References of "Noël, Agnès"
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See detailVascular endothelial growth factor expression correlates with matrix metalloproteinases MT1-MMP, MMP-2 and MMP-9 in human glioblastomas.
Munaut, Carine ULg; Noël, Agnès ULg; Hougrand, Olivier ULg et al

in International Journal of Cancer = Journal International du Cancer (2003), 106(6), 848-55

Vascular endothelial growth factor (VEGF) is the major endothelial mitogen in central nervous system neoplasms and it is expressed in 64-95% of glioblastomas (GBMs). Tumour cells are the main source of ... [more ▼]

Vascular endothelial growth factor (VEGF) is the major endothelial mitogen in central nervous system neoplasms and it is expressed in 64-95% of glioblastomas (GBMs). Tumour cells are the main source of VEGF in GBMs whereas VEGF receptors (VEGFR-1, its soluble form sVEGFR-1, VEGFR-2 and neuropilin-1) are expressed predominantly by endothelial cells. Infiltrating tumour cells and newly-formed capillaries progress through the extracellular matrix by local proteolysis involving matrix metalloproteinases (MMPs). Recent studies have shown that VEGF expression and bioavailability can be modulated by MMPs. We reported previously that the expression of MT1-MMP in human breast cancer cells was associated with an enhanced VEGF expression. We used quantitative RT-PCR, Western blot, gelatin zymography and immunohistochemistry to study the expression of VEGF, VEGFR-1, VEGFR-2, sVEGFR-1, neuropilin-1, MT1-MMP, MMP-2, MMP-9 and TIMP-2 in 20 human GBMs and 5 normal brains. The expression of these MMPs was markedly increased in most GBMs with excellent correlation between mRNA and protein levels; activated forms of MMP-2 and MMP-9 were present in 8/18 and 7/18 of GBMs. A majority of GBMs (17/20) also expressed high levels of VEGF, as previously reported, with strong correlation between VEGF and MT1-MMP gene expression levels, and double immunostaining showed that VEGF and MT1-MMP peptides co-localize in tumour and endothelial cells. Our results suggest that the interplay between metalloproteinases and VEGF previously described in experimental tumours may also be operative in human GBMs. Because of its dual ability to activate MMP-2 and to up-regulate VEGF, MT1-MMP might be of central importance in the growth of GBMs and represent an interesting target for anti-cancer treatments. [less ▲]

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See detailEstrogens reduce the expression of YKL-40 in the retina: Implications for eye and joint diseases
Rakic, Jean-Marie ULg; Lambert, Vincent ULg; Deprez, Manuel ULg et al

in Investigative Ophthalmology & Visual Science (2003), 44(4), 1740-1746

PURPOSE. To identify modifications in the gene expression profile of the ocular posterior segment in ovariectomized (OVX) mice with and without substitutive estradiol therapy and to select differentially ... [more ▼]

PURPOSE. To identify modifications in the gene expression profile of the ocular posterior segment in ovariectomized (OVX) mice with and without substitutive estradiol therapy and to select differentially expressed genes that could be relevant to the natural history of human age-related macular degeneration (AMD). METHODS. Chorioretinal tissues from two groups of 25 treated and untreated OVX mice were analyzed by using cDNA array technology. The expression level of selected genes was confirmed in triplicate by RT-PCR and related to the estrogenic status of the animals. Expression of the YKL-40 gene was further investigated in intact or diseased human retinas and in a murine model of experimental choroidal neovascularization (CNV), using laser pressure catapulting. RESULTS. Of the approximately, 10,000 genes screened, only YKL-40 expression was significantly downregulated by 17-beta-estradiol. YKL-40 was expressed in intact human neural retina and in the RPE. The expression of YKL-40 was upregulated in experimental CNV and in neovascular membranes extracted from patients affected by the exudative form of AMD. CONCLUSIONS. These observations indicate that YKL-40 expression in the retina is modulated by serum levels of estradiol. This protein could be relevant to the development of AMD and is also a new mediator to take into account when evaluating the broad consequences of hormonal replacement therapy. [less ▲]

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See detailMMP-2 and MMP-9 synergize in promoting choroidal neovascularization
Lambert, Vincent ULg; Wielockx, B.; Munaut, Carine ULg et al

in FASEB Journal (2003), 17(15), 2290-2292

Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but ... [more ▼]

