References of "Blacher, Silvia"
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See detailDysregulated circulating miRNAs in pre-eclampsia
Tebache, Linda; Munaut, Carine ULiege; Blacher, Silvia ULiege et al

Conference (2016, September 25)

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See detailNovel application assigned to toluquinol: inhibition of lymphangiogenesis by interfering with VEGF-C/VEGFR-3 signaling pathway.
Garcia-Caballero, Melissa; Blacher, Silvia ULiege; Paupert, J. et al

in British Journal of Pharmacology (2016), 173(12), 1966-87

BACKGROUND AND PURPOSE: Lymphangiogenesis is an important biological process associated with the pathogenesis of several diseases, including metastatic dissemination, graft rejection, lymphedema and other ... [more ▼]

BACKGROUND AND PURPOSE: Lymphangiogenesis is an important biological process associated with the pathogenesis of several diseases, including metastatic dissemination, graft rejection, lymphedema and other inflammatory disorders. The development of new drugs blocking lymphangiogenesis has become a promising therapeutic strategy. In this study, we aim at investigating the ability of toluquinol, a 2-methyl-hydroquinone isolated from the culture broth of the marine fungus Penicillium sp. HL-85-ALS5-R004, to inhibit lymphangiogenesis in vitro, ex vivo and in vivo. EXPERIMENTAL APPROACH: We used human lymphatic endothelial cells (LEC) to analyze the effect of toluquinol in 2D and 3D in vitro cultures, and in the ex vivo mouse lymphatic ring assay. For in vivo approaches, the transgenic Fli1:eGFPy1 zebrafish, the mouse ear sponges and cornea models were used. Western-blotting and apoptosis analyses were carried out to search for drug targets. KEY RESULTS: Toluquinol inhibited LEC proliferation, migration, tubulogenesis and sprouting of new lymphatic vessels. Furthermore, toluquinol induced LEC apoptosis after 14 h of treatment in vitro, blocked the thoracic duct development in zebrafish, and reduced the VEGF-C-induced lymphatic vessel formation and corneal neovascularization in mice. Mechanistically, we are providing evidence that this drug abrogates the VEGF-C-induced VEGFR-3 phosphorylation in a dose-dependent manner, and represses Akt and ERK1/2 phosphorylations. CONCLUSIONS AND IMPLICATIONS: Based on these findings, we propose toluquinol as a new candidate with pharmacological potential for the treatment of lymphangiogenesis-related pathologies. Notably, its ability to suppress corneal neovascularization paves the way for applications in vascular ocular pathologies. This article is protected by copyright. All rights reserved. [less ▲]

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See detailEstetrol, a natural SERM exhibiting combined estrogenic and anti-estrogenic properties on mammary gland and breast cancer
Gallez, Anne ULiege; Gérard, Céline ULiege; Blacher, Silvia ULiege et al

Poster (2016, May 30)

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would ... [more ▼]

The increased risk of breast cancer and thromboembolism in women who take hormone replacement therapy (HRT) is a major public health problem. The discovery of new drugs with better safety profile would provide useful advances for patient care. Estetrol (E4) is a liver friendly promising candidate for HRT. In preclinical and/or clinical studies, E4 has been effective against the main symptoms of menopause from a starting dose of 0.3 mg/kg/day. The aim of this study was to define the impact of E4 on mammary gland and breast cancer development. Our preclinical data show that E4 is less efficient than estradiol (E2) to induce mammary gland growth. Treatment with several concentrations of E4 has shown that E4 did not increase tumor development, when it is used at 0.3 mg/kg/day. However, at 3 mg/kg/day, E4 increased tumor growth similarly to E2 (0.08 mg/kg/day). E4 presents also some anti-estrogenic effects on mammary gland and antitumor activity on breast cancer by decreasing the strong proliferative effect of E2. While ERα is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extra-nuclear signaling pathways are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. In conclusion, our results support that E4, if it is used in strictly controlled clinical applications, could have no or only limited impact on breast and breast cancer. [less ▲]

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See detailEstetrol, a natural SERM exhibiting combined estrogenic and antiestrogenic properties on mammary gland and breast cancer
Gérard, Céline ULiege; Gallez, Anne ULiege; Blacher, Silvia ULiege et al

Conference (2016, May 09)

The increased risk of breast cancer and thromboembolism in women who take Hormone Replacement Therapy (HRT) currently is a major public health problem. The discovery of novel molecules with better safety ... [more ▼]

