Factors Involved In the Plasminogen Activation System in Human Breast Tumours

1994 ◽  
Vol 71 (05) ◽  
pp. 684-691 ◽  
Author(s):  
László Damjanovich ◽  
Csaba Turzó ◽  
Róza Ádány
Keyword(s):  
Epithelial Cells ◽  
Connective Tissue ◽  
Plasminogen Activators ◽  
Breast Tumour ◽  
Plasminogen Activation ◽  
Malignant Tumours ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Malignant Breast ◽  
Pai 1

SummaryThe plasminogen activation system is a delicately balanced assembly of enzymes which seems to have primary influence on tumour progression. The conversion of plasminogen into serine protease plasmin with fibrinolytic activity depends on the actual balance between plasminogen activators (urokinase type; u-PA and tissue type; t-PA) and their inhibitors (type 1 and 2 plasminogen activator inhibitors; PAI-1 and PAI-2). The purpose of this study was to determine the exact histological localization of all the major factors involved in plasminogen activation, and activation inhibition (plasmin system) in benign and malignant breast tumour samples. Our results show that factors of the plasmin system are present both in benign and malignant tumours. Cancer cells strongly labelled for both u-PA and t-PA, but epithelial cells of fibroadenoma samples were also stained for plasminogen activators at least as intensively as tumour cells in cancerous tissues. In fibroadenomas, all the epithelial cells were labelled for PAM. Staining became sporadic in malignant tumours, cells located at the periphery of tumour cell clusters regularly did not show reaction for PAI-1. In the benign tumour samples the perialveolar connective tissue stroma contained a lot of PAI-1 positive cells, showing characteristics of fibroblasts; but their number was strongly decreased in the stroma of malignant tumours. These findings indicate that the higher level of u-PA antigen, detected in malignant breast tumour samples by biochemical techniques, does not necessarily indicate increased u-PA production by tumour cells but it might be owing to the increased number of cells producing u-PA as well. In malignant tumours PAI-1 seems to be decreased in the frontage of malignant cell invasion; i.e. malignant cells at the host/tumour interface do not express PAI-1 in morphologically detectable quantity and in the peritumoural connective tissue the number of fibroblasts containing PAI-1 is also decreased.

The Dual Role Of Platelets In Thrombus Formation

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1098-1098
Author(s):  
Hadil Owaynat ◽  
Valeryi K Lishko ◽  
James J Faust ◽  
Tatiana P. Ugarova
Keyword(s):  
Blood Cells ◽  
Fibrinolytic Activity ◽  
Plasminogen Activators ◽  
U937 Cells ◽  
Plasminogen Activation ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Pai 1 ◽  
Excessive Accumulation ◽  
Fibrin Clots

Abstract The formation of a hemostatic thrombus during blood vessel injury is a highly regulated event which ensures that a blood clot is sufficiently stable but not overly robust to cause thrombus propagation and vessel occlusion. We have previously identified two anti-adhesive processes operating on the surface of fibrin clots that prevent excessive accumulation of blood cells such as platelets and leukocytes. In particular, binding of fibrinogen and plasminogen to fibrin creates a mechanically unstable surface through non-proteolytic and proteolytic mechanisms, respectively, which limits integrin-mediated cell adhesion. The proteolytic process depends on activation of plasminogen, which accumulates in a thin superficial layer of fibrin clots, by the plasminogen activation system assembled on transiently adherent blood cells. This is followed by plasmin generation and decomposition of the fibrin surface resulting in cell detachment under flow. We have further demonstrated that plasminogen activators tPA or uPA pre-bound to platelets can activate fibrin-bound plasminogen through the interfacial mechanism, i.e. when the components of the plasminogen activation system are assembled on different surfaces. Furthermore, plasminogen activators pre-bound to one population of platelets are able to activate plasminogen pre-bound to a separate pool of platelets. These data indicate that platelets activate both platelet- or fibrin-bound plasminogen and, potentially, could use their fibrinolytic potential during adhesion to fibrin clots. However, platelets are known also to contain high concentrations of PAI-1 which is secreted during clot formation. Therefore, it is uncertain whether the proteolytic anti-adhesive mechanism is functional when platelets encounter platelet-rich fibrin clots. To begin to address this question, we have compared fibrinolytic activity of tPA- or uPA-treated platelets placed on the surface of plasminogen-coated fibrin clots with that of platelets incorporated inside the gels prepared by mixing of fibrinogen with thrombin in the presence of uPA. The fibrinolytic activity was determined by detecting the release of 125Iodine-labeled fibrin degradation products or measuring plasmin amidolytic activity. While fibrinolysis by platelets inside the gel was completely inhibited, platelets adherent to the surface of fibrin clots retained their ability to activate plasminogen and degrade fibrin. Also, when both platelets and monocytic U937 cells, a cell line expressing endogenous uPA, were included in fibrin clots, platelets completely suppressed fibrinolytic activity of U937 cells. At the same time, proteolytic activity of U937 cells added on the top of platelet-rich gels was not affected. Confocal microscopy and Western blot analyses showed that by contrast with platelets incorporated in the gel which released substantial amounts of PAI-1, no PAI-1 was secreted from platelets adherent to the surface of the gel. These data may explain the well-known but hitherto unexplained capacity of platelets to either promote or inhibit fibrinolysis by introducing the idea that two different functions of platelets are relevant to different regions of the thrombus. Thus, platelets inside the clot, via the release of PAI-1, block fibrinolysis aiding in thrombus integrity. However, platelets transiently contacting fibrin are profibrinolytic enabling the anti-adhesive mechanism which prevents their excessive accumulation and, consequently, thrombus propagation. Disclosures: No relevant conflicts of interest to declare.

Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4212-4215 ◽  
Author(s):  
Daniel T. Eitzman ◽  
Randal J. Westrick ◽  
Zuojun Xu ◽  
Julia Tyson ◽  
David Ginsburg
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Carotid Bifurcation ◽  
Plasminogen Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Atherosclerosis Progression ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Activator Inhibitor ◽  
Pai 1

Abstract Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE−/−) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE−/− mice and mice doubly deficient for apoE and PAI-1 (PAI-1−/−/apoE−/−). Consistent with a previous report, PAI-1+/+/apoE−/−and PAI-1−/−/apoE−/− mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow.

Differences in plasminogen activation in primary rectal adenocarcinoma with and without liver metastasis.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15111-e15111
Author(s):  
Evgeniy N. Kolesnikov ◽  
Elena Alekseevna Nikipelova ◽  
Elena Mikhaylovna Frantsiyants ◽  
Larisa Kozlova ◽  
Valeria Bandovkina ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Inhibitory Control ◽  
Rectal Adenocarcinoma ◽  
Plasminogen Activators ◽  
Plasminogen Activation ◽  
Plasminogen Activation System ◽  
Α2 Macroglobulin ◽  
Activation System ◽  
Resection Line ◽  
Metastatic Activity

e15111 Background: Plasminogen activators play a key role in the cascade fibrinolytic system as they catalyze plasmin formation from plasminogen (PG). Plasminogen activators together with plasmin are directly or indirectly involved in tumor growth. The purpose of the study was to compare the plasminogen activation system in primary adenocarcinomas (РА) of the rectum (R) with and without liver metastases (LM). Methods: Tissues of tumors (РА, st. III, G2, 38-74 years) and their perifocal zone (PZ) with LM (T2-3NхM1, n = 24) and without them (T2-3N0M0, n = 32) were studied by ELISA. Results: The studied parameters did not differ in apparently intact R tissues in the resection line (RL) with and without LM. Plasmin-α2-antiplasmin complex (PAP) was 1.4 times higher in PA with LM than without LM (p < 0.05). Prourokinase and urokinase levels (uPA-Ag and uPA-act) were 12.4 and 3.7 higher than in RL. uPA-Ag and uPA-act in PA+LM were higher than without LM by 1.4 and 1.6 times. PG levels and α2-macroglobulin (α2M) activity in PA+LM were lower by 1.5 and 2.7 times than in PA without LM and lower than in RL (p < 0.01). All studied parameters, except α2M, in PA+LM were activated more than in PA without LM. Low α2M content supposed realization of effects of uPA and plasmin in insufficient inhibitory control. Most parameters in PZ+LM were between the levels in PA and RL being significantly different from both and significantly exceeding the values in PZ of PA without LM. α2М was an exception being 1.8 times lower in PZ of PA+LM than in PZ of PA without LM. The results demonstrated higher uPA and РАР levels in PA and its PZ with LM than without them, with increased PG consumption and decreased α2M activity in these parts of the rectum. Activation of plasminogen system in tissues of PA+LM and in PA without LM was unidirectional. Conclusions: Levels of uPA and PAP, as well as low α2M content in PA and PZ with LM can be used as an indicator of tumor metastatic activity.

scholarly journals Changes in the content of some components of the plasminogen activation system in the plasma of bladder cancer patients

