References of "Noël, Agnès"
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See detailMembrane Type 1 Matrix Metalloproteinase-Associated Degradation of Tissue Inhibitor of Metalloproteinase 2 in Human Tumor Cell Lines
Maquoi, Erik ULg; Frankenne, Francis ULg; Baramova, Eugénia et al

in Journal of Biological Chemistry (2000), 275(15), 11368-78

Tissue inhibitor of metalloproteinase 2 (TIMP-2) is required for the membrane type 1 matrix metalloproteinase (MT1-MMP)-dependent activation of pro-MMP-2 on the cell surface. MT1-MMP-bound TIMP-2 has been ... [more ▼]

Tissue inhibitor of metalloproteinase 2 (TIMP-2) is required for the membrane type 1 matrix metalloproteinase (MT1-MMP)-dependent activation of pro-MMP-2 on the cell surface. MT1-MMP-bound TIMP-2 has been shown to function as a receptor for secreted pro-MMP-2, resulting in the formation of a trimolecular complex. In the presence of uncomplexed active MT1-MMP, the prodomain of cell surface-associated MMP-2 is cleaved, and activated MMP-2 is released. However, the behavior of MT1-MMP-bound TIMP-2 during MMP-2 activation is currently unknown. In this study, (125)I-labeled recombinant TIMP-2 ((125)I-rTIMP-2) was used to investigate the fate of TIMP-2 during pro-MMP-2 activation by HT1080 and transfected A2058 cells. HT1080 and A2058 cells transfected with MT1-MMP cDNA (but not vector-transfected A2058 cells) were able to bind (125)I-rTIMP-2, to activate pro-MMP-2, and to process MT1-MMP into an inactive 43-kDa form. Under these conditions, (125)I-rTIMP-2 bound to the cell surface was rapidly internalized and degraded in intracellular organelles through a bafilomycin A(1)-sensitive mechanism, and (125)I-bearing low molecular mass fragment(s) were released in the culture medium. These different processes were inhibited by hydroxamic acid-based synthetic MMP inhibitors and rTIMP-2, but not by rTIMP-1 or cysteine, serine, or aspartic proteinase inhibitors. These results support the concept that the MT1-MMP-dependent internalization and degradation of TIMP-2 by some tumor cells might be involved in the regulation of pericellular proteolysis. [less ▲]

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See detailHigh Levels of Timp-2 Correlate with Adverse Prognosis in Breast Cancer
Remacle, A.; McCarthy, K.; Noël, Agnès ULg et al

in International Journal of Cancer = Journal International du Cancer (2000), 89(2), 118-21

TIMP-2 is an endogenous inhibitor of MMPs. Most data from model systems suggest that high levels of this inhibitor prevent metastasis. In human breast cancers, however, we show that high levels of TIMP-2 ... [more ▼]

TIMP-2 is an endogenous inhibitor of MMPs. Most data from model systems suggest that high levels of this inhibitor prevent metastasis. In human breast cancers, however, we show that high levels of TIMP-2 correlate with both shortened disease-free interval and overall survival. In primary breast cancers, TIMP-2 levels showed no significant relationship with either tumor size or axillary node status but correlated inversely with estrogen receptor levels. TIMP-2 levels also correlated significantly with those for TIMP-1. We conclude that high levels of endogenous TIMP-2, like other protease inhibitors such as PAI-1 and TIMP-1, correlate with progression of human breast cancer. [less ▲]

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See detailDemonstration in Vivo That Stromelysin-3 Functions through Its Proteolytic Activity
Noël, Agnès ULg; Boulay, A.; Kebers, F. et al

in Oncogene (2000), 19(12), 1605-12

Stromelysin-3 (ST3), a matrix metalloproteinase (MMP) expressed in aggressive carcinomas, has been shown to promote tumor development in different in vivo experimental models. However, the inability of ... [more ▼]

Stromelysin-3 (ST3), a matrix metalloproteinase (MMP) expressed in aggressive carcinomas, has been shown to promote tumor development in different in vivo experimental models. However, the inability of its mature form to degrade extracellular matrix components casts doubt on whether ST3 functions in vivo as a protease. In this study, we evaluated whether the ST3 tumor-promoting effect could be ascribed to its proteolytic activity and whether this putative protease could be targeted with MMP inhibitors. Catalytically inactive mutant cDNA of human (h) ST3 or mouse (m) ST3 were generated and transfected into MCF7 cells. When injected into nude mice in the presence of matrigel, the mutant-bearing cells did not exhibit the enhanced tumorigenicity elicited by MCF7 cells transfected with wild-type ST3 cDNA. In a second approach, TIMP2 overproduction in MCF7 cells expressing hST3 was induced by retroviral infection. The co-expression of ST3 and TIMP2 failed to enhance the tumorigenicity of MCF7 cells. Notably, matrigel depleted of low-molecular-weight proteins and growth factors failed to promote the tumorigenicity of ST3-expressing MCF7 cells. These findings provide the first in vivo evidence that ST3 is indeed a protease that can modulate cancer progression by remodeling extracellular matrix and probably by inducing it to release the necessary microenvironmental factors. Thus, ST3 represents an interesting target for specific MMP inhibition. [less ▲]