The increased risk of breast cancer and thromboembolism in women who take Hormone Replacement Therapy (HRT) currently is a major public health problem. The discovery of novel molecules with better safety profile would provide useful advances for patient care. Estretrol (E4) appears as a promising candidate for HRT. Indeed, in contrast to current treatment containing ethinyl estradiol or estradiol (E2), E4 has a minimal impact on liver cells activity supporting a decreased incidence on thromboembolic events. In preclinical studies, E4 has been effective against the main symptoms of menopause such as hot flushes, vaginal atrophy, and osteoporosis, from a starting dose of 0.3 mg/kg/day. The aim of this study was to define the impact of E4 on mammary gland and breast cancer development when it is used at concentrations effective for menopause symptom relief. We report preclinical data showing that E4 is less efficient than E2 to induce mammary gland growth. Treatment of estrogen receptor (ER)-positive breast cancer with several concentrations of E4 has shown that 0.3 mg/kg/day E4 did not increase tumor development. However, at 3mg/kg/day, E4 increased the growth of hormone-dependent tumors and their metastatic dissemination in ovariectomized and intact mice. This effect was similar to the one observed with E2 used at 0.08 mg/kg/day. E4 presents also some anti-estrogenic effects on mammary gland and antitumor activity on breast cancer by decreasing the strong proliferative effect of E2. While ERα is the predominant receptor mediating its effects, the dual weak-estrogenic/anti-estrogenic feature of E4 results from differential signaling pathways activation. Both nuclear and rapid extranuclear signaling pathways are necessary for a complete estrogenic effect of E4. However, the antitumor action of E4 is not due to a capacity to antagonize E2-induced nuclear activity. In conclusion, our results support that E4, if it is used in strictly controlled clinical applications, could have no or only limited impact on breast and breast cancer. [less ▲]

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See detailDynamics of Internalization and Recycling of the Pro-Metastatic Membrane Type 4-Matrix Metalloproteinase (MT4-MMP) in Breast Cancer Cells
Truong, Alice ULiege; Yip, Cassandre ULiege; PAYE, Alexandra ULiege et al

in FEBS Journal (2016), 283(4), 704-22

MT4-MMP (MMP17) is a glycosylphosphatidyl inositol (GPI)-anchored membrane-type MMP expressed on the cell surface of human breast cancer cells. In triple negative breast cancer cells, MT4-MMP promotes ... [more ▼]

MT4-MMP (MMP17) is a glycosylphosphatidyl inositol (GPI)-anchored membrane-type MMP expressed on the cell surface of human breast cancer cells. In triple negative breast cancer cells, MT4-MMP promotes primary tumor growth and lung metastases. Although trafficking and internalization of the transmembrane MT1-MMP have been extensively investigated, little is known about the regulatory mechanisms of the GPI-anchored MT4-MMP. Here, we investigated the fate and cellular trafficking of MT4-MMP by analyzing its homophilic complex interactions, internalization and recycling dynamics compared to an inert form, MT4-MMP-E249A. Oligomeric and dimeric complexes were analyzed by co-transfection of cells with FLAG- or Myc-tagged MT4-MMP by reducing and non-reducing immunoblots and co-immunoprecipitation experiments. The trafficking of MT4-MMP was studied using an antibody feeding assay and confocal microscopy analysis or cell surface protein biotinylation and Western blot analysis. We demonstrate that MT4-MMP forms homophilic complexes at the cell surface, internalizes in early endosomes, and some of the enzyme is either auto-degraded or recycled to the cell surface. Our data indicate that MT4-MMP is internalized by the CLIC/GEEC pathway, a mechanism that differs from other MT-MMP members. Although MT4-MMP localizes with caveolin-1, MT4-MMP internalization was not affected by inhibitors of caveolin-1 or clathrin endocytosis pathways but was reduced by cdc42 or RhoA silencing with siRNA. We provide a new mechanistic insight into the regulatory mechanisms of MT4-MMP, which may have implications in the design of novel therapeutic strategies for metastatic breast cancer. This article is protected by copyright. All rights reserved. [less ▲]

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See detailAdult exposure to BPA causes activational disruption of estrous cycle and folliculogenesis
Lopez Rodriguez, David ULiege; Franssen, Delphine ULiege; GERARD, Arlette ULiege et al

Conference (2016)

Our society is facing a public health challenge caused by the increasing presence of endocrine disrupting chemicals (EDCs). Bisphenol A (BPA) is a widespread EDC used in the manufacture of PVC and epoxy ... [more ▼]

