Treatment of Malignancy by Activation of the Plasminogen System

Zacharski, Leo R.; Ornstein, Deborah L.; Gabazza, Esteban C.; D’Alessandro-Gabazza, Corina N.; Brugarolas, Antonio; Schneider, Jeffrey

doi:10.1055/s-2002-20560

Cited by 15 publications

(8 citation statements)

References 42 publications

(61 reference statements)

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“…98,[100][101][102] Fibrin formation with fibrinolytic deficit in gastric cancer tissue suggests that the thrombolytic therapy might also be considered for experimental treatment of stomach cancer. 103 Candidate compounds include recombinant t-PA, available as one-chain (alteplase) and two-chain molecules (dueplase), mutant t-PA molecules (reteplase, lanoteplase, TNK-rt-PA), or chimeric t-PA. Other thrombolytic agents, such as streptokinase, anti-streptase, and urokinase, are also candidate experimental modalities. Means might also be devised for inhibiting the activity of PAI-1.…”

Section: Discussionmentioning

confidence: 99%

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

Wojtukiewicz

Sierko²,

Zacharski³

et al. 2003

Semin Thromb Hemost

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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.

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Section: Discussionmentioning

confidence: 99%

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

Wojtukiewicz

Sierko²,

Zacharski³

et al. 2003

Semin Thromb Hemost

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“…Advances in the past half‐century have added further credence to the concept that activation of plasminogen may account for Coley's observations. The substantial older literature on the effects of plasminogen activators and plasmin on both experimental animal and human malignancies has been reviewed recently [31]. Profound and long‐lasting effects following a single infusion of plasmin in some models bear striking resemblance to Coley's clinical observations.…”

Section: Plasminogen Activator Therapy For Cancermentioning

confidence: 99%

“…Documented effects of plasminogen activator therapy in patients with malignancy provide a basis for cautious implementation of formal phase I clinical trials [31]. Several commercially standardized formulations of tPA and SK having defined doses, schedules and toxicity profiles are currently on the market and available for testing.…”

Section: Plasminogen Activator Therapy For Cancermentioning

confidence: 99%

Coley's toxin revisited: immunotherapy or plasminogen activator therapy of cancer?

Zacharski

Sukhatme

2005

Journal of Thrombosis and Haemostasis

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“…Numerous studies of effects of anticoagulant drugs on human malignancy described in case reports, cohort studies, retrospective meta-analyses, uncontrolled clinical trials, and controlled prospective randomized trials have been summarized elsewhere. 21,[29][30][31] Improved cancer outcome has been reported in certain human tumor types with drugs that interfere with thrombin-generating or urokinase-initiated pathways expressed by tumor cells. For example, SCCL appears to respond to inhibitors of coagulation (warfarin, heparin) and disruption of extracellular matrix formation.…”

Section: Interventions That Alter Coagulation Reactions Change the Namentioning

confidence: 99%

“…For example, SCCL appears to respond to inhibitors of coagulation (warfarin, heparin) and disruption of extracellular matrix formation. 29,[32][33][34][35][36] By contrast, colon cancer appears to respond to inhibition of u-PA-induced plasminogen activation (aprotinin) 22 but not warfarin. 37 These studies are limited in number, and controlled clinical trials have not yet been performed in other tumor types having similar mechanisms.…”

Section: Interventions That Alter Coagulation Reactions Change the Namentioning

confidence: 99%

Malignancy as a Solid-Phase Coagulopathy: Implications for the Etiology, Pathogenesis, and Treatment of Cancer

2003

Semin Thromb Hemost

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This overview of the coagulation biology of cancer is intended primarily for those unfamiliar with the link between the coagulation mechanism and neoplasia. Because the literature on this topic is extensive, citations will be primarily of previous reviews that provide detailed references. The clotting mechanism is fundamentally deranged in malignancy and, unlike the physiological hemostatic response to injury, is incapable of self-attenuation. Clotting activation may predict future cancer and the outcome of existing cancer, and participates in tumor growth. Anticoagulant therapy in patients with malignancy achieves more than control of cancer-related thrombosis. Modification of coagulation reactions relevant to particular tumor types improves the course of the disease. Viewing malignancy as a solid-phase coagulopathy provides insights into possible "upstream" causes of malignant transformation and explanations for the aberrant behavior of transformed cells and suggests innovative experimental interventions. Coagulation biology has broadened and deepened our understanding of neoplasia, and suggested testable strategies for the prevention and treatment of cancer. However, relationships between clotting and cancer progression have been established primarily from model systems. Although limited experience to date in human disease has supported these concepts, resolution of cause-and-effect relationships will require performance of additional rationally designed clinical trials.

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Treatment of Malignancy by Activation of the Plasminogen System

Cited by 15 publications

References 42 publications

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

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

Coley's toxin revisited: immunotherapy or plasminogen activator therapy of cancer?

Malignancy as a Solid-Phase Coagulopathy: Implications for the Etiology, Pathogenesis, and Treatment of Cancer

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