2020 ◽  
Vol 80 (1) ◽  
pp. 15-19
Author(s):  
V. Dmytryk ◽  
O. Savchuk ◽  
P. Yakovlev
Keyword(s):  
Bladder Cancer ◽  
Blood Plasma ◽  
Plasminogen Activator ◽  
Tissue Type ◽  
Plasminogen Activation ◽  
Invasion And Metastasis ◽  
Plasminogen Activation System ◽  
Type Plasminogen Activator ◽  
Activation System ◽  
Pai 1

Bladder cancer (BC) continues to be a disease with a high mortality rate. Bladder cancer is the sixth for men and seventeenth for women in the incidence of malignancy worldwide. The invasion and metastasis of malignant tumors are caused by a sequence of processes, including loss of cell-cell and / or cell-matrix adhesion, proteolysis, and induction of angiogenesis. Different protease systems are involved in these processes, especially during the invasion and development of metastases. One such protease system is a plasminogen activation system or fibrinolysis system. Changes in the balance of plasminogen activation systems have been investigated in many types of malignancies, and these changes may not only indicate the functioning of this system but may also have prognostic significance. In malignancies, the components of this system are involved in the growth, invasion, and metastasis of tumors, affecting cell migration and angiogenesis. The main, but a well-studied component of the plasminogen activation system is serine proteinase – urokinase-type plasminogen activator (uPA). In contrast to uPA, tissue-type plasminogen activator (tPA) is characterized by a high affinity for fibrin and is involved in thrombolysis. Both types of plasminogen activators are synthesized in tumor tissues: tPA and uPA. The largest player among the inhibitors of fibrinolysis is the plasminogen activator inhibitor type 1 (PAI-1), involved in the pathogenesis of many cardiovascular diseases, as well as in cancer. The purpose of this study was to detect changes in the content of plasminogen activator tissue type tPA and PAI-1 in the blood plasma of patients with BC at different stages of the disease. The study involved 40 men who were verified with a diagnosis of BC. The content of tPA and PAI-1 in preoperative blood plasma was determined by enzyme immunoassay in ELISA modification. In our study, changes in the tPA and PAI-1 content of the blood plasma at different stages were identified, which can characterize tumor growth and invasion and can supplement existing disease information.

Plasminogen activator inhibitor-1 deficiency protects against atherosclerosis progression in the mouse carotid artery

Blood ◽  
2000 ◽  
Vol 96 (13) ◽  
pp. 4212-4215 ◽  
Author(s):  
Daniel T. Eitzman ◽  
Randal J. Westrick ◽  
Zuojun Xu ◽  
Julia Tyson ◽  
David Ginsburg
Keyword(s):  
Plasminogen Activator ◽  
Plasminogen Activator Inhibitor ◽  
Carotid Bifurcation ◽  
Plasminogen Activation ◽  
Plasminogen Activator Inhibitor 1 ◽  
Atherosclerosis Progression ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Activator Inhibitor ◽  
Pai 1

Dissolution of the fibrin blood clot is regulated in large part by plasminogen activator inhibitor-1 (PAI-1). Elevated levels of plasma PAI-1 may be an important risk factor for atherosclerotic vascular disease and are associated with premature myocardial infarction. The role of the endogenous plasminogen activation system in limiting thrombus formation following atherosclerotic plaque disruption is unknown. This study found that genetic deficiency for PAI-1, the primary physiologic regulator of tissue-type plasminogen activator (tPA), prolonged the time to occlusive thrombosis following photochemical injury to carotid atherosclerotic plaque in apolipoprotein E-deficient (apoE−/−) mice. However, anatomic analysis revealed a striking difference in the extent of atherosclerosis at the carotid artery bifurcation between apoE−/− mice and mice doubly deficient for apoE and PAI-1 (PAI-1−/−/apoE−/−). Consistent with a previous report, PAI-1+/+/apoE−/−and PAI-1−/−/apoE−/− mice developed similar atherosclerosis in the aortic arch. The marked protection from atherosclerosis progression at the carotid bifurcation conferred by PAI-1 deficiency suggests a critical role for PAI-1 in the pathogenesis of atherosclerosis at sites of turbulent flow, potentially through the inhibition of fibrin clearance. Consistent with this hypothesis, intense fibrinogen/fibrin staining was observed in atherosclerotic lesions at the carotid bifurcation compared to the aortic arch. These observations identify significant differences in the pathogenesis of atherosclerosis at varying sites in the vascular tree and suggest a previously unappreciated role for the plasminogen activation system in atherosclerosis progression at sites of turbulent flow.

scholarly journals Epitopes of Components of the Plasminogen Activation System are Re-exposed in Formalin-fixed Paraffin Sections by Different Retrieval Techniques

