References of "Sounni, Nor Eddine"
     in
Bookmark and Share    
Full Text
Peer Reviewed
See detailLymphangiogenesis in post-natal tissue remodeling: Lymphatic endothelial cell connection with its environment.
Paupert, Jenny ULg; Sounni, Nor Eddine ULg; Noël, Agnès ULg

in Molecular Aspects of Medicine (2011), 32(2), 146-158

The main physiological function of the lymphatic vasculature is to maintain tissue fluid homeostasis. Lymphangiogenesis or de novo lymphatic formation is closely associated with tissue inflammation in ... [more ▼]

The main physiological function of the lymphatic vasculature is to maintain tissue fluid homeostasis. Lymphangiogenesis or de novo lymphatic formation is closely associated with tissue inflammation in adults (i.e. wound healing, allograft rejection, tumor metastasis). Until recently, research on lymphangiogenesis focused mainly on growth factor/growth factor-receptor pathways governing this process. One of the lymphatic vessel features is the incomplete or absence of basement membrane. This close association of endothelial cells with the underlying interstitial matrix suggests that cell-matrix interactions play an important role in lymphangiogenesis and lymphatic functions. However, the exploration of interaction between extracellular matrix (ECM) components and lymphatic endothelial cells is in its infancy. Herein, we describe ECM-cell and cell-cell interactions on lymphatic system function and their modification occurring in pathologies including cancer metastasis. [less ▲]

Detailed reference viewed: 58 (8 ULg)
Full Text
Peer Reviewed
See detailUnimpeded skin carcinogenesis in K14-HPV16 transgenic mice deficient for plasminogen activator inhibitor
Masset, Anne; Maillard, Catherine ULg; Sounni, Nor Eddine ULg et al

in International Journal of Cancer = Journal International du Cancer (2011), 128(2), 283-93

Angiogenesis, extracellular matrix remodeling and cell migration are associated with cancer progression and involve at least, the plasminogen activating system and its main physiological inhibitor, the ... [more ▼]

Angiogenesis, extracellular matrix remodeling and cell migration are associated with cancer progression and involve at least, the plasminogen activating system and its main physiological inhibitor, the plasminogen activator inhibitor-1 (PAI-1). Considering the recognized importance of PAI-1 in the regulation of tumor angiogenesis and invasion in murine models of skin tumor transplantation, we explored the functional significance of PAI-1 during early stages of neoplastic progression in the transgenic mouse model of multistage epithelial carcinogenesis (K14-HPV16 mice). We have studied the effect of genetic deletion of PAI-1 on inflammation, angiogenesis, lymphangiogenesis, as well as tumor progression. In this model, PAI-1 deficiency neither impaired keratinocyte hyperproliferation or tumor development, nor affected the infiltration of inflammatory cells and development of angiogenic or lymphangiogenic vasculature. We are reporting evidence for concomitant lymphangiogenic and angiogenic switches independent to PAI-1 status. Taken together, these data indicate that PAI-1 is not rate limiting for neoplastic progression and vascularization during premalignant progression, or that there is a functional redundancy between PAI-1 and other tumor regulators, masking the effect of PAI-1 deficiency in this long-term model of multi-stage epithelial carcinogenesis. [less ▲]

Detailed reference viewed: 128 (27 ULg)
Full Text
Peer Reviewed
See detailStromal regulation of vessel stability by MMP14 and TGFbeta.
Sounni, Nor Eddine ULg; Dehne, K.; van Kempen, L. et al

in Disease Models & Mechanisms (2010), 3

Innate regulatory networks within organs maintain tissue homeostasis and facilitate rapid responses to damage. We identified a novel pathway regulating vessel stability in tissues involving matrix ... [more ▼]

