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See detailRegulation of membrane-type 1 matrix metalloproteinase expression by zonula occludens-2 in human lung cancer cells.
Luczka, E.; Syne, Laïdya ULg; Nawrocki-Raby, B. et al

in Clinical & Experimental Metastasis (2013)

During tumor invasion, tumor epithelial cells acquire migratory and invasive properties involving important phenotypic alterations. Among these changes, one can observe reorganization or a loss of cell ... [more ▼]

During tumor invasion, tumor epithelial cells acquire migratory and invasive properties involving important phenotypic alterations. Among these changes, one can observe reorganization or a loss of cell-cell adhesion complexes such as tight junctions (TJs). TJs are composed of transmembrane proteins (occludin, claudins) linked to the actin cytoskeleton through cytoplasmic adaptor molecules including those of the zonula occludens family (ZO-1, -2, -3). We here evaluated the potential role of ZO-2 in the acquisition of invasive properties by tumor cells. In vivo, we showed a decrease of ZO-2 expression in bronchopulmonary cancers, with a preferential localization in the cytoplasm. In addition, in vitro, the localization of ZO-2 varied according to invasive properties of tumor cells, with a cytoplasmic localization correlating with invasion. In addition, we demonstrated that ZO-2 inhibition increases invasive and migrative capacities of invasive tumor cells. This was associated with an increase of MT1-MMP. These results suggest that ZO-2, besides its structural role in tight junction assembly, can act also as a repressor of tumor progression through its ability to reduce the expression of tumor-promoting genes in invasive tumor cells. [less ▲]

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See detailRegulation of CXCL8/IL-8 expression by Zonula Occludens-1 in human breast cancer cells.
Brysse, Anne ULg; Mestdagt, Mélanie ULg; Polette, Myriam et al

in Molecular Cancer Research (2012), 10(1), 121-32

Accumulating data now suggest that ZO-1, once delocalized from tight junctions, could be implicated in the regulation of tumor promoting genes. Because of their major implication in different steps of ... [more ▼]

Accumulating data now suggest that ZO-1, once delocalized from tight junctions, could be implicated in the regulation of tumor promoting genes. Because of their major implication in different steps of tumor progression, we investigated here the influence of ZO-1 on chemokines expression in breast cancer cells. Using GeneArray analysis to compare chemokine mRNA expression in breast tumor cells transfected with a siRNA against ZO-1, we identified CXCL-8/IL-8 as a major potential target of ZO-1 signaling, being strongly downregulated following ZO-1 siRNA transfection. Examining further the relationship between ZO-1 and IL-8, we first demonstrated that CXCL8/IL-8 expression correlates with a relocalization of ZO-1 in several breast cancer cell lines. Moreover, CXCL8/IL-8 is downregulated in invasive BT549 cells transfected with 3 different ZO-1 siRNA and overexpressed in non-invasive BT20 and SKBR3 cells transfected with vectors expressing ZO-1. We also provide evidence for an activation of the CXCL8/IL-8 promoter by ZO-1. Finally, we demonstrate that the regulation of CXCL8/IL-8 by ZO-1 is independent of the beta-catenin pathway. Our results thus clearly demonstrate an implication of ZO-1 in CXCL8/IL-8 regulation. Because of the major implications of CXCL8/IL-8 in tumor invasion, such a regulation could play an important role in breast cancer progression. [less ▲]

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See detailFhit regulates invasion of lung tumor cells
Joannes, A.; Bonnomet, A.; Bindels, S. et al

in Oncogene (2010), 29(8), 1203-13

In many types of cancers, the fragile histidine triad (Fhit) gene is frequently targeted by genomic alterations leading to a decrease or loss of gene and protein expression. Fhit has been described as a ... [more ▼]