Matrix metalloproteinase 2 (MMP-2) and MMP-9 are increased in human choroidal neovascularization (CNV) occurring during the exudative most aggressive form of age-related macular degeneration (AMD), but their precise role and potential interactions remain unclear. To address the question of MMP-2 and MMP-9 functions, mice deficient in the expression of MMP-2 (MMP-2 KO), MMP-9 (MMP-9 KO), and both MMP-2 and MMP-9 (MMP-2,9 KO) with their corresponding wild-type mice (WT) underwent CNV induction by laser-induced rupture of the Bruch's membrane. Both the incidence and the severity of CNV were strongly attenuated in double deficient compared with single gene deficient mice or corresponding WT controls. The reduced neovascularization was accompanied by fibrinogen/fibrin accumulation. Furthermore, overexpression of the endogenous MMP inhibitors TIMP-1 or TIMP-2 (delivered by adenoviral vectors) in WT mice or daily injection of a synthetic and gelatinase selective MMP inhibitor (Ro 26-2853) significantly decreased the pathological reaction. These findings suggest that MMP-2 and MMP-9 may cooperate in the development of AMD and that their selective inhibition represents an alternative strategy for the treatment of choroidal neovascularization. [less ▲]

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See detailQuantification of angiogenesis on the rat aortic ring assay.
Blacher, Silvia ULg; Devy, L.; Noël, Agnès ULg et al

in Image Analysis and Stereology (2003), 22

Image analysis is used to quantify angiogenesis on the rat aortic ring model. This technique allows to determine: (1) the aortic ring area and factor shape; (2) the number of microvessels, the total ... [more ▼]

Image analysis is used to quantify angiogenesis on the rat aortic ring model. This technique allows to determine: (1) the aortic ring area and factor shape; (2) the number of microvessels, the total number of branching, the maximal microvessel length and the number of microvessels in function of the distance to the aortic ring; (3) the total number of isolated fibroblast-like cells and the number of fibroblast-like cells in function of the distance to the aortic ring. We show that this method is suitable to quantify spontaneous angiogenesis as well as to analyse a complex microvascular network induced by vascular endothelial growth factor (VEGF). [less ▲]

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See detailPresence of alpha and beta estrogen receptors in human gingiva
Fraikin, N.; Munaut, Carine ULg; Lambert, Vincent ULg et al

in Journal of Dental Research (2002, December), 81(Sp. Iss. B), 239-239

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See detailEffects of 6-substituted 2-oxo-2H-1-benzopyran-3-carbowylic acide derivatives on cellular invasion in vitro
Kempen, I.; Frankenne, F.; Noël, Agnès ULg et al

Poster (2002, November 15)

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See detailMatrix metalloproteinase-9, but not tissue inhibitor of matrix metalloproteinase-1, increases in the sputum from allergic asthmatic patients after allergen challenge
Cataldo, Didier ULg; Bettiol, J.; Noël, Agnès ULg et al

in CHEST (2002), 122(5), 1553-1559

Objective: The aim of the study was to determine whether allergen inhalation modulates the levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metallloproteinase (TIMP)-1 in the ... [more ▼]

Objective: The aim of the study was to determine whether allergen inhalation modulates the levels of matrix metalloproteinase (MMP)-9 and tissue inhibitor of matrix metallloproteinase (TIMP)-1 in the induced sputum recovered from patients during a late-phase reaction. Method: Eight allergic asthma patients and five healthy control subjects inhaled a dose of Dermatophagoides pteronyssinus extract corresponding to the provocative concentration of the allergen causing a 20% fall in FEV1 and saline solution. Lung function was carefully monitored for 6 h, and an induced sputum test was performed at 6 h after sham challenge or allergen challenge. The total and differential cell counts were analyzed, and the levels of MMP-9 (by enzyme-linked immunosorbent assay [ELISA] and zymography), TIMP-1 (by ELISA), and albumin (by rocket immunoelectrophoresis) were measured. Results: The sputum eosinophil counts (p < 0.01) and MMP-9 levels (p < 0.05) increased significantly in atopic asthma patients after undergoing the allergen challenge but did not in the control subjects. By contrast, TIMP-1 and albumin levels were not significantly increased in any group. MMP-9 levels, measured after the allergen challenge in asthmatic patients, were significantly correlated with FEV1 variations after allergen inhalation (r = 0.51; p < 0.05) and with the sputum neutrophil percentage (r = 0.71; p < 0.01). Conclusion: The levels of MMP-9, but not TIMP-1, increase after inhaled allergen challenge in the sputum of allergic asthmatic patients. This protease increase may lead to a transient imbalance between MMP-9 and TIMP-1 favoring proteolytic extracellular matrix degradation. [less ▲]

