References of "Noël, Agnès"
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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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See detailAttempt to enhance the suicide gene therapy agaisnt breast cancer cells by using connexin 43 gene
Grignet, Christine ULg; Hajitou, Amin; Noël, Agnès ULg et al

in Acta Clinica Belgica (2002), 57(2), 99

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See detailMurine 5T multiple myeloma cells induce angiogenesis in vitro and in vivo
Van Valckenborgh, E.; De Raeve, H.; Devy, L. et al

in British Journal of Cancer (2002), 86(5), 796-802

Multiple myeloma is a B cell malignancy. Recently, it has been demonstrated that bone marrow samples of patients with multiple myeloma display an enhanced angiogenesis. The mechanisms involved seem to be ... [more ▼]

Multiple myeloma is a B cell malignancy. Recently, it has been demonstrated that bone marrow samples of patients with multiple myeloma display an enhanced angiogenesis. The mechanisms involved seem to be multiple and complex. We here demonstrate that the murine 5T multiple myeloma models are able to induce angiogenesis in vitro by using a rat aortic ring assay and in vivo by determining the microvessel density. The rat aortic rings cultured in 5T multiple myeloma conditioned medium exhibit a higher number of longer and more branched microvessels than the rings cultured in control medium. In bone marrow samples from 5T multiple myeloma diseased mice, a statistically significant increase of the microvessel density was observed when compared to bone marrow samples from age-matched controls. The angiogenic phenotype of both 5T multiple myeloma cells could be related, at least in part, to their capacity to produce vascular endothelial growth factor. These data clearly demonstrate that the 5T multiple myeloma models are good models to study angiogenesis in multiple myeloma and will allow to unravel the mechanisms of neovascularisation, as well as to test new putative inhibitors of angiogenesis. [less ▲]

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See detailThe antitumoral effect of endostatin and angiostatin is associated with a down-regulation of vascular endothelial growth factor expression in tumor cells
Hajitou, Amin; Grignet, Christine ULg; Devy, L. et al

in FASEB Journal (2002), 16

Endostatin and angiostatin are known as tumor-derived angiogenesis inhibitors, but their mechanisms of action are not yet completely defined. We report here that endostatin and angiostatin, delivered by ... [more ▼]

Endostatin and angiostatin are known as tumor-derived angiogenesis inhibitors, but their mechanisms of action are not yet completely defined. We report here that endostatin and angiostatin, delivered by adenoviral vectors, reduced in vitro the neovessel formation in the mouse aortic ring assay by 85 and 40%, respectively. We also demonstrated in vivo that both endostatin and angiostatin inhibited local invasion and tumor vascularization of transplanted murine malignant keratinocytes, and reduced by 50 and 90% the development of highly vascularized murine mammary tumors. This inhibition of tumor growth was associated with a reduction of tumor vascularization. Expression analysis of vascular endothelial growth factor (VEGF) carried out in the mouse aortic ring model revealed a 3- to 10-fold down-regulation of VEGF mRNA expression in endostatin-treated rings. A similar down-regulation of VEGF expression at both mRNA and protein levels was also observed in the two in vivo cancer models after treatment with each angiogenesis inhibitor. This suggests that endostatin and angiostatin effects may be mediated, at least in part, by their ability to down-regulate VEGF expression within the tumor. This work provides evidence that endostatin and angiostatin act on tumor cells themselves. [less ▲]

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See detailUpregulation of matrix metalloproteinase-9 in murine 5T33 multiple myeloma cells by interaction with bone marrow endothelial cells
Van Valckenborgh, E.; Bakkus, M.; Munaut, Carine ULg et al

in International Journal of Cancer = Journal International du Cancer (2002), 101

MM is a B-cell malignancy mainly characterized by monoclonal expansion of plasma cells in the BM, presence of paraprotein in serum and occurrence of osteolytic bone lesions. MMPs are a family of ... [more ▼]