In many types of cancers, the fragile histidine triad (Fhit) gene is frequently targeted by genomic alterations leading to a decrease or loss of gene and protein expression. Fhit has been described as a tumor suppressor gene because of its ability to induce apoptosis and to inhibit proliferation of tumor cells. Moreover, several studies have shown a correlation between the lack of Fhit expression and tumor aggressiveness, thus suggesting that Fhit could be involved in tumor progression. In this study, we explored the potential role of Fhit during tumor cell invasion. We first showed that a low Fhit expression is associated with in vivo and in vitro invasiveness of tumor cells. Then, we showed that Fhit overexpression in Fhit-negative highly invasive NCI-H1299 cells by transfection of Fhit cDNA and Fhit inhibition in Fhit-positive poorly invasive HBE4-E6/E7 cells by transfection of Fhit small interfering RNA induce, respectively, a decrease and an increase in migratory/invasive capacities. These changes in cell behavior were associated with a reorganization of tight and adherens junction molecules and a regulation of matrix metalloproteinase and vimentin expression. These results show that Fhit controls the invasive phenotype of lung tumor cells by regulating the expression of genes associated with epithelial–mesenchymal transition. [less ▲]

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See detailThe E-cadherin-repressed hNanos1 gene induces tumor cell invasion by upregulating MT1-MMP expression
Bonnomet, A.; Polette, M.; Strumane, K. et al

in Oncogene (2008), 27(26), 3692-9

In this study, we examined the role of the E-cadherin-repressed gene human Nanos1 (hNanos1) in tumor invasion process. First, our in vivo study revealed that hNanos1 mRNAs were overexpressed in invasive ... [more ▼]

In this study, we examined the role of the E-cadherin-repressed gene human Nanos1 (hNanos1) in tumor invasion process. First, our in vivo study revealed that hNanos1 mRNAs were overexpressed in invasive lung carcinomas. Moreover, hNanos1 was co-localized with MT1-MMP (membrane type 1-matrix metalloproteinase) in E-cadherin-negative invasive lung tumor clusters. Using an inducible Tet-on system, we showed that induction of hNanos1 expression in DLD1 cells increased their migratory and invasive abilities in a three-dimensional migration and in a modified Boyden chamber assay. Accordingly, we demonstrated that hNanos1 upregulated MT1-MMP expression at the mRNA and protein levels. Inversely, using an RNA interference strategy to inhibit hNanos1 expression in invasive Hs578T, BT549 and BZR cancer cells, we observed a downregulation of MT1-MMP mRNA and protein and concomitantly a decrease of the invasive capacities of tumor cells in a modified Boyden chamber assay. Taken together, our results demonstrate that hNanos1, by regulating MT1-MMP expression, plays an important role in the acquisition of invasive properties by epithelial tumor cells. [less ▲]

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See detailbeta-Catenin and ZO-1: Shuttle molecules involved in tumor invasion-associated epithelial-mesenchymal transition processes
Polette, M.; Mestdagt, Mélanie ULg; Bindels, Sandrine ULg et al

in Cells Tissues Organs (2007), 185(1-3), 61-65

The cytoplasmic/nuclear relocalization of beta-catenin and ZO-1 from the adherens and tight junctions are common processes of the epithelial-mesenchymal transition (EMT) associated with tumor invasion ... [more ▼]

The cytoplasmic/nuclear relocalization of beta-catenin and ZO-1 from the adherens and tight junctions are common processes of the epithelial-mesenchymal transition (EMT) associated with tumor invasion. Data are now accumulating to demonstrate that these molecules, which shuttle between the plasma membrane and the nucleus or the cytosol, are involved in signaling pathways, and contribute to the regulation of genes such as vimentin or matrix metalloproteinase-14 which are turned on during EMT. Copyright (c) 2007 S. Karger AG, Basel. [less ▲]

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See detailExpression of a disintegrin and metalloprotease (ADAM and ADAMTS) enzymes in human non-small-cell lung carcinomas (NSCLC)
Rocks, Natacha ULg; Paulissen, Geneviève ULg; Quesada Calvo, Florence ULg et al

in British Journal of Cancer (2006), 94(5), 724-730

A Disintegrin and Metalloprotease (ADAM) are transmembrane proteases displaying multiple functions. ADAM with ThromboSpondin-like motifs (ADAMTS) are secreted proteases characterised by thrombospondin (TS ... [more ▼]