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See detailProgression in MCF-7 Breast Cancer Cell Tumorigenicity: Compared Effect of FGF-3 and FGF-4.
Hajitou, A.; Deroanne, Christophe ULg; Noël, Agnès ULg et al

in Breast Cancer Research and Treatment (2000), 60(1), 15-28

The transforming properties of fibroblast growth factor 3 (FGF-3) were investigated in MCF7 breast cancer cells and compared to those of FGF-4, a known oncogenic product. The short form of fgf-3 and the ... [more ▼]

The transforming properties of fibroblast growth factor 3 (FGF-3) were investigated in MCF7 breast cancer cells and compared to those of FGF-4, a known oncogenic product. The short form of fgf-3 and the fgf-4 sequences were each introduced with retroviral vectors and the proteins were only detected in the cytoplasm of the infected cells, as expected. In vitro, cells producing FGF-3 (MCF7.fgf-3) and FGF-4 (MCF7.fgf-4) displayed an amount of estrogen receptors decreased to around 45% of the control value. However, MCF7.fgf-3 cell proliferation remained responsive to estradiol supply. The sensitivity of the MCF7.fgf-4 cells, if existant, was masked by the important mitogenic action exerted by FGF-4. In vivo, the MCF7.fgf-3 and MCF7.fgf-4 cells gave rise to tumors under conditions in which the control cells were not tumorigenic. Supplementing the mice with estrogen had the paradoxical effect of totally suppressing the start of the FGF-3 as well as the FGF-4 tumors. Tumorigenicity in the presence of matrigel was similar for MCF7.fgf-3 and control cells and was increased by estrogen supplementation. Once started, the MCF7.fgf-4 tumors grew with a characteristic high rate. Remarkably, FGF-4 but not FGF-3, stimulated the secretion of vascular endothelial growth factor (VEGF165) without altering the steady-state level of its mRNA, suggesting a possible regulation of VEGF synthesis at the translational level in MCF7 cells. The increased VEGF secretion is probably involved in the more aggressive phenotype of the MCF7.fgf-4 cells while a decreased dependence upon micro-environmental factors might be part of the increased tumorigenic potential of the MCF7.fgf-3 cells. [less ▲]

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See detailInhibition of cancer cells invasion by coumarin derivatives
Kempen, I.; Pochet, L.; Doucet, C. et al

Poster (2000, January 29)

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See detailHigh production of SPARC/osteonectin/BM-40 in mouse metastatic B16 melanoma cell lines
Kato, Y.; Frankenne, F.; Noël, Agnès ULg et al

in Pathology Oncology Research (2000), 6(1), 24-26

Abstract Production of SPARC/osteonectin/BM-40 was determined in mouse B16 melanoma clones BL6 and F10 (high metastatic) and F1 (low metastatic). SPARC was produced greater amount in BL6 and F10 than in ... [more ▼]

Abstract Production of SPARC/osteonectin/BM-40 was determined in mouse B16 melanoma clones BL6 and F10 (high metastatic) and F1 (low metastatic). SPARC was produced greater amount in BL6 and F10 than in F1 cells, showing a good agreement with their metastatic potentials. Moreover, SPARC production was not influenced by culture pH, even in the acidic conditions (= pH 5.9). Although tumor tissues show often low pH due to excessive amount of acidic metabolites such as lactate, most studies have been done in neutral pH. High SPARC production in the acidic medium, therefore, is thought to be an important potential for tumor invasive behaviour. [less ▲]

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See detailLes aspects precliniques des therapeutiques anti-angiogenes
Noël, Agnès ULg; Foidart, Jean-Michel ULg

in Bulletin de l'Académie Nationale de Médecine (2000), 184(3), 569-77578

Tumor angiogenesis is one of the most important fields of cancer research. It is important to identify the putative targets for antiangiogenic strategies. To date, a number of angiogenic agents have been ... [more ▼]

