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See detailHyperglycosylated human chorionic gonadotropin stimulates angiogenesis through TGF-beta receptor activation.
Berndt, Sarah; Blacher, Silvia ULg; Munaut, Carine ULg et al

in FASEB Journal (2013), 27(4), 1309-21

Embryo implantation requires extensive angiogenesis at the maternal-fetal interface. Hyperglycosylated human chorionic gonadotropin (hCG-H), a trophoblast invasive signal produced by extravillous ... [more ▼]

Embryo implantation requires extensive angiogenesis at the maternal-fetal interface. Hyperglycosylated human chorionic gonadotropin (hCG-H), a trophoblast invasive signal produced by extravillous cytotrophoblasts and by choriocarcinoma, was evaluated for its angiogenic role. hCG-H was purified by HPLC from choriocarcinoma supernatant, and the glycosylation pattern was determined by 2D gel analysis. Angiogenesis models used were aortic ring assay with wild-type and LHCGR-knockout mice, endothelial and mural cell proliferation, and migration assays. The TGF-beta signaling pathway was studied by coimmunoprecipitation, competitive binding, TGF-beta reporter gene assays, and Smad immunoblotting. hCG-H displayed a potent angiogenic effect [3.2-fold increase of number of vessel intersections in wild-type aortic rings (11.406 to 36.964)]. hCG-H-induced angiostimulation was independent of the classic hCG signaling pathway since it persisted in LHCGR-knockout mice [4.73-fold increase of number of vessel intersections (10.826 to 51.288)]. Using TGF-beta signaling inhibitors, Tbeta-RII was identified as the hCG-H receptor responsible for its angiogenic switch. hCG-H exposure enhanced phosphorylation of Smad 2 in endothelial and mural cells and genomic activation of Smad-responsive elements. Interaction between hCG-H and Tbeta-RII was demonstrated by coimmunoprecipitation and binding competition with (125)I-TGF-beta. This new paracrine interaction between trophoblast and endothelial cells through the hCG-H and the TGF-beta receptor complex plays a key role in angiogenesis associated with placental development and tumorigenesis. [less ▲]

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See detailSéminaire des chercheurs Télévie 2013
Cimino, Jonathan ULg; Sounni, Nor Eddine ULg; Calligaris, David ULg et al

Poster (2012, December 10)

Séminaire des chercheurs Télévie 2013

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See detailUnderstanding angiogenesis through novel epigenetic modulators
Shiva Shankar, Thammadihalli Veerasangaiah ULg; Sulka, Béatrice; Blacher, Silvia ULg et al

Scientific conference (2012, June 22)

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA ... [more ▼]

DNA methylation and histone deacetylation are two key epigenetic modifications that play central role in regulation of gene expression. Several studies have shown that histone deacetylases (HDAC) and DNA methyltransferases (DNMT) inhibitors are potent anti-angiogenic compounds. Though combination of HDAC and DNMT inhibitors are now being examined in clinical trials of hematological malignancies, little work has been done to understand the effect of this combination on physiological and tumoral angiogenesis. We have designed and tested a family of twin drugs with intrinsic HDAC and DNMT inhibitory activities in relevant models of angiogenesis in vitro (Human Umbilical Vein Endothelial Cells – HUVEC and aortic ring) and in vivo (chick chorioallantoic membrane and Zebrafish). We have identified a lead compound having quantifiable anti-angiogenic effect without cytotoxicity affecting global histone acetylation and DNA methylation levels. In order to elucidate its anti-angiogenic mechanism, we characterized gene expression pattern simultaneously with the methylation profile of HUVEC cells treated with the lead compound and reference epigenetic modulators. This approach based on parallel microarray analyses permitted us to underscore a list of genes exclusively affected by the lead compound but not by other HDAC or DNMT inhibitors. These genes were then analyzed using the Ingenuity Pathway software revealing potential involvement of a subset of genes in angiogenesis. Our present work is focused on exploring the exact role of these genes on angiogenesis using RNA silencing and vectors cloned with genes of interest. We are using these novel epigenetic modulators as a tool to understand the regulatory mechanism of angiogenesis and to develop effective approaches to treat cancer. [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 detailIsoform 111 of vascular endothelial growth factor (VEGF111) improves angiogenesis of ovarian tissue xenotransplantation
Labied, Soraya ULg; Delforge, Yves ULg; Blacher, Silvia ULg et al

in Journal of Assisted Reproduction & Genetics (2012), 28(11), 1009

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See detailDoes vascular endothelial growth factor improve ovarian tissue recovery after cryopreservation?
Henry, Laurie ULg; Fransolet, Maïté ULg; Labied, Soraya ULg et al

in Giornale italiano di obstetricia e gynecologia (2012)