A Disintegrin and Metalloprotease (ADAM) are transmembrane proteases displaying multiple functions. ADAM with ThromboSpondin-like motifs (ADAMTS) are secreted proteases characterised by thrombospondin (TS) motifs in their C-terminal domain. The aim of this work was to evaluate the expression pattern of ADAMs and ADAMTS in non small cell lung carcinomas (NSCLC) and to investigate the possible correlation between their expression and cancer progression. Reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot and immunohistochemical analyses were performed on NSCLC samples and corresponding nondiseased tissue fragments. Among the ADAMs evaluated (ADAM-8, -9, -10, -12, -15, -17, ADAMTS-1, TS-2 and TS-12), a modulation of ADAM-12 and ADAMTS-1 mRNA expression was observed. Amounts of ADAM-12 mRNA transcripts were increased in tumour tissues as compared to the corresponding controls. In sharp contrast, ADAMTS-1 mRNA levels were significantly lower in tumour tissues when compared to corresponding nondiseased lung. These results were corroborated at the protein level by Western blot and immunohistochemistry. A positive correlation was observed between the mRNA levels of ADAM-12 and those of two vascular endothelial growth factor (VEGF)-A isoforms (VEGF-A(165) and VEGF-A(121)). Taken together, these results providing evidence for an overexpression of ADAM-12 and a lower expression of ADAMTS-1 in non-small-cell lung cancer suggest that these proteases play different functions in cancer progression. [less ▲]

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See detailMembrane-type 1 matrix metalloproteinase expression is regulated by zonula occludens-1 in human breast cancer cells
Polette, M.; Gilles, Christine ULg; Nawrocki-Raby, B. et al

in Cancer Research (2005), 65(17), 7691-7698

The acquisition of a migratory/invasive phenotype by tumor cells is characterized by the loss of cell-cell adhesion contacts and the expression of degradative properties. In this study, we examined the ... [more ▼]

The acquisition of a migratory/invasive phenotype by tumor cells is characterized by the loss of cell-cell adhesion contacts and the expression of degradative properties. In this study, we examined the effect of the disorganization of occludin/zomda occludens (ZO)-1 tight junction (TJ) complexes on the expression of membrane-type I matrix metalloproteinase (MT1-MMP). We first compared the expression of MT1-MMP and the localization of occludin/ZO-1 complexes in breast tumor cell lines displaying various degrees of invasiveness. We showed that the expression of MT1-MMP in invasive breast tumor cell lines correlates with the absence of occludin and with a cytoplasmic localization of ZO-1. In contrast, noninvasive cell lines displayed a membrane staining for both ZO-1 and occludin and did not express MT1-MMP. In vivo, cytoplasmic ZO-1 and MTI-MMP could be detected in invasive tumor clusters of human breast carcinomas. We then used RNA interference strategy to inhibit ZO-1 expression in invasive BT549 cells and to evaluate the effect of ZO-1 downregulation on MTI-MMP expression. We observed that ZO-1 small interfering RNA transfection down-regulates MT1-MMP mRNAs and proteins and subsequently decreases the ability of tumor cells to invade a reconstituted basement membrane in a Boyden chamber assay. Inversely, transfection of expression vectors encoding wild-type ZO-1 or the NH2-terminal fragment of ZO-1 comprising the PSD95/DLG/ZO-1 domains in BT549 activated a human MT1-MMP promoter luciferase reporter construct and increased cell invasiveness. Such transfections concomitantly activated the beta-catenin/TCF/LEF pathway. Our results therefore show that ZO-1, besides its structural role in TJ assembly, can intervene in signaling events promoting tumor cell invasion. [less ▲]

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See detailTumor invasion and matrix metalloproteinases
Polette, M.; Nawrocki-Raby, B.; Gilles, Christine ULg et al

in Critical Reviews in Oncology/Hematology (2004), 49(3), 179-86

Matrix metalloproteinases (MMPs) are proteolytic enzymes which play a major role in tumour invasion. They are mainly produced by host stromal cells in most carcinomas and their expression implies a close ... [more ▼]