MM is a B-cell malignancy mainly characterized by monoclonal expansion of plasma cells in the BM, presence of paraprotein in serum and occurrence of osteolytic bone lesions. MMPs are a family of proteolytic enzymes that can contribute to cancer growth, invasion, angiogenesis, bone degradation and other processes important in the pathogenesis of MM. We investigated MMP-9 production in the 5T33MM murine model. Expression of MMP-9 protein in supernatant and cell extracts was analyzed by gelatin zymography. The in vitro, stroma-independent variant 5T33MMvt showed no protein expression of MMP-9 in contrast to in vivo growing MM cells, 5T33MMvv. However, when 5T33MMvt cells were injected into naive mice and isolated after tumor take (5T33MMvt-vv), they secreted a significant amount of MMP-9. These results were confirmed by specific staining of cytospins with an anti-MMP-9 antibody. The MMP-9 production by 5T33MMvt-vv cells disappeared when the cells were recultured in vitro. These data demonstrated that upregulation of MMP-9 occurs in vivo and that this process is dependent on the microenvironment. Cocultures of 5T33MMvt cells with STR10 BMECs induced MMP-9 in MM cells, as determined by both gelatin zymography and flow-cytometric analysis. In conclusion, our results demonstrate that MMP-9 production by MM cells is upregulated in vivo by the interaction of MM cells with BMECs. [less ▲]

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See detailInduction of Sparc by Vegf in Human Vascular Endothelial Cells
Kato, Y.; Lewalle, J. M.; Baba, Y. et al

in Biochemical and Biophysical Research Communications (2001), 287(2), 422-6

SPARC/osteonectin/BM-40 is a matricellular protein that is thought to be involved in angiogenesis and endothelial barrier function. Previously, we have detected high levels of SPARC expression in ... [more ▼]

SPARC/osteonectin/BM-40 is a matricellular protein that is thought to be involved in angiogenesis and endothelial barrier function. Previously, we have detected high levels of SPARC expression in endothelial cells (ECs) adjacent to carcinomas of kidney and tongue. Although SPARC-derived peptide showed an angiogenic effect, intact SPARC itself inhibited the mitogenic activity of vascular endothelial growth factor (VEGF) for ECs by the inhibiting phosphorylation of flt-1 (VEGF receptor 1) and subsequent ERK activation. Thus, the role of SPARC in tumor angiogenesis, stimulation or inhibition, is still unclear. To clarify the role of SPARC in tumor growth and progression, we determined the effect of VEGF on the expression of SPARC in human microvascular EC line, HMEC-1, and human umbilical vein ECs. VEGF increased the levels of SPARC protein and steady-state levels of SPARC mRNA in serum-starved HMEC-1 cells. Inhibitors (SB202190 and SB203580) of p38, a mitogen-activated protein (MAP) kinase, attenuated VEGF-stimulated SPARC production in ECs. Since intact SPARC inhibits phosphorylation ERK MAP kinase in VEGF signaling, it was suggested that SPARC plays a dual role in the VEGF functions, tumor angiogenesis, and extravasation of tumors mediated by the increased permeability of endothelial barrier function. [less ▲]

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See detailEffects on cellular invasion of two synthetic coumarins
Kempen, I.; Papapostolou, D.; Pochet, L. et al

Conference (2001, May)

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See detailEffects on cellular invasion of 6-(acetoxymethyl)-2-oxo-2H-1-benzopyran-3-carboxylic acid derivatives
Kempen, I.; Pochet, L.; Papapostolu, D. et al

Poster (2001, April 21)

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See detailDown-Regulation of Vascular Endothelial Growth Factor by Tissue Inhibitor of Metalloproteinase-2: Effect on in Vivo Mammary Tumor Growth and Angiogenesis
Hajitou, Amin; Sounni, Nor Eddine ULg; Devy, Laetitia et al

in Cancer Research (2001), 61(8), 3450-7

The tissue inhibitor of metalloproteinases-2 (TIMP-2) has at least two independent functions, i.e., regulation of matrix metalloproteinases and growth promoting activity. We investigated the effects of ... [more ▼]

