Soluble Urokinase Receptor Is Released Selectively by Glioblastoma Cells That Express Epidermal Growth Factor Receptor Variant III and Promotes Tumor Cell Migration and Invasion*

Gilder, Andrew S.; Jones, Karra A.; Hu, Jingjing; Wang, Lei; Chen, Clark C.; Carter, Bob S.; Gonias, Steven L.

doi:10.1074/jbc.m115.637488

Cited by 14 publications

(14 citation statements)

References 57 publications

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“…The malignant potential of human meningiomas and gliomas has been correlated with uPAR expression, which parallels our finding of significantly increased uPAR expression in canine high-grade gliomas compared with other tumor types and grades 1,8,13…”

Section: Discussionsupporting

confidence: 86%

“…Similarities in the clinical behavior, morphology, molecular signatures, and genetic aberrations have been observed between human and canine brain tumors, which has resulted in the emergence of the brain tumor bearing dog as a model for translational research 9,10,24. While these tumors represent a phenotypically, clinically, and genomically heterogeneous group of cancers, a shared pathophysiological denominator that contributes to the challenges associated with their treatment is their ability to invade the brain parenchyma 8. In this study, using several complementary methods, we have demonstrated that uPAR protein and mRNA are overexpressed and uPA activity is present in the most commonly encountered canine primary brain tumors.…”

Section: Discussionmentioning

confidence: 99%

“…Participation of uPAR in tumor invasion and metastasis involves the plasminogen activation dependent breakdown of the ECM and attachment of invasive cells to ECM components, which is mediated by the specific interaction of uPAR with its ligand, uPA. However, uPAR has also been implicated in tumor progression through mechanisms that are independent of plasminogen activation including extracellular signal transduction via interactions with low-density lipoprotein receptor-related protein, integrins, vascular endothelial growth factor, epidermal growth factor receptor, or platelet-derived growth factor receptor 2,8…”

Section: Introductionmentioning

confidence: 99%

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Expression and activity of the urokinase plasminogen activator system in canine primary brain tumors

Rossmeisl¹,

Hall-Manning²,

Robertson³

et al. 2017

OTT

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BackgroundThe expression of the urokinase plasminogen activator receptor (uPAR), a glycosylphosphatidylinositol-anchored protein family member, and the activity of its ligand, urokinase-type plasminogen activator (uPA), have been associated with the invasive and metastatic potentials of a variety of human brain tumors through their regulation of extracellular matrix degradation. Domesticated dogs develop naturally occurring brain tumors that share many clinical, phenotypic, molecular, and genetic features with their human counterparts, which has prompted the use of the dogs with spontaneous brain tumors as models to expedite the translation of novel brain tumor therapeutics to humans. There is currently little known regarding the role of the uPA system in canine brain tumorigenesis. The objective of this study was to characterize the expression of uPAR and the activity of uPA in canine brain tumors as justification for the development of uPAR-targeted brain tumor therapeutics in dogs.MethodsWe investigated the expression of uPAR in 37 primary canine brain tumors using immunohistochemistry, Western blotting, real-time quantitative polymerase chain reaction analyses, and by the assay of the activity of uPA using casein–plasminogen zymography.ResultsExpression of uPAR was observed in multiple tumoral microenvironmental niches, including neoplastic cells, stroma, and the vasculature of canine brain tumors. Relative to normal brain tissues, uPAR protein and mRNA expression were significantly greater in canine meningiomas, gliomas, and choroid plexus tumors. Increased activity of uPA was documented in all tumor types.ConclusionsuPAR is overexpressed and uPA activity increased in canine meningiomas, gliomas, and choroid plexus tumors. This study illustrates the potential of uPAR/uPA molecularly targeted approaches for canine brain tumor therapeutics and reinforces the translational significance of canines with spontaneous brain tumors as models for human disease.

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Section: Discussionsupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expression and activity of the urokinase plasminogen activator system in canine primary brain tumors

Rossmeisl¹,

Hall-Manning²,

Robertson³

et al. 2017

OTT

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“…The interaction between PLAUR and EGFR was previously studied. Glioblastoma cells expressing EGFR variant III release soluble PLAUR, which promotes cell migration and invasion [55], while PLAUR induces EGFR transactivation in MCF-7 cells [56] and T-HEp3 cells [15]. Although previous studies have demonstrated that PLAUR inhibits EGFR tyrosine kinase activity, those reports did not show the expression of EGFR regulated by PLAUR.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 39%

PLAUR Confers Resistance to Gefitinib Through EGFR/P-AKT/Survivin Signaling Pathway