Matrix metalloproteinases (MMPs) are proteolytic enzymes which play a major role in tumour invasion. They are mainly produced by host stromal cells in most carcinomas and their expression implies a close co-operation between tumour and stromal cells. Increasing data also demonstrate that, in association with a process of epithelial-to-mesenchymal transition, many MMPs can be expressed by tumour cell themselves. Their most well-known role is the degradation of extra-cellular matrix macromolecules which in turn may regulate tumour invasion in some conditions. This ECM degradation generates some matrikins which are also implicated in tumour invasion and angiogenesis. Moreover, MMPs are also implicated in the degradation of cell adhesion molecules and release and activation of growth factors. [less ▲]

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See detailE-cadherin mediates MMP down-regulation in highly invasive bronchial tumor cells
Nawrocki-Raby, B.; Gilles, Christine ULg; Polette, M. et al

in American Journal of Pathology (2003), 163(2), 653-661

The disorganization of E-cadherin/catenin complexes and the overexpression of matrix metalloproteinases (MMPs) are frequently involved in the capacity of epithelial cells to acquire an invasive phenotype ... [more ▼]

The disorganization of E-cadherin/catenin complexes and the overexpression of matrix metalloproteinases (MMPs) are frequently involved in the capacity of epithelial cells to acquire an invasive phenotype. The functional link between F-cadherin and MMPs was studied by transfecting invasive bronchial BZR tumor cells with human E-cadherin cDNA. Using different in vitro (cell dispersion, modified Boyden chamber) and in vivo assays (human airway epithelial xenograft), we showed that E-cadherin-positive clones displayed a decrease of invasive abilities. As shown by immunoprecipitation, the re-expressed E-cadherin was able to sequestrate one part of free cytoplasmic beta-catenin in BZR cells. The decrease of beta-catenin transcriptional activity in E-cadherin-transfected clones was demonstrated using the TOP-FLASH reporter construct. Finally, we observed a decrease of MMP-1, MMP-3, MMP-9, and MT1-MMP, both at the mRNA and at the protein levels, in E-cadherin-positive clones whereas no changes in MMP-2, TIMP-1, or TIMP-2 were observed when compared with control clones. Moreover, zymography analysis revealed a loss of MMP-2 activation ability in E-cadherin-positive clones treated with the concanavalin A lectin. These data demonstrate a direct role of E-cadherin/catenin complex organization in the regulation of MMPs and suggest an implication of this regulation in the expression of an invasive phenotype by bronchial tumor cells. [less ▲]

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See detailUpregulation of MMPs by soluble E-cadherin in human lung tumor cells
Nawrocki-Raby, B.; Gilles, Christine ULg; Polette, M. et al

in International Journal of Cancer = Journal International du Cancer (2003), 105(6), 790-795

Loss of E-cadherin/catenin mediated cell-cell adhesion and overexpression of matrix metalloproteinases (MMPs) are largely involved in tumor invasion. It has been recently shown that high levels of a ... [more ▼]

Loss of E-cadherin/catenin mediated cell-cell adhesion and overexpression of matrix metalloproteinases (MMPs) are largely involved in tumor invasion. It has been recently shown that high levels of a soluble 80 kDa fragment of E-cadherin, resulting from a cleavage by IVIMPs, are found in serum and in urine from cancer patients. Additionally, this soluble E-cadherin (sE-CAD) promotes cell invasion into chick heart and into collagen type I gels. The aim of our study was to examine the mechanism of sE-CAD-induced cell invasion. Since MMPs play a crucial role in invasion, we looked for induction of MMPs by sE-CAD in noninvasive human lung tumor cells 16HBE. An induction of MMP-2, MMP-9 and MTI-MMP expression was observed both at the mRNA and at the protein level in the presence of sE-CAD (in conditioned medium form or in E-cadherin HAV peptide form). No induction of MMP-I, -3 and -7 or variation of the levels of their inhibitors, TIMP-I and TIMP-2, were detected. The biologic relevance of the sE-CAD-induced MMP upregulation was tested by demonstrating that sE-CAD promotes in vitro cell invasion in a modified Boyden chamber assay. These data provide new insight into mechanisms of tumor invasion by ectodomain shedding of the cell-cell adhesion molecule E-cadherin. (C) 2003 Wiley-Liss, Inc. [less ▲]

