Implant comprising a core and a tube encasing the core
; ; et al
The present invention relates to an implant comprising: - a core material comprising polydimethylsiloxane or at least one hydrogel polymer; - a tube encasing said core material comprising an ethylene ... [more ▼]
The present invention relates to an implant comprising: - a core material comprising polydimethylsiloxane or at least one hydrogel polymer; - a tube encasing said core material comprising an ethylene vinyl acetate polymer or at least one hydrogel polymer; - a sealant for closure of the open ends of said tube comprising polydimethylsiloxane or a mono-, di-, or triacetoxy derivative thereof, or at least one hydrogel polymer; and - at least one active ingredient; with the proviso that when the sealant is said at least one hydrogel polymer, the core material comprises polydimethylsiloxane. Furthermore, the invention relates to an implant for use as a medicament. In particular, the invention relates to an implant for use in the treatment of endometriosis. [less ▲]Detailed reference viewed: 26 (13 ULg)
Matrix metalloproteinase-2 governs lymphatic vessel formation as an interstitial collagenase.
Detry, Benoît ; Erpicum, Charlotte ; Paupert, Jenny 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 ▲]Detailed reference viewed: 155 (64 ULg)
The actors of human implantation: gametes, embryo and endometrium
Gridelet, Virginie ; GASPARD, Olivier ; Polese, Barbara et al
in Violin Pereira, Luis Antonio (Ed.) Embryology - Updates and Highlights on Classic Topics (2012)Detailed reference viewed: 27 (7 ULg)
Differential expression of Vegfr-2 and its soluble form in preeclampsia.
Munaut, Carine ; LORQUET, Sophie ; Pequeux, Christel et al
in PLoS ONE (2012), 7(3), 33475
Background: Several studies have suggested that the main features of preeclampsia (PE) are consequences of endothelial dysfunction related to excess circulating anti-angiogenic factors, most notably ... [more ▼]
Background: Several studies have suggested that the main features of preeclampsia (PE) are consequences of endothelial dysfunction related to excess circulating anti-angiogenic factors, most notably, soluble sVEGFR-1 (also known as sFlt-1) and soluble endoglin (sEng), as well as to decreased PlGF. Recently, soluble VEGF type 2 receptor (sVEGFR-2) has emerged as a crucial regulator of lymphangiogenesis. To date, however, there is a paucity of information on the changes of VEGFR-2 that occur during the clinical onset of PE. Therefore, the aim of our study was to characterize the plasma levels of VEGFR-2 in PE patients and to perform VEGFR-2 immunolocalization in placenta. METHODOLOGY/PRINCIPAL FINDINGS: By ELISA, we observed that the VEGFR-2 plasma levels were reduced during PE compared with normal gestational age matched pregnancies, whereas the VEGFR-1 and Eng plasma levels were increased. The dramatic drop in the VEGFR-1 levels shortly after delivery confirmed its placental origin. In contrast, the plasma levels of Eng and VEGFR-2 decreased only moderately during the early postpartum period. An RT-PCR analysis showed that the relative levels of VEGFR-1, sVEGFR-1 and Eng mRNA were increased in the placentas of women with severe PE. The relative levels of VEGFR-2 mRNA as well as expressing cells, were similar in both groups. We also made the novel finding that a recently described alternatively spliced VEGFR-2 mRNA variant was present at lower relative levels in the preeclamptic placentas. CONCLUSIONS/SIGNIFICANCE: Our results indicate that the plasma levels of anti-angiogenic factors, particularly VEGFR-1 and VEGFR-2, behave in different ways after delivery. The rapid decrease in plasma VEGFR-1 levels appears to be a consequence of the delivery of the placenta. The persistent circulating levels of VEGFR-2 suggest a maternal endothelial origin of this peptide. The decreased VEGFR-2 plasma levels in preeclamptic women may serve as a marker of endothelial dysfunction. [less ▲]Detailed reference viewed: 34 (7 ULg)
MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis
Maquoi, Erik ; ; et al
in Oncogene (2012), 31(4), 480-93
As invading breast carcinoma cells breach their underlying basement membrane, they become confronted with a dense three-dimensional reactive stroma dominated by type I collagen. To develop metastatic ... [more ▼]
As invading breast carcinoma cells breach their underlying basement membrane, they become confronted with a dense three-dimensional reactive stroma dominated by type I collagen. To develop metastatic capabilities, invading tumor cells must acquire the capacity to negotiate this novel microenvironment. Collagen influences the fate of epithelial cells by inducing apoptosis. However, the mechanisms used by invading tumor cells to evade collagen-induced apoptosis remain to be defined. We demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP/MMP-14) confers breast cancer cells with the ability to escape apoptosis when embedded in a collagen gel and after orthotopic implantation in vivo. In the absence of MMP-14-dependent proteolysis, type I collagen triggers apoptosis by inducing the expression of the pro-apoptotic Bcl-2-interacting killer in luminal-like breast cancer cells. These findings reveal a new mechanism whereby MMP-14 activity promotes tumor progression by circumventing apoptosis. [less ▲]Detailed reference viewed: 86 (20 ULg)
Individual decisions in placenta increta and percreta: a case series.
