References of "Detry, Benoît"
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See detailLymphangiogenesis and extracellular matrix remodeling
Erpicum, Charlotte ULg; Detry, Benoît ULg; Paupert, Jenny ULg et al

Conference (2013, January 28)

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See detailSunitinib inhibits inflammatory corneal lymphangiogenesis.
Detry, Benoît ULg; Blacher, Silvia ULg; Erpicum, Charlotte ULg et al

in Investigative Ophthalmology & Visual Science (2013), 54(5), 3082-93

PURPOSE: To evaluate the antilymphangiogenic potential of multi-target tyrosine kinase inhibitor sunitinib in corneal neovascularization (NV). METHODS: Inflammatory corneal NV was induced by thermal ... [more ▼]

PURPOSE: To evaluate the antilymphangiogenic potential of multi-target tyrosine kinase inhibitor sunitinib in corneal neovascularization (NV). METHODS: Inflammatory corneal NV was induced by thermal cauterization applied in the central cornea of mice, to which sunitinib malate was daily administered by gavage or not. At days 6, 11, or 17 post cauterization, lymphatic and blood vessels, as well as inflammatory cells were immunostained and quantified in whole-mounted corneas. RT-PCRs were performed to evidence VEGF-A, VEGF-C, VEGF-D, placental growth factor (PlGF), and soluble vascular endothelial growth factor receptor (VEGFR)-1 and -2 (sVEGFR-1, sVEGFR-2) expressions. Macrophages were isolated from mice peritoneal cavity following thioglycollate injection to produce conditioned medium. The effects of sunitinib were evaluated in vitro in the aortic and lymphatic ring assays in the presence or not of macrophage conditioned medium. RESULTS: Sunitinib treatment drastically reduced pathologic corneal lymphangiogenesis and angiogenesis. Reduced F4/80+ cell infiltration was evidenced in sunitinib-treated mice and was associated to decreased VEGF-A (by 50%, P < 0.01) and VEGF-C (by 35%, P < 0.01) expressions, while VEGF-D and sVEGFR-2 expressions were not affected. In vitro, sunitinib dose-dependently inhibited aortic ring outgrowth, but failed to affect lymphangiogenesis in the lymphatic ring assay. However, macrophage conditioned medium-enhanced angiogenesis and lymphangiogenesis were both strongly counteracted by sunitinib treatment. Mechanistically, sunitinib blocked VEGFR-2 phosphorylation induced by VEGF-A released by macrophages. CONCLUSIONS: Sunitinib exerts antihemangiogenic and antilymphangiogenic effects in vivo by reducing F4/80+ cell recruitment and interacting with their released factors. [less ▲]

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See detailMatrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase.
Detry, Benoît ULg; Erpicum, Charlotte ULg; Paupert, Jenny ULg et al

in Blood (2012), 119(21), 5048-56

Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to ... [more ▼]

Lymphatic dysfunctions are associated with several human diseases, including lymphedema and metastatic spread of cancer. Although it is well recognized that lymphatic capillaries attach directly to interstitial matrix mainly composed of fibrillar type I collagen, the interactions occurring between lymphatics and their surrounding matrix have been overlooked. In this study, we demonstrate how matrix metalloproteinase (MMP)–2 drives lymphatic morphogenesis through Mmp2-gene ablation in mice, mmp2 knockdown in zebrafish and in 3D-culture systems, and through MMP2 inhibition. In all models used in vivo (3 murine models and thoracic duct development in zebrafish) and in vitro (lymphatic ring and spheroid assays), MMP2 blockage or down-regulation leads to reduced lymphangiogenesis or altered vessel branching. Our data show that lymphatic endothelial cell (LEC) migration through collagen fibers is affected by physical matrix constraints (matrix composition, density and cross-linking). Transmission electron microscopy (TEM) and confocal reflection microscopy using DQ-collagen highlight the contribution of MMP2 to mesenchymal-like migration of LEC associated with collagen fiber remodeling. Our findings provide new mechanistic insight into how LEC negotiate an interstitial type I collagen barrier and reveal an unexpected MMP2-driven collagenolytic pathway for lymphatic vessel formation and morphogenesis. [less ▲]