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See detailTransactivation of vimentin by beta-catenin in human breast cancer cells
Gilles, Christine ULg; Polette, M.; Mestdagt, Mélanie ULg et al

in Cancer Research (2003), 63(10), 2658-2664

The cytoplasmic and nuclear redistribution of beta-catenin and the de novo expression of vimentin are frequently involved in the epithelial-to-mesenchymal transition associated with increased invasive ... [more ▼]

The cytoplasmic and nuclear redistribution of beta-catenin and the de novo expression of vimentin are frequently involved in the epithelial-to-mesenchymal transition associated with increased invasive/migratory properties of epithelial cells. Because beta-catenin can act as a coactivator of transcription through its binding to the T-cell factor (TCF)/lymphoid enhancer factor 1 transcription factor family, we have explored the possibility that beta-catenin/TCF could directly transactivate vimentin. We first compared vimentin expression in relation with the localization of beta-catenin in eight breast cancer cell lines displaying various degrees of invasiveness and in a model of cell migration using human mammary MCF10A cells. We could thus show a cytoplasmic and/or nuclear distribution of beta-catenin in invasive/migratory cells expressing vimentin, but not in noninvasive/stationary vimentin-negative cell lines. In addition, the human vimentin promoter was found to be up-regulated by beta-catenin and TCF-4 cotransfection. Varying with the cellular background, a diminution of this up-regulation was observed when the putative beta-catenin/TCF binding site of the vimentin promoter was mutated. Our results therefore demonstrate that the vimentin promoter is a target of the beta-catenin/TCF pathway and strongly suggest an implication of this regulation in epithelial cell migration/invasion. [less ▲]

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See detailRestricted expression of membrane type 1-matrix metalloproteinase by myofibroblasts adjacent to human breast cancer cells
Bisson, C.; Blacher, Silvia ULg; Polette, M. et al

in International Journal of Cancer = Journal International du Cancer (2003), 105(1), 7-13

The membrane type-1 matrix metalloproteinase (MT1-MMP), a protease originally identified in breast carcinoma, is characterized by its capacity to activate other MMPs (MMP-2 and MMP-13) and to degrade ... [more ▼]

The membrane type-1 matrix metalloproteinase (MT1-MMP), a protease originally identified in breast carcinoma, is characterized by its capacity to activate other MMPs (MMP-2 and MMP-13) and to degrade extracellular matrix. Our study was undertaken to localize and identify the MT1-MMP expressing cells in human breast adenocarcinomas. A textural analysis of images obtained by immunohistochemistry and in situ hybridization showed precisely the co-expression of alpha smooth muscle actin (alphaSM actin) and MT1-MMP in myofibroblasts. MT1-MMP expression is confined to myofibroblasts in close contact with tumor cells. In sharp contrast, the expression of MMP-2 was more widely distributed in both alphaSM actin positive and negative cells close to and at distance from cancer cell clusters. Our in vitro observations are consistent with the higher level of MT1-MMP expression and of MMP-2 activation observed in alphaSM actin positive fibroblasts derived from breast tumors, as compared to normal breast fibroblasts. Collectively, these results implicate myofibroblasts as major producer of MT1-MMP in breast cancer and emphasize the importance of stromal-epithelial cell interactions in their progression. [less ▲]

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See detailContribution of MT1-MMP and of Human Laminin-5 Gamma2 Chain Degradation to Mammary Epithelial Cell Migration
Gilles, Christine ULg; Polette, M.; Coraux, C. et al

in Journal of Cell Science (2001), 114(Pt 16), 2967-76

Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a membrane-anchored matrix metalloproteinase (MMP) that is frequently associated with processes involving tissue remodelling and cell migration. We ... [more ▼]