CHANTRAINE, Frédéric ; NISOLLE, Michelle ; PETIT, Philippe et al
in Journal of Perinatal Medicine (2012), 40(3), 265-70
Abstract Objective: Placenta increta or percreta is an uncommon pathology, sometimes associated with high maternal morbidity. Its prevalence increases proportionally to the number of cesarean sections ... [more ▼]
Abstract Objective: Placenta increta or percreta is an uncommon pathology, sometimes associated with high maternal morbidity. Its prevalence increases proportionally to the number of cesarean sections. This study analyzed the changes of our management strategy to devise treatment guidelines for this uncommon disorder. Materials and methodology: Between 2005 and 2011, 10 cases of placenta increta or percreta were managed at our university hospital maternity department. Results: Among the 10 cases, seven were diagnosed prenatally. Two patients were diagnosed early, at 14 and 17 weeks of gestational age, and their pregnancies were terminated. Five had hysterectomies during the intrapartum period, and despite attempted conservative treatment for the two others, hysterectomy proved necessary 2 months postpartum because of intrauterine infections. Seven of the 10 women had hysterectomies. Conclusion: Prenatal diagnosis of placenta increta or percreta is essential to plan the delivery in a competent tertiary care center. The decision to perform a cesarean hysterectomy or leave the placenta in situ for spontaneous delivery is based on the extent of infiltration, the patient's hemodynamic status, and her desire to remain fertile. The high-risk of infection and severe hemorrhage must not be overlooked should conservative treatment be chosen. This situation requires prolonged close monitoring. [less ▲]Detailed reference viewed: 37 (6 ULg)
Analgésie péridurale obstétricale et lombalgie du post-partum: un lien de cause à effet?
CHARLIER, Vanessa ; Brichant, Géraldine ; DEWANDRE, Pierre-Yves et al
in Revue Médicale de Liège (2012), 67(1), 16-20
backache is a common problem in the general population. the prevalence of backpain is increased during pregnancy and after delivery. early studies have suggested that labor epidural analgesia might be ... [more ▼]
backache is a common problem in the general population. the prevalence of backpain is increased during pregnancy and after delivery. early studies have suggested that labor epidural analgesia might be associated with an increased incidence of backache in the postpartum period. However, these initial studies were retrospective and their design included several methodological deficiencies. All the prospective studies published afterwards (prospective cohort studies and 3 ran- domized controlled trials) yield the same result : there is no relationship between labor epidural analgesia and long-term postpartum backpain. pregnant women must be aware of this in order to make an informed and appropriate choice about labor epidural analgesia, the most effective technique for intra- partum pain relief. [less ▲]Detailed reference viewed: 198 (14 ULg)
Insuffisance ovarienne prématurée : de la génétique à la clinique
; Foidart, Jean-Michel ; NISOLLE, Michelle et al
in Revue Médicale de Liège (2012), 67(7-8), 413-419
L’Insuffisance Ovarienne Prématurée (IOP) est une pathologie dont la présentation clinique est complexe. Elle survient chez 1% des femmes avant 40 ans, 0,1% avant 30 ans. Les causes sont multiples : les ... [more ▼]
L’Insuffisance Ovarienne Prématurée (IOP) est une pathologie dont la présentation clinique est complexe. Elle survient chez 1% des femmes avant 40 ans, 0,1% avant 30 ans. Les causes sont multiples : les anomalies génétiques, les maladies auto-immunes, les atteintes ovariennes iatrogènes secondaires à la chirurgie, radiothérapie, chimiothérapie, aux facteurs environnementaux tels que les virus, les toxines, le tabac, et aux facteurs métaboliques. Cependant, dans la majorité des cas, l’étiologie de l’IOP est idiopathique. [less ▲]Detailed reference viewed: 39 (6 ULg)
Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis.