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See detailThe proteolytic activity of MT4-MMP is required for its proangiogenic and pro-metastatic promoting effects
Host, Lorin; Paye, Alexandra ULg; Detry, Benoît ULg et al

in International Journal of Cancer = Journal International du Cancer (2012), 131(7), 1537-1548

MT4-MMP expression in breast adenocarcinoma stimulates tumor growth and metastatic spreading to the lung. However whether these pro-tumorigenic and pro-metastatic effects of MT4-MMP are related to a ... [more ▼]

MT4-MMP expression in breast adenocarcinoma stimulates tumor growth and metastatic spreading to the lung. However whether these pro-tumorigenic and pro-metastatic effects of MT4-MMP are related to a proteolytic action is not known yet. Through site directed mutagenesis MT4-MMP has been inactivated in cancer cells through Glutamic acid 249 substitution by Alanine in the active site. Active MT4-MMP triggered an angiogenic switch at day 7 after tumor implantation and drastically accelerated subcutaneous tumor growth as well as lung colonization in RAG -/- mice. All these effects were abrogated upon MT4-MMP inactivation. In sharp contrast to most MMPs being primarily of stromal origin, we provide evidence that tumor-derived MT4-MMP, but not host-derived MT4-MMP contributes to angiogenesis. A genetic approach using MT4-MMP-deficient mice revealed that the status of MT4-MMP produced by host cells did not affect the angiogenic response. Despite of this tumor intrinsic feature, to exert its tumor promoting effect, MT4-MMP requires a permissive microenvironment. Indeed, tumor-derived MT4-MMP failed to circumvent the lack of an host angio-promoting factor such as lasminogen activator inhibitor (PAI-1). Overall, our study demonstrates the key contribution of MT4-MMP catalytic activity in the tumor compartment, at the interface with host cells. It identifies MT4-MMP as a key intrinsic tumor cell determinant that contributes to the elaboration of a permissive microenvironment for metastatic dissemination [less ▲]

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See detailInhibition of Experimental Corneal Neovascularization by Sunitinib Administration
Detry, Benoît ULg; BLACHER, Silvia ULg; Erpicum, Charlotte ULg et al

Poster (2011, October)

Cornea engraftment is the most common organ transplantation practiced around the world. The cornea is totally devoid of blood or lymphatic vessels, except in a peripheral zone called the limbus. This ... [more ▼]

Cornea engraftment is the most common organ transplantation practiced around the world. The cornea is totally devoid of blood or lymphatic vessels, except in a peripheral zone called the limbus. This property, named “corneal angiogenic privilege”, is conserved among all mammals to maintain cornea transparency and optimal visual acuity. In pathological conditions such as trauma, infections or hypoxia, blood and lymphatic vessels can grow into the avascular cornea, reducing visual acuity. In case of keratoplasty, it also considerably increases the risk of cornea graft rejection and is so considered as a high-risk keratoplasty. Treatments improving cornea survival after transplantation need to be developed, notably aiming at blocking corneal neovascularization. Here, we evaluated the efficacy of Sunitinib, a broad-spectrum tyrosine kinase receptor inhibitor, to reduce experimental corneal neovascularization. Cornea vascularization was induced by thermal cauterization applied in the center of C57Bl6 mice cornea, daily feeded with 40mg/kg Sunitinib or vehicule. Corneas were immunolabeled as whole mounts for CD31 and Lyve-1 to evidence blood and lymphatic vessels, 7, 11 and 17 days after cauterization. Whole mount pictures were analyzed by computer-assisted quantification, and relative vascular area, end-point density, node density, length density and maximal length of the vessels were determined to finely characterize blood and lymphatic vascular networks. We observed an inhibition of angiogenesis after 17 days in Sunitinib treated mice, where blood vessel relative surface, end-point density, branching density and length density were 1.8-fold decreased. Maximum length of blood vessels was also significantly reduced in the Sunitinib treated group at days 11 and 17. Lymphangiogenesis was strongly inhibited from day 6 to day 17 after cauterization where all parameters, except maximum length of lymphatic vessels, were significantly decreased. In case of transient Sunitinib administration (feeding during the 7 first days), we did not observe any reduction in the extent of blood or lymphatic networks developing 21 days after lesion induction. In vitro experimentations using the aortic and lymphatic ring assays showed a strong angiogenesis inhibition induced by Sunitinib while lymphangiogenesis was not inhibited. Our results show that the use of Sunitinib can strongly affect corneal neovascularisation and could enter in early treatment of such eye lesions to avoid vision loss and risk of cornea graft rejection. However, a punctual use of such tyrosine kinase inhibitor is not sufficient to stem neovascular reaction. In vitro experimentations show strong angiogenesis inhibition but normal lymphangiogenesis, suggesting indirect inhibitory effect of Sunitinib on corneal lymphangiogenesis. [less ▲]

