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

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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3The Expression Pattern of the Urokinase Plasminogen Activation System in Human Colon Cancer Is Recapitulated in Liver Metastases with Desmoplastic Encapsulation

Apmis ◽

10.1111/j.1600-0463.2008.001165_16.x ◽

2008 ◽

Vol 116 (5) ◽

pp. 419-419

Author(s):

M. Illemann ◽

N. Bird ◽

A. Majeed ◽

O. D. Laerum ◽

L. R. Lund ◽

...

Keyword(s):

Colon Cancer ◽

Liver Metastases ◽

Expression Pattern ◽

Human Colon ◽

Plasminogen Activation ◽

Human Colon Cancer ◽

Plasminogen Activation System ◽

Activation System

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The plasminogen activation system in tumor growth, invasion, and metastasis

Cellular and Molecular Life Sciences ◽

10.1007/s000180050497 ◽

2000 ◽

Vol 57 (1) ◽

pp. 25-40 ◽

Cited By ~ 591

Author(s):

P. A. Andreasen ◽

R. Egelund ◽

H. H. Petersen

Keyword(s):

Tumor Growth ◽

Plasminogen Activation ◽

Invasion And Metastasis ◽

Plasminogen Activation System ◽

Activation System

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

Cancers ◽

10.3390/cancers13081838 ◽

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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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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