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See detailRole of endocrine status and cell type in adhesion of human endometrial cells to the peritoneum in nude mice
Beliard, Aude ULg; Noël, Agnès ULg; Goffin, Frédéric ULg et al

in Fertility and Sterility (2002), 78(5), 973-978

Objective: To investigate the role of different cellular types (epithelial and stromal endometrial cells and peritoneal cells) in the ectopic implantation of endometrium and to evaluate the importance of ... [more ▼]

Objective: To investigate the role of different cellular types (epithelial and stromal endometrial cells and peritoneal cells) in the ectopic implantation of endometrium and to evaluate the importance of endocrine environment on the adhesion of endometrial cells to the peritoneum. Design: Experimental prospective study. Setting: University hospital, department of cell biology. Animal(s): One hundred one nude mice. Intervention(s): Monolayer culture of human epithelial and stromal endometrial cells obtained from patients undergoing hysterectomy or laparoscopy for benign disease. Intraperitoneal injection of cells into nude mice. Main Outcome Measure(s): Two weeks after cell injection, adhesion of endometrial cells was evaluated by histological and immunohistochemical examination. Result(s): Mixed cultures of stromal and epithelial cells, but not purified epithelial or stromal cells alone, adhered to the mouse peritoneum and led to endometriotic-like nodules. Pretreatment of cells with estrogen alone or with estrogen and progestin resulted in a higher percentage of animals developing endometriotic-like nodules, whereas treatment with progestin alone did not affect endometriotic implantation. Conclusion(s): Our data indicate that the success of endometrial cell implantation is dependent on the cooperativeness between stromal and epithelial endometrial cells, as well as on the endocrine environment of endometrial cells, but not that of recipient animals. The results emphasize the role of both endometrial cell types for ectopic implantation. (C) 2002 by American Society for Reproductive Medicine. [less ▲]

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See detailMouse Aortic Ring Assay: A New Approach of the Molecular Genetics of Angiogenesis
Masson, Véronique ULg; Devy, L.; Grignet-Debrus, Christine ULg et al

in Biological Procedures Online (2002), 4

Angiogenesis, a key step in many physiological and pathological processes, involves proteolysis of the extracellular matrix. To study the role of two enzymatic families, serine-proteases and matrix ... [more ▼]

Angiogenesis, a key step in many physiological and pathological processes, involves proteolysis of the extracellular matrix. To study the role of two enzymatic families, serine-proteases and matrix metalloproteases in angiogenesis, we have adapted to the mouse, the aortic ring assay initially developed in the rat. The use of deficient mice allowed us to demonstrate that PAI-1 is essential for angiogenesis while the absence of an MMP, MMP-11, did not affect vessel sprouting. We report here that this model is attractive to elucidate the cellular and molecular mechanisms of angiogenesis, to identify, characterise or screen "pro- or anti-angiogenic agents that could be used for the treatment of angiogenesis-dependent diseases. Approaches include using recombinant proteins, synthetic molecules and adenovirus-mediated gene transfer. [less ▲]

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See detailMatrix metalloproteinase-9 contributes to choroidal neovascularization
Lambert, Vincent ULg; Munaut, Carine ULg; Jost, M. et al

in American Journal of Pathology (2002), 161(4), 1247-1253

Age-related macular degeneration (AMD) is the primary cause of irreversible photoreceptors loss in adult patients and current therapies are limited. Increased levels of matrix metalloproteinases (MMPs ... [more ▼]

Age-related macular degeneration (AMD) is the primary cause of irreversible photoreceptors loss in adult patients and current therapies are limited. Increased levels of matrix metalloproteinases (MMPs) have been documented in neovascularization of severe ocular pathologies such as AMD and proliferative diabetic retinopathy. We report here that MMP-9 (gelatinase B) expression is induced and temporally regulated in the course of experimental choroidal neovascularization. We used transgenic mice expressing beta-galactosidase reporter gene under the dependence of MMP-9 promoter and RT-PCR analysis on choroidal neovascular structures microdissected from serial sections by laser pressure catapulting to show that MMP-9 expression is up-regulated concomitantly with the appearance of inflammatory cells in the subretinal lesion. In mice deficient in MMP-9 expression the development of choroidal neovascularization induced by laser photocoagulation still occurred, but at a reduced level. [less ▲]