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See detailDigging deeper into lymphatic vessel formation in vitro and in vivo
Detry, Benoît ULg; Bruyère, F.; Erpicum, Charlotte ULg et al

in BMC Cell Biology (2011), 12

Background Abnormal lymphatic vessel formation (lymphangiogenesis) is associated with different pathologies such as cancer, lymphedema, psoriasis and graft rejection. Lymphatic vasculature displays ... [more ▼]

Background Abnormal lymphatic vessel formation (lymphangiogenesis) is associated with different pathologies such as cancer, lymphedema, psoriasis and graft rejection. Lymphatic vasculature displays distinctive features than blood vasculature, and mechanisms underlying the formation of new lymphatic vessels during physiological and pathological processes are still poorly documented. Most studies on lymphatic vessel formation are focused on organism development rather than lymphangiogenic events occurring in adults. We have here studied lymphatic vessel formation in two in vivo models of pathological lymphangiogenesis (corneal assay and lymphangioma). These data have been confronted to those generated in the recently set up in vitro model of lymphatic ring assay. Ultrastructural analyses through Transmission Electron Microscopy (TEM) were performed to investigate tube morphogenesis, an important differentiating process observed during endothelial cell organization into capillary structures. [less ▲]

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See detailInvolvement of z-MMP-2 in Zebrafish lymphangiogenesis
Paupert, Jenny ULg; Pendeville, Hélène; Detry, Benoît ULg et al

Poster (2011, May)

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See detailLymphangiogenesis and extracellular matrix remodeling
Erpicum, Charlotte ULg; Detry, Benoît ULg; Paupert, Jenny ULg et al

Poster (2011)

Lymphangiogenesis, the formation of new lymphatic vessels from preexisting ones, is an important biological process associated with diverse pathologies, such as metastatic dissemination and graft ... [more ▼]

Lymphangiogenesis, the formation of new lymphatic vessels from preexisting ones, is an important biological process associated with diverse pathologies, such as metastatic dissemination and graft rejection. Our laboratory has previously identified MMP2 as a key regulator of lymphangiogenesis in vitro and in vivo. However, the exact function of MMP2 in this process is yet unknown. The present work aims at elucidating the mechanisms of MMP2 action during lymphangiogenesis. MMP2 could either act as a growth factor activator or as a regulator of matrix remodeling. To address this question, we studied the effect of MMP2 on lymphangiogenesis in an novel in vitro model of sprouting cells from small aggregates (spheroids) seeded in a collagen gel. In this model, quantification of the lymphangiogenic response is performed through computerized methods allowing the measurement of the distance of migration, but also the evaluation of how the cell are migrating. We evaluated the impact of MMP2 blockage through the use of physiological (TIMP2) or chemical inhibitors or by downregulating its expression with specific siRNA. The importance of extracellular matrix composition is evaluated by embedding these spheroids into different matrices (matrigel versus collagen; pepsinized collagen versus native collagen; different collagen concentrations). Our results reveal a modification of cell migration through collagen gel after MMP2 inhibition. The utilization of DQ collagen and microscopy refractance confirmed the importance of MMP2 collagenoyitic activity for lymphangiogenesis. [less ▲]