Membrane-type matrix metalloproteinase 1 (MT1-MMP) is a membrane-anchored matrix metalloproteinase (MMP) that is frequently associated with processes involving tissue remodelling and cell migration. We have examined MT1-MMP expression and subcellular distribution as a function of MCF10A mammary epithelial cell migration using an in vitro outgrowth migration assay. Stronger expression of MT1-MMP was observed at the mRNA and at the protein level in cells at the periphery of the outgrowth. As shown by videomicroscopy, these cells were involved in an orientated cell migration, in contrast to stationary cells distant from the periphery. Furthermore, MT1-MMP was mainly distributed in lamellipodia of migratory cells, as well as at their basal surface in contact with the substrate. Laminin-5 (Ln-5), a recently described substrate for MT1-MMP, was deposited preferentially in the matrix by migratory cells. Fragments of the gamma2 subunit of Ln-5 were also identified in migratory cultures of MCF10A cells, attesting to its proteolytic degradation. These fragments corresponded in size to those we observed after incubation of purified human Ln-5 with the recombinant catalytic domain of human MT1-MMP. We also show that anti-Ln5 blocking antibodies, MMP inhibitors (BB94 and TIMP-2) and MT1-MMP antisense oligonucleotides significantly decreased MCF10A cell migration. Taken together, these observations demonstrate that MT1-MMP is spatially and temporally regulated during MCF10A cell migration, and suggest that MT1-MMP-mediated pericellular proteolysis of Ln-5 gamma2 chain could contribute to this process. [less ▲]

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See detailDown-Regulation of MT1-MMP expression by the alpha3 chain of type IV collagen inhibits bronchial tumor cell line invasion
Martinella-Catusse, C.; Polette, M.; Noël, Agnès ULg et al

in Laboratory Investigation : Journal of Technical Methods & Pathology (2001), 81

The basement membrane (BM) is the first barrier encountered by tumor cells when they become invasive. Moreover, some invasive tumor clusters are surrounded by a remnant or neosynthetized BM material. We ... [more ▼]

The basement membrane (BM) is the first barrier encountered by tumor cells when they become invasive. Moreover, some invasive tumor clusters are surrounded by a remnant or neosynthetized BM material. We have previously reported the presence of a particular alpha chain of type IV collagen, the alpha3(IV) chain, in bronchopulmonary carcinomas. This chain was not detected in the normal bronchial epithelium, but was found around some invasive tumor cluster BM. In the present study, we examined the effects of the alpha3(IV) chain on the invasive properties of bronchial tumor cell lines, with special emphasis on their expression of matrix metalloproteinase-2 (MMP-2) and its activator, membrane type 1-matrix metalloproteinase (MT1-MMP), which is largely involved in tumor progression. Two epithelial bronchial cell lines (16HBE14o- and BZR), showing different invasive abilities, were evaluated. Using the Boyden chamber invasion assay, we demonstrated that the alpha3(IV) chain inhibits the invasive properties of BZR cells and modifies their morphology by inducing an epithelial cell shape. In the presence of the recombinant NC1 domain of the alpha3(IV) chain, the expression of MMP-2 and tissue inhibitor of metalloproteinase-2 (TIMP-2) was not modified in either cell line. The NC1 alpha3(IV) domain did not modulate the MT1-MMP expression of noninvasive 16HBE14o- cells, whereas a 50% decrease of MT1-MMP mRNA was observed in invasive BZR cells. Accordingly, Western blot analyses showed a disappearance of the 45-kd MT1-MMP form when BZR cells were treated with the recombinant NC1 alpha3(IV) domain. These findings suggest that the alpha3 chain of type IV collagen may play a role in tumor invasion, at least by decreasing the expression and synthesis of MT1-MMP. [less ▲]

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See detailVimentin Contributes to Human Mammary Epithelial Cell Migration
Gilles, Christine ULg; Polette, M.; Zahm, J. M. et al

in Journal of Cell Science (1999), 112((Pt 24)), 4615-25

Vimentin expression in human mammary epithelial MCF10A cells was examined as a function of their migratory status using an in vitro wound-healing model. Analysis of the trajectories of the cells and their ... [more ▼]