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See detailTumor cell and stromal cell interactions during breast cancer progression
Noël, Agnès ULg; Foidart, Jean-Michel ULg

in Journal of Molecular Medicine (2002, September)

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See detailHuman breast adenocarcinoma cell lines promote angiogenesis by providing cells with uPA-PAI-1 and by enhancing their expression
Bajou, Khalid ULg; Lewalle, J. M.; Martinez, C. R. et al

in International Journal of Cancer = Journal International du Cancer (2002), 100(5), 501-506

During angiogenesis, endothelial cells use uPA and PAI-I to migrate and degrade the basement membrane surrounding capillary blood vessels. Invasive tumor cells produce a large amount of uPA that could ... [more ▼]

During angiogenesis, endothelial cells use uPA and PAI-I to migrate and degrade the basement membrane surrounding capillary blood vessels. Invasive tumor cells produce a large amount of uPA that could bind uPAR present at the endothelial cell surface to facilitate their invasion. To verify this hypothesis, endothelial cells were incubated with conditioned medium (CM) from two breast cancer cell lines (MCF7 and MDA MB 231 cells). Within a short incubation period (30 min) with both CM, an increase of uPA, PAW and uPA-PAI-I complex was detected in endothelial cell layer as assessed by casein zymography, ELISA and uPA immunostaining. The extent of this enhancement was related to the levels of uPA secreted by tumor cells (high in MDA MB 231 cells and low in MCF7 cells). After 2 hr of incubation, the CM from both tumor cells upregulated uPA and PAI-I mRNA levels in endothelial cells in a time-dependent manner. The uPA increase in the cell layer could not be attributable to an increase of uPAR level. Only the CM from highly invasive MDA MB 231 cells increased the angiogenic morphotype of endothelial cells assessed in a collagen gel. A single addition of amino-terminal fragment of uPA (ATF) was able to abolish the angiogenic effect induced by MDA MB 231 cell CM. Our data demonstrate that the interactions occurring between breast tumor cells and endothelial cells can modulate tumor angiogenesis at least by two mechanisms: an increase of uPA and PAI-I cell surface-binding and of their expression by endothelial cells. (C) 2002 Wiley-Liss, Inc. [less ▲]

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See detailMatrix metalloproteinase-9 deficiency impairs cellular infiltration and bronchial hyperresponsiveness during allergen-induced airway inflammation
Cataldo, Didier ULg; Tournoy, K. G.; Vermaelen, K. et al

in American Journal of Pathology (2002), 161(2), 491-498

We investigated the specific role of matrix metalloproteinase (MMP)-9 in allergic asthma using a murine model of allergen-induced airway inflammation and airway hyperresponsiveness in MMP-9(-/-) mice and ... [more ▼]

We investigated the specific role of matrix metalloproteinase (MMP)-9 in allergic asthma using a murine model of allergen-induced airway inflammation and airway hyperresponsiveness in MMP-9(-/-) mice and their corresponding wild-type (WT) littermates. After a single intraperitoneal sensitization to ovalbumin, the mice were exposed daily either to ovalbumin (1%) or phosphate-buffered saline aerosols from days 14 to 21. Significantly less peribronchial mononuclear cell infiltration of the airways and less lymphocytes in the bronchoalveolar lavage fluid were detected in challenged MMP-9(-/-) as compared to WT mice. In contrast, comparable numbers of bronchoalveolar lavage fluid eosinophils; were observed in both genotypes. After allergen exposure, the WT mice developed a significant airway hyperresponsiveness to carbachol whereas the MMP-9(-/-) mice failed to do so. Allergen exposure induced an increase of MMP-9-related gelatinolytic activity in WT lung extracts. Quantitative reverse transcriptase-polymerase chain reaction showed increased mRNA levels of MMP-12, MMP-14, and urokinase-type plasminogen activator after allergen exposure in the lung extracts of WT mice but not in MMP-9-deficient mice. in contrast, the expression of tissue inhibitor of metalloproteinases-1 was enhanced after allergen exposure in both groups. We conclude that MMP-9 plays a key role in the development of airway inflammation after allergenexposure. [less ▲]

