]. In the control specimens, primary antibody was omitted from the procedure.…”

Section: Methodsmentioning

confidence: 99%

Protein Z/protein Z-dependent protease inhibitor system in loco in human gastric cancer

et al. 2013

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In gastric cancer, hemostatic system components contribute to cancer progression, as activation of factor X (FX) was observed. The protein Z (PZ)/protein Z-dependent protease inhibitor (ZPI) complex inhibits factor Xa proteolytic activity. The purpose of this study was to determine the distribution of ZPI and PZ in relation to FX, and prothrombin fragment (F1 + 2), a standard marker for blood coagulation activation, in human gastric cancer tissue. ABC procedures and a double staining method employed polyclonal antibodies against PZ, FX, and F1 + 2 and a monoclonal antibody against ZPI. In situ hybridization (ISH) methods employed biotin-labeled 25-nucleotide single-stranded DNA probes directed to either PZ or ZPI mRNAs. FX and components of PZ/ZPI coagulation inhibitory system were observed in cancer cells. F1 + 2 was observed in gastric cancer cells as well. Double staining studies revealed FX/PZ, FX/ZPI, and PZ/ZPI co-localization on gastric cancer cells. ISH studies demonstrated the presence of PZ mRNA and ZPI mRNA in gastric cancer cells indicating induced synthesis of these proteins. The co-localization of PZ/ZPI and FX in gastric cancer cells indicates in loco that these proteins may play a role in anticoagulant events at the tumor tissue.

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“…In the past 4 years, several studies have been published, using more modern methods for the measurement of analytes to reassess the thrombogenic phenomenon. These studies include the measurement of thrombin-antithrombin complex, fibrinopeptide A, prothrombin activation peptide F1+2, protein S, protein C, activated protein C [79, 80], TFPI, tPA, uPA and urinary TF [81]. The etiology and pathophysiology of the hypercoagulable state associated with neoplasia is still unclear.…”

Section: Coagulation Activationmentioning

confidence: 99%

Update on Tumor Cell Procoagulant Factors

Gale

Gordon²

2001

Acta Haematol

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Tumor cells produce tissue factor, cancer procoagulant, plasminogen activators and other factors that interact with the coagulation system, the fibrinolytic system and vascular or blood cells such that they can upset the normal homeostasis and balance between activation and inhibition of the coagulation and fibrinolytic systems. These activities play a role in tumor cell growth and metastasis, vascular wall function, and hemostasis. Proteases and their inhibitors are intimately involved in all aspects of the hemostatic, cell proliferation and cellular signalling systems. This review provides a brief examination of recent observations in this complex interaction of cellular and hemostatic factors.

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Expression of Prothrombin Fragment 1+2 in Cancer Tissue as an Indicator of Local Activation of Blood Coagulation

Cited by 34 publications

References 31 publications

Rapamycin-Induced Endothelial Cell Death and Tumor Vessel Thrombosis Potentiate Cytotoxic Therapy against Pancreatic Cancer

Rapamycin-Induced Endothelial Cell Death and Tumor Vessel Thrombosis Potentiate Cytotoxic Therapy against Pancreatic Cancer

Protein Z/protein Z-dependent protease inhibitor system in loco in human gastric cancer

Update on Tumor Cell Procoagulant Factors

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