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See detailBone Marrow-derived Myofibroblasts Are the Providers of Pro-invasive Matrix Metalloproteinase 13 in Primary Tumor.
Lecomte, Julie ULg; Masset, Anne; Blacher, Silvia ULg 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 ▲]

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See detailStromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis.
Pequeux, Christel ULg; Raymond-Letron, I; Blacher, Silvia ULg 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 ▲]

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See detailEffect of CO2 activation of carbon xerogels on the adsorption of methylene blue
Páez Martínez, Carlos ULg; Contreras, M. S.; Léonard, Angélique ULg et al

in Adsorption (2012), 18(3-4), 199-211

The effect of physical activation with CO2 of carbon xerogels, synthesized by pyrolysis of a resorcinolformaldehyde aqueous gel, on the adsorption capacities of Methylene Blue (MB) was studied. The ... [more ▼]

The effect of physical activation with CO2 of carbon xerogels, synthesized by pyrolysis of a resorcinolformaldehyde aqueous gel, on the adsorption capacities of Methylene Blue (MB) was studied. The activation with CO2 lead to carbon materials with micropore volumes ranging from 0.28 to 0.98 cm³/g -1 C. MB-adsorption isotherm studies showed that the increase of micropore volume and corresponding surface area led to: (i) a significant improvement in the capacity of MB-adsorption at monolayer coverage, from 212 to 714 mgg -1 C, and (ii) an increase of the binding energy related to Langmuir isotherm constant up to 45 times greater than those of commercial microporous activated carbons used as reference (NORIT R2030, CALGON BPL and CALGON NC35). It is proposed that the increase of the binding energy results from chemical cleaning of the O-groups onto carbon surface as a consequence of CO2-activation, increasing the π-π interaction between MB and graphene layers of the carbon xerogels. Finally, a series of batch kinetics were performed to investigate the effect of CO2-activation conditions on the mechanism of MB-adsorption. Experimental data were fitted using pseudo-first-order, pseudo-second-order and intraparticle diffusion kinetic models. From pseudo-second-order kinetic model, one observes an increase in the initial rate of MB-adsorption from 0.019 to 0.0565 min -1, by increasing the specific surface area from 630 to 2180 m²/g -1 C via CO2-activation. Depending on the activation degree of the carbons, two different mechanisms control the MB-adsorption rate: (i) at low activation degree, the intraparticle diffusion is the rate-limiting phenomenon, whereas (ii) at high activation degree, the reactions occurring at the solid/liquid interface are the rate-limiting steps. © 2012 Springer Science+Business Media, LLC. [less ▲]

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See detailAbnormal vascular architecture at the placental-maternal interface in placenta increta
CHANTRAINE, Frédéric ULg; Blacher, Silvia ULg; Berndt, Sarah et al

in American Journal of Obstetrics and Gynecology (2012), 207(3), 1881-9

Objective The objective of the study was to characterize the vascular architecture at the placental-maternal interface in pregnancies complicated by placenta increta and normal pregnancies. Study Design ... [more ▼]

Objective The objective of the study was to characterize the vascular architecture at the placental-maternal interface in pregnancies complicated by placenta increta and normal pregnancies. Study Design Vessel numbers and cross-section area density and spatial and area distributions in 13 placenta-increta placental beds were compared with 9 normal placental beds using computer-assisted image analysis of whole-slide CD31 immunolabeled sections. Results The total areas occupied by vessels in normal and placenta-increta placental beds were comparable, but vessels were significantly sparser and larger in the latter. Moreover, placenta-increta–vessel distributions (area and distance from the placental–myometrial junction) were more heterogeneous. Conclusion Size and spatial organization of the placenta-increta vascular architecture at the placental-maternal interface differed from normal and might partially explain the severe hemorrhage observed during placenta-increta deliveries. [less ▲]

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See detailAdsorption of methylene blue on activated carbon xerogels
Páez Martínez, Carlos ULg; Contreras, Maria Soledad; Léonard, Angélique ULg et al

Poster (2011, November 30)

Detailed reference viewed: 57 (11 ULg)