Tissue Plasminogen Activator and Inhibitors of Fibrinolysis in Malignant Melanoma

Kwaan, Hau C.; Radosevich, James A.; Xu, Cong Gao; Lastre, Clara

doi:10.1159/000217576

Cited by 12 publications

(6 citation statements)

References 14 publications

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“…120 Detailed analysis of tPA, uPA, uPAR, and PAI-1 in cancer has shown that an unfavorable prognosis is correlated with the expression of uPA, uPAR, and PAI-1, but not with that of tPA 122 (with the exception of melanoma). 123,124 The types of cancer include those of the gastrointestinal tract, lung, breast, ovary, prostate, bone, brain, and leukemia. PAI-2 is less studied but was also found to be increased and associated with poor outcome in invasive carcinoma of cervix, 125 SCCL, 126 colorectal carcinoma, 127 pancreatic ductal carcinoma, 128 bladder carcinoma, RCC, 129 and oral cancer.…”

Section: Presence Of Fibrinolytic Components In Cancer Tissues As An mentioning

confidence: 99%

Fibrin and Fibrinolysis in Cancer

Kwaan

Lindholm

2019

Semin Thromb Hemost

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103

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In 1878, Billroth discovered that tumor cells invest themselves in a fibrin thrombus, and he hypothesized that fibrin promotes tumor growth and invasion. Since then, many observations have supported this concept, showing that many hemostatic factors including fibrinogen, fibrin, and components of the fibrinolytic system have indeed a complex interaction with cancer growth and metastasis. Fibrin promotes cell migration by providing a matrix for tumor cell migration and by interactions with adhesive molecules and integrins. Fibrin-containing vascular endothelial growth factor promotes angiogenesis. Fibrin interacts with platelets and leukocytes, and promotes their respective carcinogenic properties. Fibrinolytic components exert different effects on tumors. Plasmin activates latent growth factors, and breaks down extracellular matrix (ECM), while urokinase plasminogen activator (uPA) and the uPA receptor (uPAR) form complexes with vitronectin and integrins to promote tumor cells to adhere to the ECM. This complex also binds the epidermal growth factor receptor on the tumor cell membrane, and signals the RAF-MEK-ERK pathway. The complex also binds to the G protein-coupled receptors leading to cell proliferation. Plasminogen activator inhibitor 1 (PAI-1) inhibits apoptosis, and increases tumor cell survival. PAI-1 also enhances cell senescence, leading to production of tumorigenic cytokines by the senescence secretome. The presence of uPA/uPAR and PAI-1 represents a strong biomarker for tumor aggressiveness and poor prognosis. Multiple attempts by blocking various carcinogenic steps have shown tumor-suppressing effects in experimental animals, but human responses are uncertain without clinical trials.

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Section: Presence Of Fibrinolytic Components In Cancer Tissues As An mentioning

confidence: 99%

Fibrin and Fibrinolysis in Cancer

Kwaan

Lindholm

2019

Semin Thromb Hemost

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103

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“…Proteinase inhibitor of fibrinolysis (α2-antiplasmin, α2-macroglobulin)-secreted in the tumor microenvironment/in high doses/in cancers with increased risk of venous thromboembolism [49]. Immunohistochemical studies demonstrate the expression of fibrinolytic inhibitors only in tumor cells, which could explain the absence of fibrinolytic activity in some tumors [50].…”

Section: Tumor Metastasismentioning

confidence: 99%

Hemostatic System in Malignancy: Providing the “Soil” in Metastatic Niche Formation

Beleva¹,

Попов²,

Grudeva-Popova³

2016

Tumor Metastasis

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Malignancy arises and progresses in tight association with changes in the tumor microenvironment and deregulation of hemostatic system. Cancer induces hemostatic imbalance through production and secretion of procoagulant substances, suppression of anticoagulant mechanisms, endothelial activation, and angiogenic switch. Cancer cells are equipped with certain coagulation signaling receptors such as tissue factor TF and urokinase plasminogen activator receptor uPAR . Tissue factor as major initiator of coagulation, TF is considered the main cause for hypercoagulability in cancer. Constitutive TF expression by cancer cells is a hallmark of malignancy rendering tumors proangiogenic and prometastatic. TF fosters metastasis through coagulation-dependent pathways leading to fibrin deposition in the evolving premetastatic niche. TF has been identified as an independent predictor for metastatic development and adverse prognosis. uPAR Tissue overexpression of uPAR is demonstrated in almost all human cancers and is associated with advanced disease. Increased uPAR expression is driven by molecular events involving K-ras and SRC oncogenes. Transactivation of these receptors, mediated by binding to hemostatic proteins, activates intracellular signaling pathways, modulates gene expression and facilitates processes of tumor initiation, epithelial-to-mesenchymal transition, anoikis, and metastasis. By manipulating hemostatic processes, tumor induces tolerant host environment necessary for evasion of defense attacks, survival, and progression.

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“…Kwaan [102] tPA and inhibitors of fibrinolysis (e.g., ␣ 2 PI) expressed in tumor cells, but only tPA found in melanoma cell lines & xenografts. Increased fibrinolytic inhibitors may contribute to hypercoagulability.…”

Section: Melanomamentioning

confidence: 99%

The Plasminogen Activator System and Cancer

McMahon

Kwaan²

2007

Pathophysiol Haemos Thromb

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138

105

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The fibrinolytic system, more appropriately referred to as the plasminogen activator system, controls not only the intravascular fibrin deposition but also participates in a wide variety of physiologic and pathologic processes. In cancer, the components of this system are involved in tumor growth, invasion and metastasis, through their effect on angiogenesis and cell migration. These components are found in most tumors and their expression signifies not only their function but also carries a prognostic value. Their expression is in turn modulated by cytokines and growth factors, many of which are up-regulated in cancer. Though both plasminogen activators, tPA and uPA, are expressed in tumor cells, uPA with its receptor (uPAR) is mostly involved in cellular functions, while tPA with its receptor annexin II on endothelial surface regulates intravascular fibrin deposition. Among the inhibitors of fibrinolysis, PAI-1 is a major player in the pathogenesis of many vascular diseases as well as in cancer. Therapeutic intervention, either using plasminogen activators or use of experimental inhibitor agents against PAI-1, has shown encouraging results in experimental tumors but not verified clinically. Information provided in this brief review is aimed to promote greater interest in the role of the plasminogen activator system in cancer.

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Tissue Plasminogen Activator and Inhibitors of Fibrinolysis in Malignant Melanoma

Cited by 12 publications

References 14 publications

Fibrin and Fibrinolysis in Cancer

Fibrin and Fibrinolysis in Cancer

Hemostatic System in Malignancy: Providing the “Soil” in Metastatic Niche Formation

The Plasminogen Activator System and Cancer

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