Vimentin expression in human mammary epithelial MCF10A cells was examined as a function of their migratory status using an in vitro wound-healing model. Analysis of the trajectories of the cells and their migratory speeds by time lapse-video microscopy revealed that vimentin mRNA and protein expression were exclusively induced in cells at the wound's edge which were actively migrating towards the center of the lesion. Actin labeling showed the reorganization of actin filaments in cells at the wound's edge which confirmed the migratory phenotype of this cell subpopulation. Moreover, the vimentin protein disappeared when the cells became stationary after wound closure. Using cells transfected with the vimentin promoter controlling the green fluorescent protein gene, we also demonstrated the specific activation of the vimentin promoter in the migratory cells at the wound's edge. Transfection of the antisense vimentin cDNA into MCF10A cells clearly reduced both their ability to express vimentin and their migratory speed. Taken together, these observations demonstrate that vimentin is transiently associated with, and could be functionally involved in, the migratory status of human epithelial cells. [less ▲]

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See detailMatrix-metalloproteinases in bronchopulmonary carcinomas.
Martinella-Catusse, C.; Nawrocki, B.; Gilles, Christine ULg et al

in Histology and Histopathology (1999), 14(3), 839-43

Matrix metalloproteinases (MMPs) represent a group of enzymes involved in the degradation of most of the components of the extracellular matrix and therefore participate in tumoural invasion. MMPs ... [more ▼]

Matrix metalloproteinases (MMPs) represent a group of enzymes involved in the degradation of most of the components of the extracellular matrix and therefore participate in tumoural invasion. MMPs, especially gelatinases A and B, MT1-MMP, the activator of gelatinase A, and stromelysin-3 were found overexpressed in many cancers including bronchopulmonary carcinomas. In vivo observations revealed that fibroblasts are the principal source of production of MMPs. Some of these enzymes such as MT1-MMP and stromelysin 3, displayed a focal stromal localisation near preinvasive and invasive tumour clusters. Furthermore, some tumour cell lines were shown to stimulate the expression of MT1-MMP by fibroblasts. All these in vivo and in vitro results suggest that certain tumour cells produce diffusible factors which could influence the MMP stromal expression. Among these factors, the TCSF (Tumor Collagenase Stimulatory Factor) which is known to upregulate some MMPs in vitro could be a good candidate for this stromal regulation, since it is produced by bronchial tumour cells in vivo. In this review, we address such a cooperation between tumour and stromal cells for the production of MMPs and emphasize their necessity for tumoural progression in bronchopulmonary carcinomas [less ▲]

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See detailAirway epithelial cell migration dynamics. MMP-9 role in cell-extracellular matrix remodeling
Legrand, C.; Gilles, Christine ULg; Zahm, J. M. et al

in Journal of Cell Biology (1999), 146(2), 517-29

Cell spreading and migration associated with the expression of the 92-kD gelatinase (matrix metalloproteinase 9 or MMP-9) are important mechanisms involved in the repair of the respiratory epithelium. We ... [more ▼]

Cell spreading and migration associated with the expression of the 92-kD gelatinase (matrix metalloproteinase 9 or MMP-9) are important mechanisms involved in the repair of the respiratory epithelium. We investigated the location of MMP-9 and its potential role in migrating human bronchial epithelial cells (HBEC). In vivo and in vitro, MMP-9 accumulated in migrating HBEC located at the leading edge of a wound and MMP-9 expression paralleled cell migration speed. MMP-9 accumulated through an actin-dependent pathway in the advancing lamellipodia of migrating cells and was subsequently found active in the extracellular matrix (ECM). Lamellipodia became anchored through primordial contacts established with type IV collagen. MMP-9 became amassed behind collagen IV where there were fewer cell-ECM contacts. Both collagen IV and MMP-9 were involved in cell migration because when cell-collagen IV interaction was blocked, cells spread slightly but did not migrate; and when MMP-9 activation was prevented, cells remained fixed on primordial contacts and did not advance at all. These observations suggest that MMP-9 controls the migration of repairing HBEC by remodeling the provisional ECM implicated in primordial contacts. [less ▲]

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See detailAssociation of fibroblastoid features with the invasive phenotype in human bronchial cancer cell lines
Polette, M.; Gilles, Christine ULg; de Bentzmann, S. et al

in Clinical & Experimental Metastasis (1998), 16(2), 105-12

The acquisition of a metastatic phenotype by epithelial cells implicates a series of changes altering their differentiation, their overall behavior and morphology. In the present study, we have examined ... [more ▼]

