Involvement of Urokinase‐Type Plasminogen Activator System in Cancer: An Overview

Mekkawy, Ahmed H.; Pourgholami, Mohammad H.; Morris, David L.

doi:10.1002/med.21308

Cited by 126 publications

(113 citation statements)

References 300 publications

(334 reference statements)

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“…The uPA system comprises uPA; its receptor, uPAR; substrate molecules, such as plasminogen; and the inhibitory factors, plasminogen activator inhibitor types 1 and 2. It is the major enzyme system involved in degradation of the extracellular matrix and in cell-mediated transfer in the body, under physiological or pathological conditions (3). Furthermore, uPA is involved in tissue remodeling, cell migration and tumor metastasis.…”

Section: Introductionmentioning

confidence: 99%

“…uPA and uPAR are predominantly expressed in blood cells, including neutrophils, monocytes, macrophages and activated T cells, and are hypothesized to be important for the ability of these cells to degrade fibrin, and to extravasate and migrate during an inflammatory response (6). A recent study demonstrated that malignant plasma cells may express uPA and uPAR, and the initiation of proteolytic events by this system may contribute to the process of invasion and destruction of the bone marrow by myeloma cells (3). This type of interaction is an important biological process, which may affect the degradation of marrow, stromal infiltration of plasma cells and the patient's clinical condition.…”

Section: Introductionmentioning

confidence: 99%

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Analysis of soluble urokinase plasminogen activator receptor in multiple myeloma for predicting prognosis

Shen

Wang

et al. 2015

Oncology Letters

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Analysis of soluble urokinase plasminogen activator receptor in multiple myeloma for predicting prognosis

Shen

Wang

et al. 2015

Oncology Letters

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“…Moreover, several reports have been indicated that PAI-2 encourages cancer cell growth by inhibiting apoptosis and the high expression of PAI-2 was found in cervical, oral, colon and lung cancers. 34,35) PAI-1 can potentially influence cells motility at several levels by competing with uPAR and intergrins to bind vitronectin which promotes the cells ability to detach from ECM. 36) Furthermore, a down regulation in the expression of PAI-1 in MDA-MB-231 cells was associated with an inhibition of the cell invasion.…”

Section: Discussionmentioning

confidence: 99%

Proanthocyanidin in Red Rice Inhibits MDA-MB-231 Breast Cancer Cell Invasion <i>via</i> the Expression Control of Invasive Proteins

Pintha

Yodkeeree

Limtrakul

2015

Biological & Pharmaceutical Bulletin

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Proanthocyanidin is one of the main active compounds found in red jasmine rice. We previously reported that red rice extract could reduce cancer cell invasion. However, the direct effect of proanthocyanidin from red rice on the invasion of cancer cells and the exact molecular mechanism remained unclear. Here, we report for the first time that proanthocyanidin-rich fraction from red rice (PRFR) reduced the migration and invasion of MDA-MB-231 human breast cancer cells. The types of proanthocyanidin in PRFR were identified as procyanidins and prodelphinidins by acid hydrolysis. For cancer cell invasion, degradation of the extracellular matrix (ECM) is required. Treatment of the cells with PRFR reduced the expression of ECM degradation-associated proteins, including matrix metalloproteinase-9 (MMP-9), membrane type-1 matrix metalloproteinase, urokinase plasminogen activator, urokinase plasminogen activator receptor and plasminogen activator-1. Moreover, PRFR also reduced the activity of collagenase and MMP-9. Furthermore, PRFR significantly suppressed the expression of intercellular adhesion molecule-1 and interleukin-6. We also found that PRFR reduced the DNA-binding activity of nuclear factor kappa B (NF-κB), which is the expressed mediator of ECM degradation-associated proteins. These results suggest that proanthocyanidin from red rice mediates MDA-MB-231 breast cancer cell invasion by altering the expression of the invasion-associated proteins, possibly by targeting NF-κB activity.Key words proanthocyanidin; red rice; invasion; nuclear factor kappa B Breast cancer is a leading cause of mortality among women worldwide including in Thailand. The metastasis of breast cancer to other sites such as the liver, bones, the lungs and lymph nodes is a critical factor contributing to the increased rate of mortality in breast cancer patients.1) The metastasis of cancer cells is a complex process involving cell adhesion, migration and proteolytic degradation of the extracellular matrix (ECM). Degradation of ECM components is an important step in the metastatic process, and it is regulated by the activation of ECM degradation enzymes such as matrix metalloproteinases (MMPs) and urokinase plasminogen activator (uPA). 2)Several scientific studies have shown that uPA plays an important role in tumor metastasis and over-expression of uPA in breast cancer is a strong indicator of the poor prognosis.3)The uPA converts the inactive plasminogen into the active serine protease plasmin, which is involved in the degradation of ECM. The uPA system consists of uPA, the uPA receptor (uPAR), plasminogen and its inhibitor, plasminogen inhibitor types 1 and 2 (PAI-1 and -2). The binding of uPA to uPAR not only promotes cancer metastasis but also generates signal transduction that allows enhanced cell survival and migration. 3)MMPs essentially degrade all ECM components surrounding the cancer cells, allowing them to spread from the primary site. Up-regulation of several MMPs such as MMP-2, -3, -9 and membrane type-1 matrix metalloproteinases ...