Our society is facing a public health challenge caused by the increasing presence of endocrine disrupting chemicals (EDCs). Bisphenol A (BPA) is a widespread EDC used in the manufacture of PVC and epoxy resins. While early postnatal exposure to BPA disrupts sexual maturation andpubertal timing, , its effects on fertility after adult exposure have not yet been studied. Female Wistar rats were exposed for 15 days to corn oil or a low (25ng/kg/d) or a high (5mg/kg/d) BPA dose subcutateouslyat 90 days of age. Animals exposed to both doses showed a disruption of the estrous cyclicity characterized by a decrease in the average time spent in proestrus. We observed a disruption on folliculogenesis characterized by a significant decrease of antral follicles and increase of atretic follicles. The exposed females showed a regular cycle one month after the last dose of BPAWe did not observe any difference in the frequency or amplitude of GnRH secretion 24h after the end of exposure. We also observed that early postnatal exposure to BPA for 15 days disrupted estrous cycle during adulthood with a decrease in time spent in proestrus. In conclusion, exposure to BPA neonatally or during adulthood disrupts the estrous cycle and folliculogenesis. The effects of exposure to BPA during adulthood might be independent of GnRH secretion. Moreover, the effects of early postnatal exposure to BPA are persistent while exposure to BPA during adulthood appears to causeeactivational, non persistent alteration of the oestrus cycle. [less ▲]

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See detailActivational and organizational disruption of folliculogenesis and estrous cycle after an exposure to Bisphenol A (BPA) during early postnatal or adult window of exposure
Lopez Rodriguez, David ULiege; Franssen, Delphine ULiege; GERARD, Arlette ULiege et al

Poster (2016)

The increasing presence of endocrine disruption chemicals (EDCs) has been link with a reduction in fertility rate and alterations of pubertal timing. Bisphenol A (BPA) is a ubiquitous EDC used in the ... [more ▼]

The increasing presence of endocrine disruption chemicals (EDCs) has been link with a reduction in fertility rate and alterations of pubertal timing. Bisphenol A (BPA) is a ubiquitous EDC used in the manufacture of polyvinyl chloride (PVC) and epoxy resins that we can find in food containers and plastics. Our previous studies have shown that an early postnatal exposure to a low dose of BPA disrupts sexual maturation and pubertal timing. However, its long-term and adult effects on fertility have not yet been studied. Daily s.c injections of BPA were administered for 15 days to 1 and 90 day-old female Wistar rats at two different doses: a low dose of 25ng/kg/d and a high dose of 5mg/kg/d. The early postnatal exposure to both BPA doses produces a decrease in the percentage of female with a regular cycle characterized by a decrease on the time spend in proestrus (BPA-25ng 13,6±3,4; BPA-5mg 12,2±3,1%; OIL 18,7±3,2%). During exposure at adulthood, both doses caused a disruption of the estrous cycle characterized by a significant decrease in the average time spent in proestrus (BPA-25ng 18,9±2,2%; BPA-5mg 16,9±1,3%; OIL 23,3±0,9%). This effect was We also observed a disruption of folliculogenesis characterized by a significant decrease of antral follicles (BPA-25ng 21,4±2.1%; BPA-5mg 20,94±2%; OIL 35,6±1,6%) and increase of atretic follicles (BPA-25ng 24,2±3,9%; BPA-5mg 26,2±6,3%; OIL 15,5±0,8%). The exposed females showed a regular cycle one month after the last dose of BPA. In conclusion, both BPA doses have been found to produce a disruption of oestrus cycle and folliculogenesis depending on the window of exposure. While BPA produces persistent effects after early postnatal exposure, exposure during adulthood appears to cause activational, non-persistent alterations. [less ▲]

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See detailElastin density: Link between histological and biomechanical properties of vaginal tissue in women with pelvic organ prolapse?
DE LANDSHEERE, Laurent ULiege; Brieu, Mathias; Blacher, Silvia ULiege et al

in International Urogynecology Journal & Pelvic Floor Dysfunction (2016)

INTRODUCTION AND HYPOTHESIS: The aim of the study was to correlate histological and biomechanical characteristics of the vaginal wall in women with pelvic organ prolapse (POP). METHODS: Tissue samples ... [more ▼]