Pequeux, Christel ; ; Blacher, Silvia et al
in Cancer Research (2012), 72(12), 3010-3019
Estrogens directly promote the growth of breast cancers that express the Estrogen Receptor (ERalpha). However, the contribution of stromal expression of ERalpha in the tumor microenvironment to the pro ... [more ▼]
Estrogens directly promote the growth of breast cancers that express the Estrogen Receptor (ERalpha). However, the contribution of stromal expression of ERalpha in the tumor microenvironment to the pro-tumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17beta-estradiol (E2) impacts the microenvironment and modulates tumor development of ERalpha-negative tumors. Using different mouse models of ER-negative cancer cells grafted subcutaneously into syngeneic ovariectomized immunocompetent mice, we found that E2 potentiates tumor growth, increases intratumoral vessel density and modifies tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ERalpha-deficient mice, demonstrating a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERalpha was deficient in Tie2- positive cells, but still expressed by bone marrow derived cells. These results were extended by clinical evidence of ERalpha-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore suggest that E2 promotes the growth of ERalpha-negative cancer cells through the activation of stromal ERα (not hematopoiteic but Tie2-dependent expression of ERalpha), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumor demand preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment. [less ▲]Detailed reference viewed: 39 (13 ULg)
Le cas clinique du mois. Hepatite herpetique au 3eme trimestre de la grossesse.
GINER LLORET, Caroline ; ; et al
in Revue Médicale de Liège (2012), 67(11), 557-9
Acute liver diseases of pregnancy are common and usually transient and reversible. Given the number of different possible diagnoses, performing a large biological screening and a proper iconographic ... [more ▼]
Acute liver diseases of pregnancy are common and usually transient and reversible. Given the number of different possible diagnoses, performing a large biological screening and a proper iconographic documentation is key. It makes sure no etiology fatal to the mother and her fetus is missed. [less ▲]Detailed reference viewed: 42 (12 ULg)
Isoform 111 of vascular endothelial growth factor (VEGF111) improves angiogenesis of ovarian tissue xenotransplantation
Labied, Soraya ; Delforge, Yves ; Blacher, Silvia et al
in Journal of Assisted Reproduction & Genetics (2012), 28(11), 1009Detailed reference viewed: 28 (10 ULg)
Does vascular endothelial growth factor improve ovarian tissue recovery after cryopreservation?
Henry, Laurie ; Fransolet, Maïté ; Labied, Soraya et al
in Giornale italiano di obstetricia e gynecologia (2012)Detailed reference viewed: 24 (6 ULg)
Adverse obstetrical outcomes after treat- ment of precancerous cervical lesions : a Belgian multicenter study
; GOFFIN, Frédéric ; et al
Poster (2012)Detailed reference viewed: 4 (0 ULg)
Endométriose : pourquoi se développe-telle ?
BELIARD, Aude ; Foidart, Jean-Michel ; Nisolle, Michelle
in Références en Gynécologie Obstétrique (2012), 14
Endometriosis is an estrogen-dependent disorder that can result in substantial morbidity, including multiple operations, and pelvic pain. New findings on the genetics, the possible roles of the ... [more ▼]
Endometriosis is an estrogen-dependent disorder that can result in substantial morbidity, including multiple operations, and pelvic pain. New findings on the genetics, the possible roles of the environment, the immune system, and the inflammation have given insight into the pathogenesis of this disorder and serve as the background for new treatments and new diagnostic approach. [less ▲]Detailed reference viewed: 96 (15 ULg)
Control of Allergen-Induced Inflammation and Hyperresponsiveness by the Metalloproteinase ADAMTS-12
Paulissen, Geneviève ; ; Rocks, Natacha et al
in Journal of Immunology (2012), 189
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) constitute a family of endopeptidases related to matrix metalloproteinases. These proteinases have been largely implicated in tissue ... [more ▼]
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) constitute a family of endopeptidases related to matrix metalloproteinases. These proteinases have been largely implicated in tissue remodeling associated with pathological processes. Among them, ADAMTS12 was identified as an asthma-associated gene in a human genome screening program. However, its functional implication in asthma is not yet documented. The present study aims at investigating potential ADAMTS-12 functions in experimental models of allergic airways disease. Two different in vivo protocols of allergen-induced airways disease were applied to the recently generated Adamts12-deficient mice and corresponding wild-type mice. In this study, we provide evidence for a protective effect of ADAMTS-12 against bronchial inflammation and hyperresponsiveness. In the absence of Adamts12, challenge with different allergens (OVA and house dust mite) led to exacerbated eosinophilic inflammation in the bronchoalveolar lavage fluid and in lung tissue, along with airway dysfunction assessed by increased airway responsiveness following methacholine exposure. Furthermore, mast cell counts and ST2 receptor and IL-33 levels were higher in the lungs of allergen-challenged Adamts12-deficient mice. The present study provides, to our knowledge, the first experimental evidence for a contribution of ADAMTS-12 as a key mediator in airways disease, interfering with immunological processes leading to inflammation and airway hyperresponsiveness. [less ▲]Detailed reference viewed: 60 (23 ULg)
A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer.