Zhou

Kwak

Wu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Tyrosine kinase inhibitor gefitinib significantly improves the survival of patients with non-small-cell lung cancer (NSCLC) by inhibiting epidermal growth factor receptor (EGFR) tyrosine kinase. However, patients eventually develop resistance to gefitinib through uncharacterized mechanisms. It is known that plasminogen activator urokinase receptor (PLAUR) plays an important role in cell proliferation, migration and apoptosis. However, the role of PLAUR, particularly exosomal PLAUR in gefitinib resistance in NSCLC has not been reported. The aim of this study is to determine the relationship between PLAUR and gefitinib resistance. Methods: In this study, a tethered cationic lipoplex nanoparticle (TCLN) biochip containing molecular beacons was used as probes to detect PLAUR mRNA in plasma exosomes from patients with gefitinib-sensitive and -resistant NSCLC. In vitro, Real-time PCR was used to examine the expression of PLAUR mRNA and Western blot was applied to examine the expression of related proteins. The gene knockdown was achieved by Lentivirus based RNA silence technique. The cell counting kit-8 assay and EdU incorporation were used to examine cell proliferation. The flow cytometry was applied to determine cell apoptosis and cell cycle, while the mitochondrial membrane potential was measured by JC-1 dye assay. Signaling pathway affected by PLAUR knockdown was identified by cDNA Microarray. The effect of PLAUR knockdown on tumorigenesis was analyzed in vivo. Results: We found that the exosomal PLAUR mRNA in the plasma of gefitinib-resistant NSCLC patients was significantly increased compared to that of gefitinib-sensitive NSCLC patients. The PLAUR mRNA and soluble PLAUR protein were also significantly increased in gefitinib-resistant human lung adenocarcinoma PC9R cells compared to gefitinib-sensitive PC9 cells. Silencing PLAUR in PC9R cells impaired mitochondrial membrane potential and increased cell apoptosis via EGFR/p-AKT/survivin signaling pathway. Furthermore, EGFR was upregulated in the geftinib-resistant PC9R cells, and knockdown of EGFR significantly increased cell apoptosis. Conclusions: Taken together, our results demonstrated that PLAUR induces geftinib-resistance through EGFR/p-AKT/survivin signaling pathway in gefitinib-resistant human lung adenocarcinoma cells. PLAUR could be a novel therapeutic target for gefitinib-resistant NSCLC patients.

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“…During development uPA-uPAR binding promotes neuritogenesis and neuronal migration via a combination of proteolytic and non-proteolytic mechanisms [17,18] . More specifically, during the early stages of development uPAR regulates the reorganization of the cytoskeleton in post-mitotic neurons via activation of integrins and the focal kinase adhesion (FAK) pathway [17] , thus promoting axonal growth, and neuronal migration [19] and branching [20] . Interestingly, it has also been reported that uPAR participates in the formation of those neuronal circuits that underlie language and cognition, and that dysregulation of the uPA-uPAR signaling pathway is related with the development of epilepsy [21] .…”

Section: Upa-upar Expression In the Central Nervous Systemmentioning

confidence: 99%

Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) Promote Neurorepair in the Ischemic Brain

Merino

Diaz

Yepes

2017

Receptor Clin Invest

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Despite the fact that ischemic stroke has been considered a leading cause of mortality in the world, recent advances in our understanding of the pathophysiological mechanisms underlying the ischemic injury and the treatment of acute ischemic stroke patients have led to a sharp decrease in the number of stroke deaths. However, this decrease in stroke mortality has also led to an increase in the number of patients that survive the acute ischemic injury with different degrees of disability. Unfortunately, to this date we do not have an effective therapeutic strategy to promote neurological recovery in these growing population of stroke survivors. Cerebral ischemia not only causes the destruction of a large number of axons and synapses but also activates endogenous mechanisms that promote the recovery of those neurons that survive its harmful effects. Here we review experimental evidence indicating that one of these mechanisms of repair is the binding of the serine proteinase urokinase-type plasminogen activator (uPA) to its receptor (uPAR) in the growth cones of injured axons. Indeed, the binding of uPA to uPAR in the periphery of growth cones of injured axons induces the recruitment of β1-integrin to the plasma membrane, β1-integrin-mediated activation of the small Rho GTPase Rac1, and Rac1-induced axonal regeneration. Furthermore, we found that this process is modulated by the low density lipoprotein receptor-related protein (LRP1). The data reviewed here indicate that the uPA-uPAR-LRP1 system is a potential target for the development of therapeutic strategies to promote neurological recovery in acute ischemic stroke patients.Keywords: Urokinase-type plasminogen activator (uPA); urokinase-type plasminogen activator receptor (uPAR); plasmin; cerebral ischemia; neurorepair; low density lipoprotein receptor-related protein 1 (LRP1)To cite this article: Paola Merino, et al. Urokinase-type plasminogen activator (uPA) and its receptor (uPAR) promote neurorepair in the ischemic brain.

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Soluble Urokinase Receptor Is Released Selectively by Glioblastoma Cells That Express Epidermal Growth Factor Receptor Variant III and Promotes Tumor Cell Migration and Invasion*

Cited by 14 publications

References 57 publications

Expression and activity of the urokinase plasminogen activator system in canine primary brain tumors

Expression and activity of the urokinase plasminogen activator system in canine primary brain tumors

PLAUR Confers Resistance to Gefitinib Through EGFR/P-AKT/Survivin Signaling Pathway

Urokinase-type Plasminogen Activator (uPA) and its Receptor (uPAR) Promote Neurorepair in the Ischemic Brain

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