Innate regulatory networks within organs maintain tissue homeostasis and facilitate rapid responses to damage. We identified a novel pathway regulating vessel stability in tissues involving matrix metalloproteinase 14 (MMP14) and transforming growth factor beta (TGFbeta)1. Whereas plasma proteins rapidly extravasate out of vasculature in wildtype mice following acute damage, short-term treatment of mice in vivo with a broad-spectrum metalloproteinase inhibitor, neutralizing antibodies to TGFbeta1 or an ALK5 inhibitor significantly enhanced vessel leakage. In contrast, in a mouse model of age-related dermal fibrosis where MMP14 activity and TGFbeta bioavailability are chronically elevated, or in mice that ectopically express TGFbeta in epidermis, cutaneous vessels are resistant to acute leakage. Characteristic responses to tissue damage are reinstated if fibrotic mice are pre-treated with metalloproteinase inhibitors or TGFbeta signaling antagonists. Neoplastic tissues on the other hand are in a constant state of tissue damage and exhibit altered hemodynamics due to hyperleaky angiogenic vasculature. In two distinct transgenic mouse tumor models, inhibition of ALK5 further enhanced vascular leakage into interstitium and facilitated increased delivery of high molecular weight compounds into premalignant tissue and tumors. Taken together, these data define a central pathway involving MMP14 and TGFbeta that mediate vessel stability and vascular response to tissue injury. Antagonists of this pathway could be therapeutically exploited to improve delivery of therapeutics or molecular contrast agents into tissues where chronic damage or neoplastic disease limits their efficient delivery. [less ▲]

Detailed reference viewed: 437 (9 ULg)
See detailMMPs and their inhibitors in vascular remodeling and vascular disease
Sounni, Nor Eddine ULg

Conference (2010, March)

Detailed reference viewed: 10 (0 ULg)
Full Text
Peer Reviewed
See detailTIMP-2 binding with cellular MT1-MMP stimulates invasion-promoting MEK/ERK signaling in cancer cells
Sounni, Nor Eddine ULg; Rozanov, D. V.; Remacle, A. G. et al

in International Journal of Cancer = Journal International du Cancer (2010), 126(5), 1067-78

Both invasion-promoting MT1-MMP and its physiological inhibitorTIMP-2 play a significant role in tumorigenesis and are identified in the most aggressive cancers. Despite its antiproteolytic effects in ... [more ▼]

Both invasion-promoting MT1-MMP and its physiological inhibitorTIMP-2 play a significant role in tumorigenesis and are identified in the most aggressive cancers. Despite its antiproteolytic effects in vitro, clinical data suggest that TIMP-2 expression is positively associated with tumor recurrence, thus emphasizing the wide-ranging role of TIMP-2 in malignancies. To shed light on this role of TIMP-2, we report that low concentrations of TIMP-2, by interacting with MT1-MMP (a specific membrane receptor of TIMP-2), induce the MEK/ERK signaling cascade in fibrosarcoma HT1080 cells which express MT1-MMP naturally. TIMP-2 binding with cell surface-associated MT1-MMP stimulates phosphorylation of MEK1/2, which is upstream of ERK1/2, and the ERK1/2 substrate p90RSK. Consistent with volumes of literature, we confirmed that the activation of ERK stimulated cell migration. Both the transcriptional silencing of MT1-MMP and the inhibition of MEK1/2 reversed the signaling effects of TIMP-2/MT1-MMP while the active site-targeting MMP inhibitor GM6001 did not. Our data suggest that both the interactions of TIMP-2 with MT1-MMP, which activate the pro-migratory ERK signaling cascade, and the conventional inhibition of MT1-MMP's catalytic activity by TIMP-2, play a role in the invasion-promoting function of MT1-MMP. The TIMP-2-induced stimulation of ERK signaling in cancer cells explains the direct, as opposed to the inverse, association of TIMP-2 expression with poor prognosis in cancer. [less ▲]

Detailed reference viewed: 58 (9 ULg)
See detailMMPs regulation of vascular permeability in cancer
Sounni, Nor Eddine ULg

Conference (2009, May 29)

Detailed reference viewed: 10 (1 ULg)
Full Text
Peer Reviewed
See detailBiochemical evidence of the interactions of membrane type-1 matrix metalloproteinase (MT1-MMP) with adenine nucleotide translocator (ANT): potential implications linking proteolysis with energy metabolism in cancer cells.
Radichev, I. A.; Remacle, A. G.; Sounni, Nor Eddine ULg et al

in Biochemical Journal (2009), 420(1), 37-47

Invasion-promoting MT1-MMP (membrane type-1 matrix metalloproteinase) is a key element in cell migration processes. To identify the proteins that interact and therefore co-precipitate with this proteinase ... [more ▼]

