References of "Bajou, Khalid"
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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 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 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 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 detailRole de l'inhibiteur des activateurs de plasminogene de type 1 dans l'angiogenese tumorale
Bajou, Khalid ULg; Devy, L.; Masson, Véronique ULg et al

in Thérapie (2001), 56(5, Sep-Oct), 465-72

The plasminogen/plasmin system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumour cell migration. High levels of components of the plasminogen ... [more ▼]

The plasminogen/plasmin system plays a key role in cancer progression, presumably via mediating extracellular matrix degradation and tumour cell migration. High levels of components of the plasminogen activation system, and paradoxically also its inhibitor, plasminogen activator inhibitor 1 (PAI-1), have been correlated with a poor prognosis for patients with cancers of different types. Recent findings clearly suggest that PAI-1 is essential for capillary sprouting during tumour angiogenesis. Moreover, there is accumulating evidence that both the urokinase receptor and PAI-1 are multifunctional proteins involved not only in extracellular matrix proteolysis but also in cellular adhesion and migration through their binding site for vitronectin. The understanding of whether PAI-1 plays a regulatory role in angiogenesis by tightly controlling proteolytic activity or by influencing cell migration could allow a new anti-angiogenic approach for tumour therapy. [less ▲]

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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 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 detailFgf-3 and Fgf-4 Elicit Distinct Oncogenic Properties in Mouse Mammary Myoepithelial Cells
Hajitou, Amin; Baramova, Eugénia; Bajou, Khalid ULg et al

in Oncogene (1998), 17(16), 2059-71

Fibroblast Growth Factors 3 (FGF-3) and 4 (FGF-4) were compared for the effects they each exert on EF43 mouse cells. This non-transformed mammary cell line appears to be myoepithelial mainly because it ... [more ▼]

Fibroblast Growth Factors 3 (FGF-3) and 4 (FGF-4) were compared for the effects they each exert on EF43 mouse cells. This non-transformed mammary cell line appears to be myoepithelial mainly because it expresses alpha-smooth muscle actin. The EF43 cells were infected with similar vectors that carry either the short fgf-3 sequence (the product of which goes into the secretory pathway), fgf-4 or the selection gene only as control. In syngeneic animals, EF43.fgf-3 cells were tumorigenic only when orthotopically implanted whereas EF43.fgf-4 cells invariably gave rise to aggressive tumors. However, both tumor types were metastatic as evidenced by the blue micrometastases observed when the implanted cells expressed lacZ. In vitro, the FGF-3 producing cells were strongly invasive in matrigel coated chambers whereas the EF43.fgf-4 cells only were invasive in type I-collagen gels. Interestingly, FGF-3 production greatly stimulated the synthesis of pro-MMP-9 (Matrix Metalloprotease-9) and, to a lesser extent, that of pro-MMP-2. FGF-3 also up-regulated the production of plasminogen activators. In contrast, FGF-4 had no effect on these secretions and the medium conditioned by the EF43.fgf-4 cells displayed the largest plasminogen activator-inhibitor activity. These results show that FGF-3 and FGF-4 have distinct mechanisms of action on myoepithelial cells. [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 detailEndothelial Cell Intracellular Ca2+ Concentration Is Increased Upon Breast Tumor Cell Contact and Mediates Tumor Cell Transendothelial Migration
Lewalle, J. M.; Cataldo, Didier ULg; Bajou, Khalid ULg et al

in Clinical & Experimental Metastasis (1998), 16(1), 21-9

Tumor cell extravasation is a determinant step in the process of hematogenous metastasis. The signal transduction pathways involved in the interactions between tumor cells and the vascular endothelium ... [more ▼]

