DU145 human prostate carcinoma invasiveness is modulated by urokinase receptor (uPAR) downstream of epidermal growth factor receptor (EGFR) signaling

Mamoune, Asmaa; Kassis, Jareer; Kharait, Sourabh; Kloeker, Susanne; Manos, Elisabeth; Jones, David A.; Wells, Alan

doi:10.1016/j.yexcr.2004.05.008

Cited by 49 publications

(37 citation statements)

References 42 publications

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“…This biphasic behavior can again be interpreted in terms of a balance between forward and rearward traction forces as the density of ligand is varied. Our 3D results showing an increase in speed with EGFR overexpression agree with migration experiments in 2D, which have shown an increase in speed with EGFR overexpression in DU-145 cells (17).…”

Section: Resultssupporting

confidence: 90%

“…To understand how these factors are convolved, we investigate here the migration of DU-145 human prostate carcinoma cells (15), both parental and EGF receptor (EGFR)-overexpressors, through 3D fibronectin-constituted Matrigel environments (16,17). We observe seemingly paradoxical effects of blocking integrin͞matrix adhesion using anti-integrin antibodies as the Matrigel density and concentration of added fibronectin are varied, contrasting with expectations from previous understanding for 2D systems.…”

Section: Migration Of Tumor Cells In 3d Matricesmentioning

confidence: 83%

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Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Zaman

Trapani

Sieminski

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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1,061

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Cell migration on 2D surfaces is governed by a balance between counteracting tractile and adhesion forces. Although biochemical factors such as adhesion receptor and ligand concentration and binding, signaling through cell adhesion complexes, and cytoskeletal structure assembly/disassembly have been studied in detail in a 2D context, the critical biochemical and biophysical parameters that affect cell migration in 3D matrices have not been quantitatively investigated. We demonstrate that, in addition to adhesion and tractile forces, matrix stiffness is a key factor that influences cell movement in 3D. Cell migration assays in which Matrigel density, fibronectin concentration, and β1 integrin binding are systematically varied show that at a specific Matrigel density the migration speed of DU-145 human prostate carcinoma cells is a balance between tractile and adhesion forces. However, when biochemical parameters such as matrix ligand and cell integrin receptor levels are held constant, maximal cell movement shifts to matrices exhibiting lesser stiffness. This behavior contradicts current 2D models but is predicted by a recent force-based computational model of cell movement in a 3D matrix. As expected, this 3D motility through an extracellular environment of pore size much smaller than cellular dimensions does depend on proteolytic activity as broad-spectrum matrix metalloproteinase (MMP) inhibitors limit the migration of DU-145 cells and also HT-1080 fibrosarcoma cells. Our experimental findings here represent, to our knowledge, discovery of a previously undescribed set of balances of cell and matrix properties that govern the ability of tumor cells to migration in 3D environments.

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Section: Resultssupporting

confidence: 90%

Section: Migration Of Tumor Cells In 3d Matricesmentioning

confidence: 83%

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Zaman

Trapani

Sieminski

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

1,061

1,005

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“…uPA and its receptor (u-PAR) contribute to prostate cancer metastases by promoting extracellular matrix degradation and growth factor activation. 33,34 Our results show that PC3-and LNCaP-derived prostasomes are characterized by increases of proteolytic activities, which may degrade the extracellular matrix and control cell adhesion and migration through the reorganization of the actin cytoskeleton. These data are in agreement with the hypothesis that proteolytic degradation is one of the processes responsible for invasion and metastatsis.…”

Section: Resultsmentioning

confidence: 80%

Extracellular matrix degrading enzymes at the prostasome surface

Bellezza¹,

Aisa²,

Palazzo³

et al. 2005

Prostate Cancer Prostatic Dis

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Prostasomes, prostatic secretory vesicles found in human ejaculates, were analyzed to verify the existence at their surfaces of enzymes involved in the degradation of the extracellular matrix. Findings were compared with those of prostasomes isolated from two human adenocarcinoma cell lines that reflect clinical features and molecular pathways of androgen-insensitive and hormone-responsive prostate cancer. Our aim was to determine whether neoplastic transformation is accompanied by changes of glycosidase and protease activities. Our results show that decreases of dipeptidyl peptidase IV and increases of urokinase plasminogen activator and cathepsin B are consistent with the clinical features of the cell lines, whereas increases of glycosidase activities seem to be of scarce biological significance.

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“…STAT3 is required for EGFR-mediated fibroblast and human prostate tumour cell motility and invasiveness EGFR signalling drives motility in fibroblasts and carcinoma cells (Pedersen et al, 2004) and invasion of human prostate carcinoma cells (Xie et al, 1995;Mamoune et al, 2004). Not surprisingly, sustained motility also requires de novo RNA synthesis (Chen et al, 1994).…”

Section: Results Egf Activates Stat3 In Fibroblasts and Prostate Carcmentioning

confidence: 99%

“…the mouse sequence in human cells). From earlier studies using eGFP, we found that this procedure resulted in 485% of the prostate caricnoma cells expressing the eGFP plasmid (Mamoune et al, 2004).…”

Section: Oligonucleotides and Transfectionsmentioning

confidence: 92%

STAT3 is required but not sufficient for EGF receptor-mediated migration and invasion of human prostate carcinoma cell lines

Zhou¹,

Grandis

Wells³

2006

Br J Cancer

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Growth factor-induced migration is a rate-limiting step in tumour invasiveness. The molecules that regulate this cellular behaviour would represent novel targets for limiting tumour cell progression. Epidermal growth factor (EGF) receptor (EGFR)-mediated motility, present in both autocrine and paracrine modes in prostate carcinomas, requires de novo transcription to persist over times greater than a few hours. Therefore, we sought to define specific signalling pathways that directly alter cellular transcription. Signal transducer and activator of transcription 3 (STAT3) is activated, as determined by electrophoretic motility shift assays, by EGFR in DU145 and PC3 human prostate carcinoma cells in addition to the motility model NR6 fibroblast cell line. Inhibition of STAT3 activity by antisense or siRNA downregulation or expression of a dominant-negative construct limited cell motility as determined by an in vitro wound healing assay and invasiveness through a extracellular matrix barrier. The expression of constitutively activated STAT3 did not increase the migration, which indicates that STAT3 is necessary but not sufficient for EGFR-mediated migration. These findings suggest that STAT3 signalling may be a new target for limiting prostate tumour cell invasion. In a microarray gene analysis of what transcription units are altered by EGF in a STAT3-dependent manner we found that the expression of motility-limiting VASP protein and the apoptosis nexus caspase 3 were both downregulated upon EGF exposure. These findings suggest a molecular basis for the STAT3 dependence of EGFR-mediated prostate tumour progression.

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DU145 human prostate carcinoma invasiveness is modulated by urokinase receptor (uPAR) downstream of epidermal growth factor receptor (EGFR) signaling

Cited by 49 publications

References 42 publications

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Migration of tumor cells in 3D matrices is governed by matrix stiffness along with cell-matrix adhesion and proteolysis

Extracellular matrix degrading enzymes at the prostasome surface

STAT3 is required but not sufficient for EGF receptor-mediated migration and invasion of human prostate carcinoma cell lines

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