Invasion-promoting MT1-MMP (membrane type-1 matrix metalloproteinase) is a key element in cell migration processes. To identify the proteins that interact and therefore co-precipitate with this proteinase from cancer cells, we used the proteolytically active WT (wild-type), the catalytically inert E240A and the C-end truncated (tailless; ΔCT) MT1-MMP–FLAG constructs as baits. The identity of the pulled-down proteins was determined by LC-MS/MS (liquid chromatography tandem MS) and then confirmed by Western blotting using specific antibodies. We determined that, in breast carcinoma MCF cells (MCF-7 cells), ANT (adenine nucleotide translocator) efficiently interacted with the WT, E240A and ΔCT constructs. The WT and E240A constructs also interacted with α-tubulin, an essential component of clathrin-mediated endocytosis. In turn, tubulin did not co-precipitate with the ΔCT construct because of the inefficient endocytosis of the latter, thus suggesting a high level of selectivity of our test system. To corroborate these results, we then successfully used the ANT2–FLAG construct as a bait to pull-down MT1-MMP, which was naturally produced by fibrosarcoma HT1080 cells. We determined that the presence of the functionally inert catalytic domain alone was sufficient to cause the proteinase to interact with ANT2, thus indicating that there is a non-proteolytic mode of these interactions. Overall, it is tempting to hypothesize that by interacting with pro-invasive MT1-MMP, ANT plays a yet to be identified role in a coupling mechanism between energy metabolism and pericellular proteolysis in migrating cancer cells. [less ▲]

Detailed reference viewed: 25 (0 ULg)
Full Text
Peer Reviewed
See detailEpigenetic control of the invasion-promoting MT1-MMP/MMP-2/TIMP-2 axis in cancer cells
Chernov, Andrei V.; Sounni, Nor Eddine ULg; Remacle, Albert G. et al

in Journal of Biological Chemistry (2009), 284(19), 12727-34

Membrane type-1 matrix metalloproteinase (MT1-MMP) is an activator of soluble MMP-2. The activity of both MMPs is regulated by their physiological inhibitor TIMP-2. An MT1-MMP/MMP-2/TIMP-2 axis plays a ... [more ▼]

Membrane type-1 matrix metalloproteinase (MT1-MMP) is an activator of soluble MMP-2. The activity of both MMPs is regulated by their physiological inhibitor TIMP-2. An MT1-MMP/MMP-2/TIMP-2 axis plays a key role in the invasive behavior of many cell types. Despite its importance, epigenetic control of this pro-invasive axis is insufficiently studied, and, as a result, its modification in a rational and clinically beneficial manner is exceedingly difficult. Therefore, we performed an epigenetic analysis of the MT1-MMP, MMP-2, and TIMP-2 gene promoters in highly migratory glioblastoma cells and in low migratory breast carcinoma MCF-7 cells. We determined, for the first time, that the epigenetic control leading to the transcriptional silencing of both MMPs includes hypermethylation of the corresponding CpG regions and histone H3 lysine-27 trimethylation (H3K27me3). In turn, undermethylation of the CpG islands and low levels of histone H3 lysine-27 trimethylation are features of transcriptionally active MT1-MMP and MMP-2 genes in invasive cancer cells. Additional histone modifications we have analyzed, including H3ac and H3K4me2, are present in both transcriptionally active and inactive promoters of both MMPs. Histone H3 lysine-4 trimethylation is likely to play no significant role in regulating MT1-MMP and MMP-2. The pattern of epigenetic regulation of TIMP-2 was clearly distinct from that of MMPs and included the coordinated methylation and demethylation of the two CpG regions in the promoter. Our results suggest that the epigenetic control plays an important role in both the balanced regulation of the MT1-MMP/MMP-2/TIMP-2 axis and the invasive behavior in cancer cells. [less ▲]

Detailed reference viewed: 21 (4 ULg)
Full Text
Peer Reviewed
See detailDevelopment of an optimized activatable MMP-14 targeted SPECT imaging probe
Watkins, G. A.; Jones, E. F.; Scott Shell, M. et al

in Bioorganic & Medicinal Chemistry (2009), 15(17), 653-9

Matrix metalloproteinase-14 (MT1-MMP or MMP-14) is a membrane-associated protease implicated in a variety of tissue remodeling processes and a molecular hallmark of select metastatic cancers. The ability ... [more ▼]