Tumor angiogenesis is one of the most important fields of cancer research. It is important to identify the putative targets for antiangiogenic strategies. To date, a number of angiogenic agents have been identified: bFGF, the different VEGF isoforms, integrins, proteases (matrix metalloproteases and serine proteases),... Furthermore, several physiological anti-angiogenic agents have been isolated such as endostatin, angiostatin, 16 K prolactin,.... The recent development of mice deficient for one gene involved during angiogenesis gives a new insight into the molecular mechanisms regulating this process. It leads to the identification of plasminogen activator inhibitor-1 or PAI-1 as a new target for tumor treatment. Although, PAI-1 is very attractive as a target for new therapeutic strategies, a better understanding of its mechanism of action is needed urgently. [less ▲]

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See detailCoumarin derivatives as putative antiinvasive agents in cancer
Kempen, I.; Doucet, C.; Pochet, L. et al

in Fundamental & Clinical Pharmacology (2000), 14

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See detailCoumarin derivatives as putative antiinvasive agents in cancer
Kempen, I.; Doucet, C.; Pochet, L. et al

Poster (1999, November 20)

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See detailMolecular interactions involving urokinase plasminogen activator (uPA), its receptor (uPAR) and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), as new targets for tumour therapy
Frankenne, F.; Noël, Agnès ULg; Bajou, Khalid ULg et al

in Expert Opinion on Therapeutic Targets (1999), 3(3), 469-48113

In the promotion of cancer progression, a classical role had previously been ascribed to the plasminogen activation system on the basis of urokinase plasminogen activator (uPA) proteolytic activity and ... [more ▼]

In the promotion of cancer progression, a classical role had previously been ascribed to the plasminogen activation system on the basis of urokinase plasminogen activator (uPA) proteolytic activity and plasminogen activation triggering a focalised pericellular activation cascade involving matrix metalloproteinases (MMPs). As a result, many pharmaceutical companies have undertaken the development of synthetic uPA inhibitors. However, during the last few years, data have accumulated that uPA, as well as urokinase-type plasminogen activator receptor (uPAR) and plasminogen activator inhibitor-1 (PAI-1), are likely to play an essential role in tumour progression through non-proteolysis-related activities. Such activities endow them with new and likely key functions in tumour progression-associated events, such as cellular adhesion, migration, invasion and angiogenesis. Since these activities essentially depend upon protein-protein interactions, they represent new therapeutic targets. [less ▲]

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See detailCell-Cell and Cell-Matrix Interactions During Breast Cancer Progression
Noël, Agnès ULg; Kebers, F.; Maquoi, Erik ULg et al

in Current Topics in Pathology. Ergebnisse der Pathologie (1999)

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See detailPurification of active matrix metalloproteinase catalytic domains and its use for screening of specific stromelysin-3 inhibitors.
Kannan, R.; Ruff, M.; Kochins, J. G. et al

in Protein Expression & Purification (1999), 16

The matrix metalloproteinase (MMP) stromelysin-3 (ST3) has been shown to be involved in malignant tumor progression and therefore represents an attractive therapeutical target. In order to screen for ST3 ... [more ▼]

The matrix metalloproteinase (MMP) stromelysin-3 (ST3) has been shown to be involved in malignant tumor progression and therefore represents an attractive therapeutical target. In order to screen for ST3 synthetic inhibitors, we have produced and purified the catalytic domain of ST3, matrilysin, stromelysin-2, and membrane type-1 MMP from inclusion bodies in a bacterial system. Our strategy allowed the purification of MMPs directly in the active form, thereby avoidingin vitroactivation. A total of 140,000 synthetic compounds from the Bristol-Myers Pharmaceutical Research Institute chemical deck were tested, using a substrate-based colorimetric enzymatic assay, in which ST3 activity was evaluated through its ability to cleave and inactivate α-1 proteinase inhibitor. One ST3 inhibitor belonging to the cephalosporin family of antibiotics was thereby identified. [less ▲]

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See detailRegulation of cancer invasion and vascularization by plasminogen activator inhibitor-1
Noël, Agnès ULg; Bajou, Khalid ULg; Masson, Véronique ULg et al

in Fibrinolysis and Proteolysis (1999), 13(6), 220-225

Acquisition of invasive/metastatic potential through protease expression is a key event in tumor progression. The proteolytic enzyme plasmin is generated from the precursor plasminogen by the action of ... [more ▼]