1998 ◽  
Vol 46 (4) ◽  
pp. 469-476 ◽  
Author(s):  
Cilia M. Ferrier ◽  
Winny L. van Geloof ◽  
Hans H. de Witte ◽  
Michael D. Kramer ◽  
Dirk J. Ruiter ◽  
...  
Keyword(s):  
Negative Control ◽  
Antigen Retrieval ◽  
Plasminogen Activation ◽  
Paraffin Sections ◽  
Systematic Analysis ◽  
Plasminogen Activation System ◽  
Formalin Fixed Paraffin ◽  
Activation System ◽  
Formalin Fixed ◽  
Pai 1

We present a systematic analysis of the sensitivity and specificity of immunohistochemical stainings for components of the plasminogen activation system, i.e., uPA, tPA, PAI-1, PAI-2, and uPAR, on routinely processed (formalin-fixed, paraffin-embedded) tissues. Five to nine antibodies per component were tested and the influence of different antigen retrieval regimens on immunoreactivity was investigated. We studied six different microwave-mediated pretreatments and two pretreatments by proteolytic digestion. First, positive and negative control tissues were stained. Then, frozen and paraffin sections from the same cancer lesions were stained after specific modes of pretreatment and with selected antibodies. For each component, one or a few of the tested Abs gave optimal staining on paraffin sections when combined with a particular tissue pretreatment. For PAI-1, and to a lesser degree also for tPA, an underrepresentation of stromal cell staining in paraffin material was found, whereas tumor cells showed good staining. For uPA, PAI-2, and uPAR, consistent staining results were obtained on paraffin sections.

scholarly journals Urokinase and tissue plasminogen activators and their inhibitor for thyroid diseases

2004 ◽  
Vol 50 (3) ◽  
pp. 25-29
Author(s):  
N. E. Kushlinskii ◽  
I. A. Kazantseva ◽  
E. S. Gershtein ◽  
T. Yu. Kharitidi ◽  
L. T. Lyakina
Keyword(s):  
Tissue Level ◽  
Plasminogen Activation ◽  
Thyroid Adenoma ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Tissue Plasminogen ◽  
Low Levels ◽  
Toxic Goiter ◽  
Pai 1 ◽  
Benign Thyroid

The results of a comparative study of the level of the components of the plasminogen activation system - и Pa, tPA, and PAI-1 in the tissues of cancer and benign masses of the thyroid are presented. Nineteen patients with nodal colloidal goiter (NCG) with adeno­matosis, 43 patients with NCG without adenomatosis, 9patients with diffuse toxic goiter (DTG) with adenomatosis, 13 patients without adenomatosis, 18 patients with thyroid adenoma (TA), and 44 patients with thyroid cancer (TC) were examined. The concentrations of the studied proteins were determined by enzyme immunoassay in tissue cytosols. The lowest levels of tPA and the highest values of и PA and PAI-1 were found in the tumors of patients with TC whereas the high values of tPA and the relatively low levels of и PA were typical of benign thyroid hyperplasias and TA. The lowest levels of PAI-1 were detected in patients both with and without DTG. The tissue level of the components of the plasminogen activation system in TC did not virtually depend on the histological features of a tumor, but it significantly correlated with the extent of a process.

scholarly journals Plasmin and Plasminogen System in the Tumor Microenvironment: Implications for Cancer Diagnosis, Prognosis, and Therapy

Cancers ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1838
Author(s):  
Alamelu G. Bharadwaj ◽  
Ryan W. Holloway ◽  
Victoria Miller ◽  
David Waisman
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cancer Progression ◽  
Cancer Diagnosis ◽  
Stromal Cells ◽  
Plasminogen Activation ◽  
Malignant Cells ◽  
Plasminogen Activation System ◽  
Activation System ◽  
Pai 1

The tumor microenvironment (TME) is now being widely accepted as the key contributor to a range of processes involved in cancer progression from tumor growth to metastasis and chemoresistance. The extracellular matrix (ECM) and the proteases that mediate the remodeling of the ECM form an integral part of the TME. Plasmin is a broad-spectrum, highly potent, serine protease whose activation from its precursor plasminogen is tightly regulated by the activators (uPA, uPAR, and tPA), the inhibitors (PAI-1, PAI-2), and plasminogen receptors. Collectively, this system is called the plasminogen activation system. The expression of the components of the plasminogen activation system by malignant cells and the surrounding stromal cells modulates the TME resulting in sustained cancer progression signals. In this review, we provide a detailed discussion of the roles of plasminogen activation system in tumor growth, invasion, metastasis, and chemoresistance with specific emphasis on their role in the TME. We particularly review the recent highlights of the plasminogen receptor S100A10 (p11), which is a pivotal component of the plasminogen activation system.  

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