The acquisition of a metastatic phenotype by epithelial cells implicates a series of changes altering their differentiation, their overall behavior and morphology. In the present study, we have examined the relationships between the cellular morphology, E-cadherin expression, matrix metalloproteinases expression and in vitro invasive properties in two human bronchial immortalized cell lines. The (16HBE14o-) cell line which did not show any invasive abilities in the Boyden chamber assay displayed a typical epithelial morphology in monolayer, expressed high levels of E-cadherin and synthesized neither MMP-2 and MT1-MMP nor vimentin. In contrast, the BZR cell line which was highly invasive displayed a more elongated phenotype in monolayer, did not produce E-cadherin but expressed vimentin, MMP-2 and MT1-MMP. Our data therefore suggest that the metastatic progression of broncho-pulmonary cancer cells results in a cellular dedifferentiation and the gain of some mesenchymal attributes (loss of E-cadherin and expression of vimentin) associated with enhanced degradative properties (expression of metalloproteinases) [less ▲]

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See detailExpression of Stromelysin-3 in the Human Placenta and Placental Bed
Maquoi, Erik ULg; Polette, M.; Nawrocki, B. et al

in Placenta (1997), 18(4), 277-85

Human placentation is mediated by fetal trophoblastic cells which penetrate into the decidualized uterine endometrium. Trophoblast invasion requires the precisely regulated secretion of specific ... [more ▼]

Human placentation is mediated by fetal trophoblastic cells which penetrate into the decidualized uterine endometrium. Trophoblast invasion requires the precisely regulated secretion of specific proteinases able to degrade the endometrial basement membranes and extracellular matrix. To document further the involvement of these proteinases during human placentation, we evaluated in vivo the expression of stromelysin-3, a member of the metalloproteinase family, during the first and third trimesters of pregnancy, by means of immunohistochemistry, in situ hybridization and Northern blot analysis. Human extravillous trophoblasts invading the maternal decidua produced stromelysin-3 during both, the first and third trimesters of pregnancy, but to a lesser extent during the latter. In floating villi, stromelysin-3 expression was restricted to the syncytiotrophoblasts that line intervillous vascular spaces. In conclusion, stromelysin-3 is expressed by differentiated, non-proliferative villous and extravillous trophoblastic cells in early and late placental beds and villi, and its pattern of expression evolves during pregnancy. Our observations suggest that stromelysin-3 could play a role in human placentation. [less ▲]

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See detailInduction of membrane-type matrix metalloproteinase 1 (MT1-MMP) expression in human fibroblasts by breast adenocarcinoma cells.
Polette, M.; Gilles, Christine ULg; Marchand, V. et al

in Clinical & Experimental Metastasis (1997), 15(2), 157-63

Membrane-type matrix metalloproteinase 1 (MT1-MMP) has been recently described as an activator of proMMP-2 (MMP-2) which is involved in tumor invasion. We have shown by in situ hybridization that MT1-MMP ... [more ▼]

Membrane-type matrix metalloproteinase 1 (MT1-MMP) has been recently described as an activator of proMMP-2 (MMP-2) which is involved in tumor invasion. We have shown by in situ hybridization that MT1-MMP is produced by stromal cells in close contact to preinvasive and invasive tumor cells of breast carcinomas. Of particular interest was the observation that some fibroblasts express this enzyme in focal areas in preinvasive lesions, suggesting that particular tumor cells may stimulate fibroblasts to produce MT1-MMP. We have therefore compared the ability of two different breast cancer cell lines, one non-invasive (MCF7) and one invasive (MDA-MB-231) to stimulate MT1-MMP production in human fibroblasts with consequent proMMP-2-activation. The MDA-MB-231 conditioned medium induced MT1-MMP mRNAs in human fibroblasts and a parallel activation of proMMP-2 whereas MCF7 conditioned medium did not have any effect. These results suggest the existence of soluble factor(s) secreted by invasive or some preinvasive breast tumor cells which stimulate fibroblasts to produce and activate MMPs, and emphasize the cooperation between cancer and stromal cells in tumor invasion. [less ▲]

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