Acquisition of invasive/metastatic potential through protease expression is a key event in tumor progression. The proteolytic enzyme plasmin is generated from the precursor plasminogen by the action of urokinase-type plasminogen activator (urokinase, uPA) or tissue-type plasminogen activator (tPA). Plasminogen activator inhibitor-1 or PAI-1 is the main inhibitor of uPA and tPA. High levels of components of this proteolytic system, including uPA and its cell surface receptor (uPAR), have been correlated with a poor prognosis for different cancers. It was therefore anticipated that PAI-1 expression would be associated with favorable outcome. Paradoxically, high rather than low PAI-1 levels predict poor survival of patients suffering from a variety of cancers. Recent observations indicate a much more complex role of PAI-1 in tumor progression and angiogenesis than initially expected. The exact mechanisms of this multifunctional molecule remain puzzling. [less ▲]

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See detailAbsence of Host Plasminogen Activator Inhibitor 1 Prevents Cancer Invasion and Vascularization
Bajou, Khalid ULg; Noël, Agnès ULg; Gerard, R. D. et al

in Nature Medicine (1998), 4(8), 923-8

Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase ... [more ▼]

Acquisition of invasive/metastatic potential through protease expression is an essential event in tumor progression. High levels of components of the plasminogen activation system, including urokinase, but paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI1), have been correlated with a poor prognosis for some cancers. We report here that deficient PAI1 expression in host mice prevented local invasion and tumor vascularization of transplanted malignant keratinocytes. When this PAI1 deficiency was circumvented by intravenous injection of a replication-defective adenoviral vector expressing human PAI1, invasion and associated angiogenesis were restored. This experimental evidence demonstrates that host-produced PAI is essential for cancer cell invasion and angiogenesis. [less ▲]

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See detailInduction of Endothelial Cell Apoptosis by Solid Tumor Cells
Kebers, F.; Lewalle, J. M.; Desreux, Joëlle ULg et al

in Experimental Cell Research (1998), 240(2), 197-205

The mechanisms by which tumor cells extravasate to form metastasis remain controversial. Previous studies performed in vivo and in vitro demonstrate that the contact between tumor cells and the vascular ... [more ▼]

The mechanisms by which tumor cells extravasate to form metastasis remain controversial. Previous studies performed in vivo and in vitro demonstrate that the contact between tumor cells and the vascular wall impairs endothelium integrity. Here, we investigated the effect of breast adenocarcinoma MCF-7 cells on the apoptosis of human umbilical vein endothelial cells (HUVEC). TUNEL labeling, nuclear morphology, and DNA electrophoresis indicated that MCF-7 cells induced a two- to fourfold increase in HUVEC apoptosis. Caspase-3 activity was significantly enhanced. Neither normal cells tested (mammary epithelial cells, fibroblasts, leukocytes) nor transformed hematopoietic cells tested (HL60, Jurkat) induced HUVEC apoptosis. On the contrary, cells derived from solid tumors (breast adenocarcinoma, MDA-MB-231 and T47D; fibrosarcoma, HT 1080) had an effect similar to that of MCF-7 cells. The induction of apoptosis requires cell-to-cell contact, since it could not be reproduced by media conditioned by MCF-7 cells cultured alone or cocultured with HUVEC. Our results suggest that cells derived from solid tumors may alter the endothelium integrity by inducing endothelial cell apoptosis. On the contrary, normal or malignant leukocytes appear to extravasate by distinct mechanisms and do not damage the endothelium. Our data may lead to a better understanding of the steps involved in tumor cell extravasation. [less ▲]

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See detailInhibition of Stromal Matrix Metalloproteases: Effects on Breast-Tumor Promotion by Fibroblasts
Noël, Agnès ULg; Hajitou, Amin; L'Hoir, Cécile et al

in International Journal of Cancer = Journal International du Cancer (1998), 76(2), 267-73

Co-injection of fibroblasts with human epithelial breast-tumor MCF7 cells in the presence of Matrigel enhances tumor growth in nude mice. While most of the matrix metalloproteinases (MMPs) have been shown ... [more ▼]

Co-injection of fibroblasts with human epithelial breast-tumor MCF7 cells in the presence of Matrigel enhances tumor growth in nude mice. While most of the matrix metalloproteinases (MMPs) have been shown to be produced by stromal cells, tumor cells such as MCF7 cells are unable to produce MMPs. We therefore, hypothesized that the tumor-promoting effect of fibroblasts could be related to their production of MMPs. In order to inhibit stromal proteases, over-production of TIMP-2 was induced in MCF7 cells by in vitro retroviral-mediated gene transfer. TIMP-2-producing MCF7 cells were then co-injected with fibroblasts into nude mice. Alternatively, we evaluated the effect of Batimastat, a synthetic inhibitor of MMPs, on the tumorigenicity of MCF7 cells co-inoculated with fibroblasts into nude mice. Both physiological (TIMP-2) and synthetic (Batimastat) inhibitors of MMPs were able to abolish the tumor-promoting effect of fibroblasts. On the contrary, they failed to modulate the tumorigenicity of MCF7 cells injected alone. Interestingly, Matrigel from which low-molecular-weight proteins or growth factors had been removed failed to favor the tumorigenicity of MCF7 cells inoculated with fibroblasts. These findings emphasize the importance of fibroblasts in cancer progression, and suggest that their role could be related at least in part to production of proteases which can induce the release of factors from the extracellular matrix. [less ▲]