The tissue inhibitor of metalloproteinases-2 (TIMP-2) has at least two independent functions, i.e., regulation of matrix metalloproteinases and growth promoting activity. We investigated the effects of TIMP-2 overexpression, induced by retroviral mediated gene transfer, on the in vivo development of mammary tumors in syngeneic mice inoculated with EF43.fgf-4 cells. The EF43.fgf-4 cells established by stably infecting the normal mouse mammary EF43 cells with a retroviral expression vector for the fgf-4 oncogene, are highly tumorigenic and overproduce vascular endothelial growth factor (VEGF). Despite a promotion of the in vitro growth rate of EF43.fgf-4 cells overexpressing timp-2, the in vivo tumor growth was delayed. At day 17 post-cell injection, the volume of tumor derived from TIMP-2-overexpressing cells was reduced by 80% as compared with that obtained with control cells. Overexpression of TIMP-2 was associated with a down-regulation of VEGF expression in vitro and in vivo, a reduction of vessel size, density, and blood supply in the induced tumors. In addition, TIMP-2 completely inhibited the angiogenic activity of EF43.fgf-4 cell-conditioned medium in vitro using a rat aortic ring model. Our findings suggest that overexpression of TIMP-2 delays growth and angiogenesis of mammary carcinoma in vivo and that down-regulation of VEGF expression may play an important role in this TIMP-2-mediated antitumoral and antiangiogenic effects. Finally the in vivo delivery of TIMP-2, as assessed by i.v. injection of recombinant adenoviruses vectors, significantly reduced the growth of the EF43.fgf-4-induced tumors. This effect of TIMP-2 was shown to be equally comparable with that of angiostatin, a known potent inhibitor of angiogenesis. [less ▲]

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See detailNew Functions of Stromal Proteases and Their Inhibitors in Tumor Progression
Noël, Agnès ULg; Albert, V.; Bajou, Khalid ULg et al

in Surgical Oncology Clinics of North America (2001), 10(2), 417-32

Acquisition of invasive metastatic potential through protease expression is a key event in tumor progression. In carcinomas, the production of metalloproteinases and serine proteinases is regulated by a ... [more ▼]

Acquisition of invasive metastatic potential through protease expression is a key event in tumor progression. In carcinomas, the production of metalloproteinases and serine proteinases is regulated by a cross talk between stromal cells and cancer cells. Paradoxically, high rather than low levels of their inhibitors predict poor survival of patients suffering from a variety of cancers. Recent observations suggest a much more complex role of these inhibitors in tumor progression than expected initially. [less ▲]

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See detailInfluence of Plasminogen Activator Inhibitor Type 1 on Choroidal Neovascularization
Lambert, Vincent ULg; Munaut, Carine ULg; Frankenne, F. et al

in FASEB Journal (2001), 15(6), 1021-7

High levels of the plasminogen activators, but also their inhibitor, plasminogen activator inhibitor 1 (PAI-1), have been documented in neovascularization of severe ocular pathologies such as diabetic ... [more ▼]

High levels of the plasminogen activators, but also their inhibitor, plasminogen activator inhibitor 1 (PAI-1), have been documented in neovascularization of severe ocular pathologies such as diabetic retinopathy or age-related macular degeneration (AMD). AMD is the primary cause of irreversible photoreceptors loss, and current therapies are limited. PAI-1 has recently been shown to be essential for tumoral angiogenesis. We report here that deficient PAI-1 expression in mice prevented the development of subretinal choroidal angiogenesis induced by laser photocoagulation. When systemic and local PAI-1 expression was achieved by intravenous injection of a replication-defective adenoviral vector expressing human PAI-1 cDNA, the wild-type pattern of choroidal angiogenesis was restored. These observations demonstrate the proangiogenic activity of PAI-1 not only in tumoral models, but also in choroidal experimental neovascularization sharing similarities with human AMD. They identify therefore PAI-1 as a potential target for therapeutic ocular anti-angiogenic strategies. [less ▲]