; Syne, Laïdya ; Brysse, Anne et al
in Oncogene (2012), 31(33), 3741-53
Epithelial-to-mesenchymal transition (EMT) processes endow epithelial cells with enhanced migratory/invasive properties and are therefore likely to contribute to tumor invasion and metastatic spread ... [more ▼]
Epithelial-to-mesenchymal transition (EMT) processes endow epithelial cells with enhanced migratory/invasive properties and are therefore likely to contribute to tumor invasion and metastatic spread. Because of the difficulty in following EMT processes in human tumors, we have developed and characterized an animal model with transplantable human breast tumor cells (MDA-MB-468) uniquely showing spontaneous EMT events to occur. Using vimentin as a marker of EMT, heterogeneity was revealed in the primary MDA-MB-468 xenografts with vimentin-negative and vimentin-positive areas, as also observed on clinical human invasive breast tumor specimens. Reverse transcriptase-PCR after microdissection of these populations from the xenografts revealed EMT traits in the vimentin-positive zones characterized by enhanced 'mesenchymal gene' expression (Snail, Slug and fibroblast-specific protein-1) and diminished expression of epithelial molecules (E-cadherin, ZO-3 and JAM-A). Circulating tumor cells (CTCs) were detected in the blood as soon as 8 days after s.c. injection, and lung metastases developed in all animals injected as examined by in vivo imaging analyses and histology. High levels of vimentin RNA were detected in CTCs by reverse transcriptase-quantitative PCR as well as, to a lesser extent, Snail and Slug RNA. Von Willebrand Factor/vimentin double immunostainings further showed that tumor cells in vascular tumoral emboli all expressed vimentin. Tumoral emboli in the lungs also expressed vimentin whereas macrometastases displayed heterogenous vimentin expression, as seen in the primary xenografts. In conclusion, our data uniquely demonstrate in an in vivo context that EMT occurs in the primary tumors, and associates with an enhanced ability to intravasate and generate CTCs. They further suggest that mesenchymal-to-epithelial phenomena occur in secondary organs, facilitating the metastatic growth [less ▲]Detailed reference viewed: 47 (7 ULg)
Curcumin-cyclodextrin complexes potentiate gemcitabine effects in an orthotopic mouse model of lung cancer.
Rocks, Natacha ; Bekaert, Sandrine ; et al
in British Journal of Cancer (2012), 107(7), 1083-92
Background:Overall clinical outcome for advanced lung cancer remains very disappointing despite recent advances in treatment. Curcumin has been reported as potentially active against cancer.Methods:Owing ... [more ▼]
Background:Overall clinical outcome for advanced lung cancer remains very disappointing despite recent advances in treatment. Curcumin has been reported as potentially active against cancer.Methods:Owing to poor curcumin solubility, we have used cyclodextrins (CD) as an excipient allowing a considerable increase of aqueous solubility and bioavailability of curcumin. The effects of solubilised curcumin have been evaluated in cell cultures as well as in an in vivo orthotopic lung tumour mouse model.Results:Cell proliferation was reduced while apoptosis rates were increased when lung epithelial tumour cells were cultured in the presence of curcumin-CD complexes. For in vivo experiments, cells were grafted into lungs of C57Bl/6 mice treated by an oral administration of a non-soluble form of curcumin, CDs alone or curcumin-CD complexes, combined or not with gemcitabine. The size of orthotopically implanted lung tumours was reduced upon curcumin complex administration as compared with treatments with placebo or non-solubilised curcumin. Moreover, curcumin potentiated the gemcitabine-mediated antitumour effects.Conclusion:Our data demonstrate that curcumin, when given orally in a CD-solubilised form, reduces lung tumour size in vivo. In vitro experiments show impaired tumour cell proliferation and increased cell apoptosis. Moreover, our data underline a potential additive effect of curcumin with gemcitabine thus providing an efficient therapeutic option for antilung cancer therapy. [less ▲]Detailed reference viewed: 64 (19 ULg)
Bone Marrow-derived Myofibroblasts Are the Providers of Pro-invasive Matrix Metalloproteinase 13 in Primary Tumor.