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“…The uPA system is causally involved in multiple steps of breast cancer progression, including ECM remodeling, increased cell proliferation and migration, and modulating cell adhesion 31. Therefore, it is not surprising that uPA in primary breast cancer is independently associated with adverse outcome 32.…”

Section: The Urokinase Plasminogen Activator (Upa) Systemmentioning

confidence: 99%

Candidate prognostic markers in breast cancer: focus on extracellular proteases and their inhibitors

Roy

Walsh

2014

BCTT

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The extracellular matrix (ECM) is the complex network of proteins that surrounds cells in multicellular organisms. Due to its diverse nature and composition, the ECM has a multifaceted role in both normal tissue homeostasis and pathophysiology. It provides structural support, segregates tissues from one another, and regulates intercellular communication. Furthermore, the ECM sequesters a wide range of growth factors and cytokines that may be released upon specific and well-coordinated cues. Regulation of the ECM is performed by the extracellular proteases, which are tasked with cleaving and remodeling this intricate and diverse protein matrix. Accordingly, extracellular proteases are differentially expressed in various tissue types and in many diseases such as cancer. In fact, metastatic dissemination of tumor cells requires degradation of extracellular matrices by several families of proteases, including metalloproteinases and serine proteases, among others. Extracellular proteases are emerging as strong candidate cancer biomarkers for aiding and predicting patient outcome. Not surprisingly, inhibition of these protumorigenic enzymes in animal models of metastasis has shown impressive therapeutic effects. As such, many of these proteolytic inhibitors are currently in various phases of clinical investigation. In addition to direct approaches, aberrant expression of extracellular proteases in disease states may also facilitate the selective delivery of other therapeutic or imaging agents. Herein, we outline extracellular proteases that are either bona fide or probable prognostic markers in breast cancer. Furthermore, using existing patient data and multiple robust statistical analyses, we highlight several extracellular proteases and associated inhibitors (eg, uPA, ADAMs, MMPs, TIMPs, RECK) that hold the greatest potential as clinical biomarkers. With the recent advances in high-throughput technology and targeted therapies, the incorporation of extracellular protease status in breast cancer patient management may have a profound effect on improving outcomes in this deadly disease.

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Involvement of Urokinase‐Type Plasminogen Activator System in Cancer: An Overview

Cited by 126 publications

References 300 publications

Analysis of soluble urokinase plasminogen activator receptor in multiple myeloma for predicting prognosis

Analysis of soluble urokinase plasminogen activator receptor in multiple myeloma for predicting prognosis

Proanthocyanidin in Red Rice Inhibits MDA-MB-231 Breast Cancer Cell Invasion <i>via</i> the Expression Control of Invasive Proteins

Candidate prognostic markers in breast cancer: focus on extracellular proteases and their inhibitors

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