Matrix metalloproteinase-14 (MT1-MMP or MMP-14) is a membrane-associated protease implicated in a variety of tissue remodeling processes and a molecular hallmark of select metastatic cancers. The ability to detect MMP-14 in vivo would be useful in studying its role in pathologic processes and may potentially serve as a guide for the development of targeted molecular therapies. Four MMP-14 specific probes containing a positively charged cell penetrating peptide (CPP) d-arginine octamer (r8) linked with a MMP-14 peptide substrate and attenuating sequences with glutamate (8e, 4e) or glutamate-glycine (4eg and 4egg) repeating units were modeled using an AMBER force field method. The probe with 4egg attenuating sequence exhibited the highest CPP/attenuator interaction, predicting minimized cellular uptake until cleaved. The in vitro MMP-14-mediated cleavage studies using the human recombinant MMP-14 catalytic domain revealed an enhanced cleavage rate that directly correlated with the linearity of the embedded peptide substrate sequence. Successful cleavage and uptake of a technetium-99m labeled version of the optimal probe was demonstrated in MMP-14 transfected human breast cancer cells. Two-fold reduction of cellular uptake was found in the presence of a broad spectrum MMP inhibitor. The combination of computational chemistry, parallel synthesis and biochemical screening, therefore, shows promise as a set of tools for developing new radiolabeled probes that are sensitive to protease activity. [less ▲]

Detailed reference viewed: 11 (2 ULg)
See detailMicroenvironmental Regulation of Vascular Homeostasis and Leakage
Sounni, Nor Eddine ULg

Conference (2007, May 22)

Detailed reference viewed: 5 (0 ULg)
Full Text
See detailTargeting TGFbeta Bioavailability to Regulate Vascular Stability and Leakage
Sounni, Nor Eddine ULg; Van Kempen, Leon; Dehne, Kerstin et al

in FASEB Journal (2007, April), 2007; 21:lb33

Detailed reference viewed: 15 (3 ULg)
Full Text
Peer Reviewed
See detailMembrane-type 4 matrix metalloproteinase promotes breast cancer growth and metastases
Chabottaux, Vincent; Sounni, Nor Eddine ULg; Pennington, C. J. et al

in Cancer Research (2006), 66(10), 5165-5172

Membrane-type matrix metalloproteinases (MT-MMP) constitute a subfamily of six distinct membrane-associated MMPs. Although the contribution of MT1-MMP during different steps of cancer progression has been ... [more ▼]

Membrane-type matrix metalloproteinases (MT-MMP) constitute a subfamily of six distinct membrane-associated MMPs. Although the contribution of MT1-MMP during different steps of cancer progression has been well documented, the significance of other MT-MMPs is rather unknown. We have investigated the involvement of MT4-MMP, a glycosylphosphatidylinositol-anchored protease, in breast cancer progression. Interestingly, immunohistochemical analysis shows that MT4-MMP production at protein level is strongly increased in epithelial cancer cells of human breast carcinomas compared with normal epithelial cells. Positive staining for MT4-MMP is also detected in lymph node metastases. In contrast, quantitative reverse transcription-PCR analysis reveals similar MT4-MMP mRNA levels in human breast adenocarcinomas and normal breast tissues. Stable transfection of MT4-MMP cDNA in human breast adenocarcinoma MDA-MB-231 cells does not affect in vitro cell proliferation or invasion but strongly promotes primary tumor growth and associated metastases in RAG-1 immunodeficient mice. We provide for the first time evidence that MT4-MMP overproduction accelerates in vivo tumor growth, induces enlargement of i.t. blood vessels, and is associated with increased lung metastases. These results identify MT4-MMP as a new putative target to design anticancer strategies. [less ▲]

Detailed reference viewed: 71 (22 ULg)
See detailMembrane Type Matrix Metalloproreases in tumor angiogenesis
Sounni, Nor Eddine ULg

Conference (2005, January)

Detailed reference viewed: 3 (1 ULg)
Full Text
Peer Reviewed
See detailMembrane type-matrix metalloproteinases and tumor progression
Sounni, Nor Eddine ULg; Noël, Agnès ULg

in Biochimie (2005), 87

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that process growth factors, growth factor binding proteins, cell surface proteins, degrade extracellular matrix (ECM) components and ... [more ▼]

Matrix metalloproteinases (MMPs) are a family of zinc endopeptidases that process growth factors, growth factor binding proteins, cell surface proteins, degrade extracellular matrix (ECM) components and thereby play a central role in tissue remodeling and tumor progression. Membrane-type matrix metalloproteinases (MT-MMPs) are a recently discovered subgroup of intrinsic plasma membrane proteins. Their functions have been extended from pericellular proteolysis and control of cell migration to cell signaling, control of cell proliferation and regulation of multiple stages of tumor progression including growth and angiogenesis. This review sheds light on the new functions of MT-MMPs and their inhibitors in tumor development and angiogenesis, and presents recent investigations that document their influence on various cell functions. [less ▲]

Detailed reference viewed: 34 (4 ULg)