Tumor cell extravasation is a determinant step in the process of hematogenous metastasis. The signal transduction pathways involved in the interactions between tumor cells and the vascular endothelium during transendothelial migration are still undefined. In the present study, we have investigated the influence of human breast adenocarcinoma cells (MCF7) on human umbilical vein endothelial cell (HUVEC) intracellular Ca2+ concentration ([Ca2+]i). We show that the contact between MCF7 cells and a confluent HUVEC monolayer induces an immediate and transient increase in HUVEC [Ca2+]i. This [Ca2+]i rise could not be elicited by tumor cell-conditioned medium, isolated tumor cell membranes, inert beads or normal breast epithelial cells, demonstrating the involvement of specific recognition mechanisms between MCF7 cells and HUVEC. Depletion of HUVEC intracellular Ca2+ stores by the endoplasmic reticulum Ca2+-ATPase inhibitor thapsigargin as well as the selective depletion of inositol 1,4,5-triphosphate (IP3)-sensitive Ca2+ stores by prior activation of HUVEC using histamine resulted in a complete inhibition of tumor cell-induced [Ca2+]i elevation. Similar results were obtained when HUVEC monolayers were treated with the tyrosine kinase inhibitor herbimycin A, suggesting a role for tyrosine kinase-associated cell surface receptors in tumor cell-endothelial cell interactions. The depletion of HUVEC intracellular Ca2+ stores by thapsigargin was also shown to delay MCF7-induced endothelial cell disjunction, to prevent their spreading on the subendothelial extracellular matrix and transendothelial migration in vitro. These results suggest that transient changes in endothelial [Ca2+]i may govern multiple steps of tumor cell extravasation. [less ▲]

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See detailAlteration of Interendothelial Adherens Junctions Following Tumor Cell-Endothelial Cell Interaction in Vitro
Lewalle, J. M.; Bajou, Khalid ULg; Desreux, Joëlle ULg et al

in Experimental Cell Research (1997), 237(2), 347-56

The integrity of the vascular endothelium is mainly dependent upon the organization of interendothelial adherens junctions (AJ). These junctions are formed by the homotypic interaction of a transmembrane ... [more ▼]

The integrity of the vascular endothelium is mainly dependent upon the organization of interendothelial adherens junctions (AJ). These junctions are formed by the homotypic interaction of a transmembrane protein, vascular endothelial cadherin (VE-cadherin), which is complexed to an intracellular protein network including alpha-, beta-, and gamma-catenin. Additional proteins such as vinculin and alpha-actinin have been suggested to link the VE-cadherin/catenin complex to the actin-based cytoskeleton. During the process of hematogenous metastasis, circulating tumor cells must disrupt these intercellular junctions in order to extravasate. In the present study, we have investigated the influence of tumor cell-endothelial cell interaction upon interendothelial AJ. We show that human breast adenocarcinoma cells (MCF-7), but not normal human mammary epithelial cells, induce a rapid endothelial cell (EC) dissociation which correlates with the loss of VE-cadherin expression at the site of tumor cell-EC contact and with profound changes in vinculin distribution and organization. This process could not be inhibited by metalloproteinase nor serine protease inhibitors. Immunoprecipitations and Western blot analysis demonstrate that the overall expression of VE-cadherin and vinculin as well as the composition of the VE-cadherin/catenins complex are not affected by tumor cells while the tyrosine phosphorylation status of proteins within the complex is significantly altered. Our data suggest that tumor cells modulate AJ protein distribution and phosphorylation in EC and may, thereby, facilitate EC dissociation. [less ▲]

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See detailInvolvement of Pa/Plasmin System in the Processing of Pro-Mmp-9 and in the Second Step of Pro-Mmp-2 Activation
Baramova, E. N.; Bajou, Khalid ULg; Remacle, A. et al

in FEBS Letters (1997), 405(2), 157-62

Pro-MMP2 activation is a two-step process resulting in (1) an intermediate 64 kDa form generated by the MT1-MMP activity, and (2) a mature 62 kDa form. Addition of plasminogen to HT1080 cells cultured ... [more ▼]

Pro-MMP2 activation is a two-step process resulting in (1) an intermediate 64 kDa form generated by the MT1-MMP activity, and (2) a mature 62 kDa form. Addition of plasminogen to HT1080 cells cultured under various conditions, or to their membrane preparation, induced a complete conversion of the intermediate MMP-2 form to the mature one, and processing of pro-MMP-9. The pro-MMP-2 activation was inhibited by plasmin inhibitors and anti-uPA antibody. These results provide evidence for involvement of the PA/plasmin system in the second step of MMP-2 activation. [less ▲]