INTRODUCTION AND HYPOTHESIS: The aim of the study was to correlate histological and biomechanical characteristics of the vaginal wall in women with pelvic organ prolapse (POP). METHODS: Tissue samples were collected from the anterior [point Ba; POP Questionnaire (POP-Q)] and/or posterior (point Bp; POP-Q) vaginal wall of 15 women who underwent vaginal surgery for POP. Both histological and biomechanical assessments were performed from the same tissue samples in 14 of 15 patients. For histological assessment, the density of collagen and elastin fibers was determined by combining high-resolution virtual imaging and computer-assisted digital image analysis. For biomechanical testing, uniaxial tension tests were performed to evaluate vaginal tissue stiffness at low (C0) and high (C1) deformation rates. RESULTS: Biomechanical testing highlights the hyperelastic behavior of the vaginal wall. At low strains (C0), vaginal tissue appeared stiffer when elastin density was low. We found a statistically significant inverse relationship between C0 and the elastin/collagen ratio (p = 0.048) in the lamina propria. However, at large strain levels (C1), no clear relationship was observed between elastin density or elastin/collagen ratio and stiffness, likely reflecting the large dispersion of the mechanical behavior of the tissue samples. CONCLUSION: Histological and biomechanical properties of the vaginal wall vary from patient to patient. This study suggests that elastin density deserves consideration as a relevant factor of vaginal stiffness in women with POP. [less ▲]

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See detailDysregulated circulating miRNAs in preeclampsia.
Munaut, Carine ULiege; Tebache, Linda; Blacher, Silvia ULiege et al

in Biomedical Reports (2016), 5(6), 686-692

Preeclampsia (PE) is a pregnancy-related disease with potentially severe consequences with respect to foeto-maternal morbidity and mortality. However, the molecular pathogenesis of PE remains largely ... [more ▼]

Preeclampsia (PE) is a pregnancy-related disease with potentially severe consequences with respect to foeto-maternal morbidity and mortality. However, the molecular pathogenesis of PE remains largely unknown. Recent reports have shown that microRNAs (miRNAs or miRs) may play important roles in the development of PE. Analysing the miRNAs in sera from preeclamptic women may improve our understanding of the pathophysiological mechanisms of the disease. The aim of this retrospective study was to identify whether circulating miRNAs were differentially expressed in PE patients compared with controls. Serum samples from 23 women who developed PE were compared with samples from 44 pregnant controls. Seventeen circulating miRNAs previously described in PE were chosen for evaluation of their expression by reverse transcription quantitative polymerase chain reaction (RT-qPCR). In the maternal serum, the miR-210-3p, miR-210-5p, miR-1233-3p, and miR-574-5p levels were found to be significantly higher in the PE patients than in the controls (P<0.05). Using a logistic regression model, we evaluated the discriminant power of those differentially expressed miRNAs, and the combination of miR-210-5p and miR-574-5p yielded an area under the curve of 0.7223 for discriminating PE patients from the controls. In conclusion, the fact that four circulating miRNAs (miR-210-3p, miR-210-5p, miR-1233-3p, and miR-574-5p) were differentially expressed in the sera of women who developed PE compared with controls confirms the possible pathophysiological role of miRNAs in PE. [less ▲]

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See detailTissue factor induced by epithelial-mesenchymal transition triggers a pro-coagulant state that drives metastasis of circulating tumor cells.
Bourcy, Morgane ULiege; Suarez-Carmona, Meggy ULiege; Lambert, Justine ULiege et al

in Cancer Research (2016)

Epithelial-mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific ... [more ▼]

Epithelial-mesenchymal transition (EMT) is prominent in circulating tumor cells (CTC), but how it influences metastatic spread in this setting is obscure. Insofar as blood provides a specific microenvironment for tumor cells, we explored a potential link between EMT and coagulation that may provide EMT-positive CTC with enhanced colonizing properties. Here we report that EMT induces tissue factor (TF), a major cell-associated initiator of coagulation and related pro-coagulant properties in the blood. TF blockade by antibody or shRNA diminished the pro-coagulant activity of EMT-positive cells, confirming a functional role for TF in these processes. Silencing the EMT transcription factor ZEB1 inhibited both EMT-associated TF expression and coagulant activity, further strengthening the link between EMT and coagulation. Accordingly, EMT-positive cells exhibited a higher persistance/survival in the lungs of mice colonized after intravenous injection, a feature diminished by TF or ZEB1 silencing. In tumor cells with limited metastatic capability, enforcing expression of the EMT transcription factor Snail increased TF, coagulant properties and early metastasis. Clinically, we identified a subpopulation of CTC expressing vimentin and TF in the blood of metastatic breast cancer patients consistent with our observations. Overall, our findings define a novel EMT-TF regulatory axis which triggers local activation of coagulation pathways to support metastatic colonization of EMT-positive CTC. [less ▲]

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See detailImpact of estetrol on breast cancer development, metastatic dissemination and angiogenesis
Gallez, Anne ULiege; Gérard, Céline ULiege; Blacher, Silvia ULiege et al

Poster (2016)

The increased risk of breast cancer and thromboembolism in women who take Hormone Replacement Therapy (HRT) currently is a major public health problem. The discovery of novel molecules with better safety ... [more ▼]