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See detailMT1-MMP expression promotes tumor growth and angiogenesis through an up-regulation of vascular endothelial growth factor expression
Sounni, Nor Eddine ULg; Devy, L.; Hajitou, A. et al

in FASEB Journal (2002), 16(6), 555-564

Membrane type 1 metalloprotease (MT1-MMP) is a transmembrane metalloprotease that plays a major role in the extracellular matrix remodeling, directly by degrading several of its components and indirectly ... [more ▼]

Membrane type 1 metalloprotease (MT1-MMP) is a transmembrane metalloprotease that plays a major role in the extracellular matrix remodeling, directly by degrading several of its components and indirectly by activating pro-MMP2. We investigated the effects of MT1-MMP overexpression on in vitro and in vivo properties of human breast adenocarcinoma MCF7 cells, which do not express MT1-MMP or MMP-2. MT1-MMP and MMP-2 cDNAs were either transfected alone or cotransfected. All clones overexpressing MT1-MMP 1) were able to activate endogenous or exogenous pro-MMP-2, 2) displayed an enhanced in vitro invasiveness through matrigel-coated filters independent of MMP-2 transfection, 3) induced the rapid development of highly vascularized tumors when injected subcutaneously in nude mice, and 4) promoted blood vessels sprouting in the rat aortic ring assay. These effects were observed in all clones overexpressing MT1-MMP regardless of MMP-2 expression levels, suggesting that the production of MMP-2 by tumor cells themselves does not play a critical role in these events. The angiogenic phenotype of MT1-MMP-producing cells was associated with an up-regulation of VEGF expression. These results emphasize the importance of MT1-MMP during tumor angiogenesis and open new opportunities for the development of anti-angiogenic strategies combining inhibitors of MT1-MMP and VEGF antagonists. [less ▲]

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See detailExpression of membrane type 1 matrix metalloproteinase (MT1-MMP) in A2058 melanoma cells is associated with MMP-2 activation and increased tumor growth and vascularization
Sounni, Nor Eddine ULg; Baramova, Eugénia; Munaut, Carine ULg et al

in International Journal of Cancer = Journal International du Cancer (2002), 98(1), 23-28

Membrane-type metalloproteinase-1 (MT1-MMP) is a transmembrane metalloproteinase overexpressed in tumors, which plays a major role in the first step of pro-MMP-2 activation, leading to the generation of ... [more ▼]

Membrane-type metalloproteinase-1 (MT1-MMP) is a transmembrane metalloproteinase overexpressed in tumors, which plays a major role in the first step of pro-MMP-2 activation, leading to the generation of an intermediate 62 kDa species. The second step of MMP-2 activation that yields to the mature form is less understood and could involve an autocatalytic process and/or the activity of the plasminogen/plasmin system. Human melanoma A2058 cells, which express MMP-2 only in its pro-form, were used to determine the role of MT1-MMP during pericellular proteolysis and tumor progression. The induction of MT1-MMP overexpression by MT1-MMP cDNA transfection initiated the first step of MMP-2 activation. We provide evidence that a cooperation between the plasminogen/plasmin system and MT1-MMP endowed the cells with the ability to fully activate MMP-2 and with enhanced invasive properties in vitro. When injected subcutaneously in nude mice, MT1-MMP expressing clones induced rapid tumor growth and high tumor vascularization, while the control clones were poorly or not tumorigenic. Our data provide the first demonstration, in an experimental model, that MT1-MMP expression by tumor cells promotes tumor vascularization. [less ▲]

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See detailThe pro- or antiangiogenic effect of plasminogen activator inhibitor 1 is dose dependent
Devy, L.; Blacher, Silvia ULg; Grignet-Debrus, Christine ULg et al

in FASEB Journal (2002), 16(2), 147-54

Plasminogen activator inhibitor 1 (PAI-1) is believed to control proteolytic activity and cell migration during angiogenesis. We previously demonstrated in vivo that this inhibitor is necessary for ... [more ▼]