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See detailThe Role of Stroma in Breast Carcinoma Growth in Vivo
Noël, Agnès ULg; Foidart, Jean-Michel ULg

in Journal of Mammary Gland Biology & Neoplasia (1998), 3(2), 215-25

The malignant progression of tumors is thought to be related to the expression of oncogenes and loss of expression of tumor suppressor gene. These factors are intrinsic to the cancer cells themselves ... [more ▼]

The malignant progression of tumors is thought to be related to the expression of oncogenes and loss of expression of tumor suppressor gene. These factors are intrinsic to the cancer cells themselves. However, carcinomas are also infiltrated by host cells (fibroblasts, endothelial cells, inflammatory cells) and surrounded by an extracellular matrix which is extensively remodeled. The extracellular matrix components and infiltrating host cells provide a microenvironment that conditions both tumor progression and the metastatic process. Transplantation of human tumors into athymic nude mice has become an important experimental approach to study the biology of human cancers. The different models developed so far are beginning to elucidate the role of matrix molecules, growth factors and enzymes as well as fibroblasts in tumor progression. These animal models are likely to provide a useful tool to evaluate new antitumor treatments. [less ▲]

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See detailInhibition of Matrix Metalloproteinase 2 Maturation and Ht1080 Invasiveness by a Synthetic Furin Inhibitor
Maquoi, Erik ULg; Noël, Agnès ULg; Frankenne, F. et al

in FEBS Letters (1998), 424(3), 262-6

The close correlation observed between matrix metalloproteinase 2 (MMP-2) activation and metastatic progression in various tumors suggests that MMP-2 is a 'master switch' triggering tumor spread. Recently ... [more ▼]

The close correlation observed between matrix metalloproteinase 2 (MMP-2) activation and metastatic progression in various tumors suggests that MMP-2 is a 'master switch' triggering tumor spread. Recently, membrane type 1 MMP (MT1-MMP) was identified as a potential physiological activator of MMP-2. Like all other MMPs, MT1-MMP possesses a pro-domain which must be removed for the enzyme to acquire its catalytic potential. The presence of a typical recognition motif (RXKR) for the furin-like convertases at the end of its pro-domain suggests a potential role for these proteinases in MT1-MMP processing. In order to evaluate the implication of furin in pro-MT1-MMP processing, we treated HT1080 cells with a synthetic furin inhibitor and monitored their ability to activate pro-MMP-2 as well as their invasive potential. Our results demonstrated that the furin inhibitor decreased pro-MT1-MMP processing as well as pro-MMP-2 activation and cell invasiveness. Therefore, our data bring further evidence that furin is a key factor in the maturation of MMPs associated with the invasive and metastatic potential of tumor cells. [less ▲]

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See detailAssay of Matrix Metalloproteinases Types 1, 2, 3 and 9 in Breast Cancer
Remacle, A. G.; Noël, Agnès ULg; Duggan, C. et al

in British Journal of Cancer (1998), 77(6), 926-31

Matrix metalloproteinases (MMPs) are zinc dependent endopeptidases implicated in cancer invasion and metastasis. Gelatin zymography was performed on 84 human breast carcinomas and seven normal breast ... [more ▼]

Matrix metalloproteinases (MMPs) are zinc dependent endopeptidases implicated in cancer invasion and metastasis. Gelatin zymography was performed on 84 human breast carcinomas and seven normal breast tissues. The precursor form of MMP-2 (72 kDa) was found in 11 (12%) samples, while its two activated forms, i.e. 62 kDa and 59 kDa, were found in three (6%) and 34 (40%) samples respectively. In contrast to MMP-2, most of the samples (52%) contained MMP-9 in its precursor form. Using ELISA, MMP-1 levels were found in 12% of the samples while MMP-3 levels were found in only 2% of the samples. Levels of MMP-2, -3 and -9 correlated inversely with numbers of nodal metastases. Neither MMP-2 nor -9 levels were significantly related to patient outcome. However, patients with high levels of a 50-kDa gelatinase band after zymography had a significantly better survival than patients with low levels. This species was never observed in normal breast tissue. [less ▲]

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