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See detailThe Plasminogen Activator Inhibitor PAI-1 Controls in Vivo Tumor Vascularization by Interaction with Proteases, Not Vitronectin. Implications for Antiangiogenic Strategies
Bajou, Khalid ULg; Masson, Véronique ULg; Gerard, R. D. et al

in Journal of Cell Biology (2001), 152(4), 777-84

The plasminogen (Plg)/plasminogen activator (PA) system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumor cell migration. Consequently, urokinase ... [more ▼]

The plasminogen (Plg)/plasminogen activator (PA) system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumor cell migration. Consequently, urokinase-type PA (uPA)/plasmin antagonists are currently being developed for suppression of tumor growth and angiogenesis. Paradoxically, however, high levels of PA inhibitor 1 (PAI-1) are predictive of a poor prognosis for survival of patients with cancer. We demonstrated previously that PAI-1 promoted tumor angiogenesis, but by an unresolved mechanism. We anticipated that PAI-1 facilitated endothelial cell migration via its known interaction with vitronectin (VN) and integrins. However, using adenoviral gene transfer of PAI-1 mutants, we observed that PAI-1 promoted tumor angiogenesis, not by interacting with VN, but rather by inhibiting proteolytic activity, suggesting that excessive plasmin proteolysis prevents assembly of tumor vessels. Single deficiency of uPA, tissue-type PA (tPA), uPA receptor, or VN, as well as combined deficiencies of uPA and tPA did not impair tumor angiogenesis, whereas lack of Plg reduced it. Overall, these data indicate that plasmin proteolysis, even though essential, must be tightly controlled during tumor angiogenesis, probably to allow vessel stabilization and maturation. These data provide insights into the clinical paradox whereby PAI-1 promotes tumor progression and warrant against the uncontrolled use of uPA/plasmin antagonists as tumor angiogenesis inhibitors. [less ▲]

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See detailMatrix Metalloproteinases and TIMP-1 production by peripheral blood granulocytes from COPD patients and asthmatics
Cataldo, Didier ULg; Munaut, Carine ULg; Noël, Agnès ULg et al

in Allergy (2001), 56(2), 145-51

Both asthmatic and COPD patients were found to have increased amounts of granulocytes and matrix metalloproteinase-9 (MMP-9) in their sputum. The present study was conducted to investigate whether the ... [more ▼]

Both asthmatic and COPD patients were found to have increased amounts of granulocytes and matrix metalloproteinase-9 (MMP-9) in their sputum. The present study was conducted to investigate whether the elevated amounts of MMP-9 and TIMP-1 found in such patients' airways may be linked to an enhanced secretion by granulocytes. Blood granulocytes from asthmatics (n = 10), COPD patients (n = 11), and healthy controls (n = 11) were isolated and cultured under basal conditions or after stimulation by phorbol 12-myristate 13-acetate (PMA) or N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLP). MMP-9 activity was detected by zymography while MMP-8 and TIMP-1 levels were measured by ELISA. In zymography, pro- and activated forms of MMP-9 were present in each group (healthy subjects, asthmatics, and COPD patients). Spontaneous release was not different between the three groups. Stimulation by fMLP and PMA increased to a similar extent the release of MMP-9 by granulocytes in all the three groups. TIMP-1 levels were also increased after stimulation by PMA and fMLP only in healthy subjects and COPD patients. MMP-8 levels were barely detectable. We conclude that circulating granulocytes from COPD patients and asthmatics do not display an abnormal secretion of MMP-9, and that granulocytes from asthmatics have an impaired ability to release TIMP-1 upon stimulation. [less ▲]

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