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

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.

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Factors Involved In the Plasminogen Activation System in Human Breast Tumours

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642505 ◽

1994 ◽

Vol 71 (05) ◽

pp. 684-691 ◽

Cited By ~ 9

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.

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NS-398 inhibits tumor growth and liver metastasis of colon cancer through induction of apoptosis and suppression of the plasminogen activation system in a mouse model1

Journal of the American College of Surgeons ◽

10.1016/j.jamcollsurg.2004.05.265 ◽

2004 ◽

Vol 199 (3) ◽

pp. 428-435 ◽

Cited By ~ 14

Author(s):

M NISHIKAWA

Keyword(s):

Colon Cancer ◽

Liver Metastasis ◽

Tumor Growth ◽

Plasminogen Activation ◽

Plasminogen Activation System ◽

Activation System ◽

Induction Of Apoptosis

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The Dual Role Of Platelets In Thrombus Formation

Blood ◽

10.1182/blood.v122.21.1098.1098 ◽

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.

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