Lecomte, Julie ; ; Blacher, Silvia et al
in Neoplasia : An International Journal for Oncology Research (2012), 14(10), 943-51
Carcinoma-associated fibroblasts are key contributors of the tumor microenvironment that regulates carcinoma progression. They consist of a heterogeneous cell population with diverse origins, phenotypes ... [more ▼]
Carcinoma-associated fibroblasts are key contributors of the tumor microenvironment that regulates carcinoma progression. They consist of a heterogeneous cell population with diverse origins, phenotypes, and functions. In the present report, we have explored the contribution of bone marrow (BM)-derived cells to generate different fibroblast subsets that putatively produce the matrix metalloproteinase 13 (MMP13) and affect cancer cell invasion. A murine model of skin carcinoma was applied to mice, irradiated, and engrafted with BM isolated from green fluorescent protein (GFP) transgenic mice. We provide evidence that one third of BM-derived GFP(+) cells infiltrating the tumor expressed the chondroitin sulfate proteoglycan NG2 (pericytic marker) or alpha-smooth muscle actin (alpha-SMA, myofibroblast marker), whereas almost 90% of Thy1(+) fibroblasts were originating from resident GFP-negative cells. MMP13producing cells were exclusively alpha-SMA(+) cells and derived from GFP(+) BM cells. To investigate their impact on tumor invasion, we isolated mesenchymal stem cells (MSCs) from the BM of wild-type and MMP13-deficient mice. Wild-type MSC promoted cancer cell invasion in a spheroid assay, whereas MSCs obtained from MMP13-deficient mice failed to. Our data support the concept of fibroblast subset specialization with BM-derived alpha-SMA(+) cells being the main source of MMP13, a stromal mediator of cancer cell invasion. [less ▲]Detailed reference viewed: 45 (17 ULg)
Nebulized Anti-IL-13 Monoclonal Antibody Fab' Fragment Reduces Allergen-Induced Asthma
Hacha, Jonathan ; ; Maertens, Ludovic et al
in American Journal of Respiratory Cell and Molecular Biology (2012), sous presse
Rationale: Interleukin-13 (IL-13) is a prototypic Th2 cytokine and a central mediator of the complex cascade of events leading to asthmatic phenotype. Indeed, IL-13 plays key roles in IgE synthesis ... [more ▼]
Rationale: Interleukin-13 (IL-13) is a prototypic Th2 cytokine and a central mediator of the complex cascade of events leading to asthmatic phenotype. Indeed, IL-13 plays key roles in IgE synthesis, bronchial hyperresponsiveness, mucus hypersecretion, subepithelial fibrosis and eosinophil infiltration. Objectives: We assessed the potential efficacy of inhaled anti-IL-13 monoclonal antibody Fab' fragment on allergen-induced airway inflammation, hyperresponsiveness and remodeling in an experimental model of allergic asthma. Anti-IL-13 Fab' was administered to mice as a liquid aerosol generated by inExpose® inhalation system in a tower allowing a nose-only exposure. Methods: BALB/c mice were treated by PBS, anti-IL-13 Fab' or A33 Fab' fragment and subjected to ovalbumin (OVA) exposure for 1 and 5 weeks (short term (ST) and long term (LT) protocols). Measurements and Main Results: Our data demonstrate a significant anti-asthma effect following nebulization of anti-IL-13 Fab' in a model of asthma driven by allergen exposure as compared to saline and non-immune Fab fragments. In short and long terms protocols, administration of the anti-IL-13 Fab' by inhalation significantly decreased bronchial responsiveness to methacholine, BALF eosinophilia, inflammatory cell infiltration in lung tissue, and many features of airway remodeling. Levels of pro-inflammatory mediators and matrix metalloprotease levels were significantly lower in lung parenchyma of mice treated with anti-IL-13 Fab'. Conclusions: These data demonstrate that an inhaled anti-IL-13 Fab' significantly reduces airway inflammation, hyperresponsiveness and remodeling. Specific neutralization of IL-13 in the lungs using an inhaled anti-IL-13 Fab' could represent a novel and effective therapy for the treatment of asthma. [less ▲]Detailed reference viewed: 91 (8 ULg)
The proteolytic activity of MT4-MMP is required for its proangiogenic and pro-metastatic promoting effects
; Paye, Alexandra ; Detry, Benoît 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 ▲]Detailed reference viewed: 49 (13 ULg)