Plasminogen activator inhibitor 1 (PAI-1) is believed to control proteolytic activity and cell migration during angiogenesis. We previously demonstrated in vivo that this inhibitor is necessary for optimal tumor invasion and vascularization. We also showed that PAI-1 angiogenic activity is associated with its control of plasminogen activation but not with the regulation of cell-matrix interaction. To dissect the role of the various components of the plasminogen activation system during angiogenesis, we have adapted the aortic ring assay to use vessels from gene-inactivated mice. The single deficiency of tPA, uPA, or uPAR, as well as combined deficiencies of uPA and tPA, did not dramatically affect microvessel formation. Deficiency of plasminogen delayed microvessel outgrowth. Lack of PAI-1 completely abolished angiogenesis, demonstrating its importance in the control of plasmin-mediated proteolysis. Microvessel outgrowth from PAI-1(-/-) aortic rings could be restored by adding exogenous PAI-1 (wild-type serum or purified recombinant PAI-1). Addition of recombinant PAI-1 led to a bell-shaped angiogenic response clearly showing that PAI-1 is proangiogenic at physiological concentrations and antiangiogenic at higher levels. Using specific PAI-1 mutants, we could demonstrate that PAI-1 promotes angiogenesis at physiological (nanomolar) concentrations through its antiproteolytic activity rather than by interacting with vitronectin. [less ▲]

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See detailMatrix and serine protease expression during leukemic cell differentiation induced by aclacinomycin and all-trans-retinoic acid
Devy, L.; Hollender, P.; Munaut, Carine ULg et al

in Biochemical Pharmacology (2002), 63(2), 179-189

In myeloid leukemia, immature leukemic cells are able to egress into peripheral blood to infiltrate extra-medullary organs. We therefore analyzed the migrating and invasive potential of human HL-60 and ... [more ▼]

In myeloid leukemia, immature leukemic cells are able to egress into peripheral blood to infiltrate extra-medullary organs. We therefore analyzed the migrating and invasive potential of human HL-60 and NB4 cell lines, representative of acute myelogenous leukemia, their ability to express matrix metalloproteases (MMPs), tissue inhibitors of metalloproteases (TIMPs) and urokinase plasminogen activator (uPA) in response to differentiating agents. Granulocytic differentiation by all-trans-retinoic acid (ATRA) and aclacinomycin (ACLA) strongly increased HL-60 and NB4 cell migration and invasion. At mRNA and protein levels, these cell lines produced significant amounts of MMP-9 (HL-60 < NB4). Granulocytic differentiation by ACLA increased both pro and active forms of MMP-9 whereas ATRA decreased them and stimulated uPA mRNAs. TIMP-1, the physiological MMP inhibitor, increased during granulocytic differentiation whereas TIMP-2 did not significantly vary. Use of Batimastat and aprotinin suggests that ATRA was active by modulating the uPA system while ACLA interfered with MMP expression. In conclusion, our data demonstrate that HL-60 and NB4 cells express MMPs and uPA which are differentially regulated by the differentiating agents ATRA and ACLA and suggest the clinical usefulness of MMPs and serine protease inhibitors in the prophylaxis and treatment of the ATRA syndrome. (C) 2002 Elsevier Science Inc. All rights reserved. [less ▲]

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See detailStimulation of matrix metalloproteinase-9 expression in human fibrosarcoma cells by synthetic matrix metalloproteinase inhibitors.
Maquoi, Erik ULg; Munaut, Carine ULg; Colige, Alain ULg et al

in Experimental Cell Research (2002), 275(1), 110-21

Enhanced expression and activation of matrix metalloproteinase-2 (MMP-2) and MMP-9 have been associated with tumor progression, invasion, and metastasis. The use of synthetic MMP inhibitors to block the ... [more ▼]

Enhanced expression and activation of matrix metalloproteinase-2 (MMP-2) and MMP-9 have been associated with tumor progression, invasion, and metastasis. The use of synthetic MMP inhibitors to block the proteolytic activity of these enzymes recently emerged as a potential therapeutic tool to treat cancer. In this study, we report that GI129471, a synthetic broad-spectrum MMP inhibitor, efficiently reduced the in vitro invasiveness of HT1080 cells through type IV collagen, a major component of basement membranes. This reduced invasion was paralleled by a complete inhibition of pro-MMP-2 activation; however, GI129471 strongly increased the amount of secreted pro-MMP-9, which could be subsequently activated through a plasminogen-dependent mechanism. Quantitative RT-PCR and northern blot analysis revealed that GI129471 specifically increased the MMP-9 mRNA steady-state level. Moreover, transient transfection of HT1080 cells with beta-galactosidase reporter vectors containing different lengths of the 5'-flanking region of the MMP-9 gene revealed an upregulation of the transcriptional activity of the corresponding promoter. Well-known modulators of MMP-9 expression such as Il-1beta and TNF-alpha were not involved in this upregulation. These findings emphasize the complexity of the regulation of MMP expression and the requirement for a detailed characterization of the potential adverse side effects associated with the use of broad-spectrum MMPIs. [less ▲]

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