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See detailProduction and activation of matrix metalloprotease-9 (MMP-9) by HL-60 promyelocytic leukemia cells
Devy, L.; Noël, Agnès ULg; Baramova, E. et al

in Biochemical and Biophysical Research Communications (1997), 238

Human promyelocytic HL-60 cells have been used as a model of acute leukemia to investigate the expression and the regulation of matrix metalloproteases (MMPs), known to contribute to the degradation of ... [more ▼]

Human promyelocytic HL-60 cells have been used as a model of acute leukemia to investigate the expression and the regulation of matrix metalloproteases (MMPs), known to contribute to the degradation of extracellular matrix components. As shown by gelatin zymography, HL-60 cells constitutively released significant amounts of proMMP-9 (92 kDa) and moderate amounts of proMMP-2 (72 kDa). Furthermore, casein zymography confirmed the presence of serine proteases in the form of pro-urokinase. Activation of proMMP-9 was dependent on the plasminogen activator/plasmin (PA/plasmin) system and was inhibited by aprotinin. MMP-9 was only detected in cellular extracts or conditioned media incubated with HL-60 cells, indicating that cells are essential to the activation process. Addition of plasminogen increased by 3-fold the basal invasive rate of these cells across a matrigel layer (2.1%versus0.7% in control cells after 4 h of incubation). Taken together, these results indicate that HL-60 cells exhibit an autocrine activation mechanism of proMMP-9 via the PA/plasmin system and that activation of proMMP-9 increases their invasive potential [less ▲]

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See detailEmerging Roles for Proteinases in Cancer
Noël, Agnès ULg; Gilles, Christine ULg; Bajou, Khalid ULg et al

in Invasion & Metastasis (1997), 17(5), 221-39

Metalloproteinases and serine proteinases have been associated with tumor invasion and formation of metastasis which represent the major obstacles to cancer cure. The contribution of proteinases in these ... [more ▼]

Metalloproteinases and serine proteinases have been associated with tumor invasion and formation of metastasis which represent the major obstacles to cancer cure. The contribution of proteinases in these processes was initially thought to be the destruction of extracellular matrices. However, recent evidence suggests that they mainly affect tumor growth rather than invasion. Proteinases can indeed generate active matrix protein fragments, influence the release, the activation and the bioavailability of growth factors, and consequently modulate tumor cell growth, apoptosis and angiogenesis. Additionally, proteinases, their receptors and/or inhibitors can be directly involved in cell migration and in the processing or shedding of cell surface proteins. Further elucidation of the functions of proteinases is essential for the development of novel anticancer strategies. [less ▲]

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See detailInteractions between endothelial cells and smooth muscle cells after their activation by hypoxia. A possible etiology for venous disease.
Michiels, C.; Arnould, T.; Janssens, D. et al

in International Angiology : A Journal of the International Union of Angiology (1996), 15(5), 124-130

Because of their localization at the interface between blood and tissue, endothelial cells are responsible for the maintenance of vascular homeostasis. They fulfil a series of various functions and ... [more ▼]

Because of their localization at the interface between blood and tissue, endothelial cells are responsible for the maintenance of vascular homeostasis. They fulfil a series of various functions and constantly interact with circulating leukocytes and with the smooth muscle cells (SMC) present in the media. Any disturbance of their metabolism can thus lead to alterations of the blood vessel functions. We have shown that hypoxia, for example resulting from venous stasis, induces the activation of endothelial cells which then release inflammatory mediators able to activate neutrophils and to induce their infiltration as well as growth factors for SMC. We propose that these processes are the beginning of a cascade of events eventually leading to structural and functional modifications of the venous wall similar to the ones observed in varicose vein wall. The endothelium alterations resulting from venous stasis would thus be the origin of the development of the venous disease. Pharmacological and clinical evidence reinforce this hypothesis. [less ▲]

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