The increased risk of breast cancer and thromboembolism in women who take Hormone Replacement Therapy (HRT) currently is a major public health problem. The discovery of novel molecules with better safety profile would provide useful advances for patient care. Estretrol (E4) appears as a promising candidate for HRT. Indeed, in contrast to current treatment containing ethinyl estradiol or estradiol (E2), E4 has a minimal impact on liver cells activity supporting a decreased incidence on thromboembolic events. In preclinical studies, E4 has been effective against the main symptoms of menopause such as hot flushes, vaginal atrophy, and osteoporosis, from a starting dose of 0.3 mg/kg/day. The aim of this study was to define the impact of E4 on breast cancer development when it is used at concentrations effective for menopause symptom relief. Treatment of estrogen receptor (ER)-positive breast cancer-developing mice (MMTV-PyMT) with several concentrations of E4 has shown that 0.3 mg/kg/day E4 did not increase tumor development and metastasis dissemination. However, at 3mg/kg/day, E4 increased the growth of hormone-dependent tumors and their metastatic dissemination in ovariectomized and intact mice. This effect was similar to the one observed with E2 used at 0.08 mg/kg/day. In an in vivo model of ER-negative tumors, we observed that 3mg/kg/day E4 improved tumor growth by increasing angiogenesis, and subsequently decreasing necrosis and tumor hypoxia. In contrast, 0.3 mg/kg/day E4 did not induce any of these effects on ER-negative tumors and tumor microenvironment. In conclusion, we have shown that 0.3 mg/kg/day E4, already reported to prevent menopause symptoms, does not increase breast tumor growth, metastasis dissemination, and angiogenesis. However, similarly to E2, higher concentrations of E4 are pro-tumorous. These results support that E4, if it is used in strictly controlled clinical applications, could have no or only limited impact on breast cancer. [less ▲]

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See detailQuantitative assessment of mouse mammary gland morphology using automated digital image processing and TEB detection.
Blacher, Silvia ULiege; Gérard, Céline ULiege; Gallez, Anne ULiege et al

in Endocrinology (2016)

The assessment of rodent mammary gland morphology is largely used to study the molecular mechanisms driving breast development and to analyze the impact of various endocrine disruptors with putative ... [more ▼]

The assessment of rodent mammary gland morphology is largely used to study the molecular mechanisms driving breast development and to analyze the impact of various endocrine disruptors with putative pathological implications. In this work, we propose a methodology relying on fully automated digital image analysis methods including image processing and quantification of the whole ductal tree and of the terminal end buds (TEB) as well. It allows to accurately and objectively measure both growth parameters and fine morphological glandular structures. Mammary gland elongation was characterized by two parameters: the length and the epithelial area of the ductal tree. Ductal tree fine structures were characterized by: 1) branch end-point density, 2) branching density and 3) branch length distribution. The proposed methodology was compared to quantification methods classically used in the literature. This procedure can be transposed to several software and thus largely used by scientists studying rodent mammary gland morphology. [less ▲]

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See detailSupplementation of transport and freezing media with anti-apoptotic drugs improves ovarian cortex survival
HENRY, Laurie ULiege; Fransolet, Maïté ULiege; LABIED, Soraya ULiege et al

in Journal of Ovarian Research (2016)

Background: Ovarian tissue preservation is proposed to patients at risk of premature ovarian failure, but this procedure still needs to be optimized. To limit injury during ovarian tissue cryopreservation ... [more ▼]

Background: Ovarian tissue preservation is proposed to patients at risk of premature ovarian failure, but this procedure still needs to be optimized. To limit injury during ovarian tissue cryopreservation, anti-apoptotic drugs were added to the transport and freezing media of ovarian cortex tissue. Methods: Sheep ovaries were transported, prepared and frozen in solutions containing vehicle or anti-apoptotic drugs (Z-VAD-FMK, a pan-caspase inhibitor, or sphingosine-1-phosphate (S1P), a bioactive lipid). After the tissue was thawed, the ovarian cortex was cultured for 2 or 6 days. Follicular quantification and morphological and proliferation analyses were performed on histological sections. Results: After 2 days of culture, S1P improved the quality of primordial follicles; higher densities of morphologically normal and proliferative primordial follicles were found. Z-VAD-FMK displayed similar effects by preserving global primordial follicular density, but this effect was evident after 6 days of culture. This drug also improved cell proliferation after 2 and 6 days of culture. Conclusions: Our results showed that the addition of S1P or Z-VAD-FMK to the transport and freezing media prior to ovarian tissue cryopreservation improves primordial follicular quality and therefore improves global tissue survival. This should ultimately lead to improved fertility restoration after auto-transplantation. [less ▲]

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