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See detailInvolvement of z-MMP-2 in Zebrafish lymphangiogenesis
Paupert, Jenny ULg; Pendeville, Hélène; Detry, Benoît ULg et al

Conference (2011)

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See detailBone marrow-derived mesenchymal cells and MMP13 contribute to experimental choroidal neovascularization.
Lecomte, Julie ULg; Louis, Krystel; Detry, Benoît ULg et al

in Cellular and Molecular Life Sciences : CMLS (2011), 68

In this study, we evaluate the potential involvement of collagenase-3 (MMP13), a matrix metalloproteinase (MMP) family member, in the exudative form of age-related macular degeneration characterized by a ... [more ▼]

In this study, we evaluate the potential involvement of collagenase-3 (MMP13), a matrix metalloproteinase (MMP) family member, in the exudative form of age-related macular degeneration characterized by a neovascularisation into the choroid. RT-PCR analysis revealed that human neovascular membranes issued from patients with AMD expressed high levels of Mmp13. The contribution of MMP13 in choroidal neovascularization (CNV) formation was explored by using a murine model of laser-induced CNV and applying it to wild-type mice (WT) and Mmp13-deficient mice (Mmp13 ( -/- ) mice). Angiogenic and inflammatory reactions were explored by immunohistochemistry. The implication of bone marrow (BM)-derived cells was determined by BM engraftment into irradiated mice and by injecting mesenchymal stem cells (MSC) isolated from WT BM. The deficiency of Mmp13 impaired CNV formation which was fully restored by WT BM engraftment and partially rescued by several injections of WT MSC. The present study sheds light on a novel function of MMP13 during BM-dependent choroidal vascularization and provides evidence for a role for MSC in the pathogenesis of CNV. [less ▲]

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See detailDoes plasminogen activator inhibitor-1 drive lymphangiogenesis?
Bruyere, Francoise; Melen-Lamalle, Laurence; Blacher, Silvia ULg et al

in PLoS ONE (2010), 5(3), 9653

The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators ... [more ▼]

The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and by regulating endothelial cell survival and migration. Protease system's role in lymphangiogenesis is unknown yet. Thus, based on its important pro-angiogenic effect, we hypothesized that PAI-1 may regulate lymphangiogenesis associated at least with metastatic dissemination of cancer cells. To address this issue, we studied the impact of PAI-1 deficiency in various murine models of tumoral lymphangiogenesis. Wild-type PAI-1 proficient mice were used as controls. We provide for the first time evidence that PAI-1 is dispensable for tumoral lymphangiogenesis associated with breast cancers either induced by mammary carcinoma cell injection or spontaneously appearing in transgenic mice expressing the polyomavirus middle T antigen (PymT) under the control of a mouse mammary tumor virus long-terminal repeat promoter (MMTV-LTR). We also investigated inflammation-related lymphatic vessel recruitment by using two inflammatory models. PAI-1 deficiency did neither affect the development of lymphangioma nor burn-induced corneal lymphangiogenesis. These novel data suggest that vascular remodelling associated with lymphangiogenesis and angiogenesis involve different molecular determinants. PAI-1 does not appear as a potential therapeutic target to counteract pathological lymphangiogenesis. [less ▲]

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See detailAdditional parameters for the morphometry of angiogenesis and lymphangiogenesis in corneal flatmounts
Blacher, Silvia ULg; Detry, Benoît ULg; Bruyere, Françoise et al

in Experimental Eye Research (2009), 89(2), 274-276

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See detail1H NMR metabolomic approach of the laser-induced choroidal neovascularization in mice
Lambert, Vincent ULg; Frederich, Michel ULg; Rousseau, Rousseau et al

Poster (2008, August)

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