References of "Noël, Agnès"
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See detailEar Sponge Assay: A Method to Investigate Angiogenesis and Lymphangiogenesis in Mice.
Van De Velde, Maureen ULiege; Garcia-Caballero, Melissa; Durré, Tania ULiege et al

in Proteases and Cancer: Methods and Protocols (2018)

Angiogenesis and lymphangiogenesis have become important research areas in the biomedical field. The outgrowth of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels from preexisting ones ... [more ▼]

Angiogenesis and lymphangiogenesis have become important research areas in the biomedical field. The outgrowth of new blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels from preexisting ones is involved in many pathologies including cancer. In-depth investigations of molecular determinants such as proteases in these complex processes require reliable in vivo models. Here we present the ear sponge assay as an easy, rapid, quantitative and reproducible model of angiogenesis and lymphangiogenesis. In this system, a gelatin sponge soaked with tumor cells, cell-conditioned medium, or a compound to be tested is implanted, for 2-4 weeks, between the two mouse ear skin layers. The two vascular networks are next examined through histological procedures. [less ▲]

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See detailInflammation-Generated Extracellular Matrix Fragments Drive Lung Metastasis
BEKAERT, Sandrine; Fillet, Marianne ULiege; Detry, Benoit et al

in Cancer Growth and Metastasis (2017), 10

Mechanisms explaining the propensity of a primary tumor to metastasize to a specific site still need to be unveiled, and clinical studies support a link between chronic inflammation and cancer ... [more ▼]

Mechanisms explaining the propensity of a primary tumor to metastasize to a specific site still need to be unveiled, and clinical studies support a link between chronic inflammation and cancer dissemination to specific tissues. Using different mouse models, we demonstrate the role of inflammation-generated extracellular matrix fragments ac-PGP (N-acetyl-proline-glycine-proline) on tumor cells dissemination to lung parenchyma. In mice exposed to cigarette smoke or lipopolysaccharide, lung neutrophilic inflammation produces increased levels of MMP-9 (matrix metalloproteinase 9) that contributes to collagen breakdown and allows the release of ac-PGP tripeptides. By silencing CXCR2 gene expression in tumor cells, we show that these generated ac-PGP tripeptides exert a chemotactic activity on tumor cells in vivo by binding CXCR2. [less ▲]

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See detailERα- and dose-dependent effect of estetrol on angiogenesis and tumor growth
Gallez, Anne ULiege; BLACHER, Silvia ULiege; Gérard, Céline et al

Poster (2017, November 07)

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See detailESTROGEN RECEPTORS AND ESTETROL-DEPENDENT NEUROPROTECTIVE ACTIONS: A PILOT STUDY
Tskitishvili, Ekaterine ULiege; Pequeux, Christel ULiege; Munaut, Carine ULiege et al

Conference (2017, October 20)

Context: Estetrol (E4) has strong antioxidative, neurogenic and angiogenic effects in neural system resulting in the attenuation of neonatal hypoxic–ischemic encephalopathy. Objective: We aimed to define ... [more ▼]

Context: Estetrol (E4) has strong antioxidative, neurogenic and angiogenic effects in neural system resulting in the attenuation of neonatal hypoxic–ischemic encephalopathy. Objective: We aimed to define the role of estrogen receptors in E4-dependent actions in neuronal cell cultures and prove the promyelinating effect of E4. Methods: In vitro the antioxidative and cell survival/proliferating effects of E4 on H2O2-induced oxidative stress in primary hippocampal cell cultures were studied using different combinations of specific inhibitors for ERα (MPP dihydrochloride), ERβ (PHTTP), GPR30 (G15) and palmytoilation (2-BR). LDH activity and cell survival assays were performed. In vivo the promyelinating role of different concentrations of E4 (1 mg/kg/day, 5 mg/kg/day, 10 mg/kg/day, 50 mg/kg/day) was investigated using the hypoxic–ischemic brain damage model in the 7-day-old immature rats before/after the induction of hypoxic–ischemic insult. Myelin basic protein (MBP) immunostaining was performed on brain coronal sections. Results: Our results show that LDH activity is significantly upregulated in cell cultures where the E4’s effect was completely blocked by concomitant treatment either with ERα and ERβ inhibitors (MPP and PHTPP, respectively), or ERα and ERβ inhibitors combined with 2-BR. Cell survival is significantly downregulated in cell cultures where the effect of E4 was blocked by ERβ inhibitor (PHTTP) alone. The blockage of GRP30 receptor did affect neither LDH activity nor cell survival. MBP immunostaining is significantly upregulated in E4-pretreated groups at a concentration of 5 mg/kg/day and 50 mg/kg/day E4, whereas the MBP-positive area OD ratio is significantly increased in all the E4-treated groups. Conclusions: E4’s antioxidative actions mostly depend on ERα and ERβ, whereas neurogenesis and possibly promyelinating activities might be realized through ERβ. [less ▲]

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See detailFrom Metabolomics Study of Age-Related Macular Degeneration (AMD) to the Development of New Pyruvate Dehydrogenase Kinase Inhibitors (PDK)
Arslan, Deniz ULiege; Schoumacher, Matthieu ULiege; Pirotte, Bernard ULiege et al

Poster (2017, September 14)

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small part of ... [more ▼]

Age-related macular degeneration (AMD) is a leading cause of blindness in the elderly population of industrialized countries. This blindness results from the deterioration of the macula, a small part of the retina specialized for the high-acuity vision. Exudative AMD, called “wet”, is characterized by the formation of new blood vessels growing under the retina according to a process named choroidal neovascularization (CNV). Currently, the aetiology and pathogenesis of AMD remain unclear. Nevertheless, a recent metabolomics study performed on the serum of “wet” AMD patients and on a CNV murine model, that mimics the effect of “wet” AMD, have demonstrated that lactate level is clearly involved in the severity of the pathology as well as the relationship between lactate, CNV and AMD [1]. According to this result, we suggest a new therapeutic approach of AMD based on the normalization of blood lactate level. The modulation of the lactate plasma concentration by treatment of the animals with synthetic compounds and more specifically Pyruvate Dehydrogenase Kinase (PDK) inhibitors significantly decrease the CNV. PDK and its four isoforms (PDK1-4) regulate the activity of the pyruvate dehydrogenase complex (PDH), a mitochondrial enzyme that plays a major role in the metabolic pathway of glucose, by reversible phosphorylation. Starting from these results, development of new PDK inhibitors could open the way to innovative treatment opportunities in AMD disease. Different analogues of (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (fig.1) have been already synthetized and pharmacological evaluation is currently in progress. According to the results obtained, various pharmacomodulations will be investigated. [less ▲]

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See detailNF-kB-dependent regulation of TET1 in breast cancers
Canale, Annalisa ULiege; Collignon, Evelyne; Al Wardi, Clémence et al

Poster (2017, June 26)

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See detailCharacterization of the pre-metastatic niche in lymph node, in experimental and clinical settings
Noël, Agnès ULiege; Balsat, Cédric; Garcia Caballero, Melissa et al

Poster (2017, June 08)

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See detailDose-Dependant effect of Estetrol on Angiogenesis and Tumor growth
Gallez, Anne ULiege; BLACHER, Silvia ULiege; Lenfant, Françoise et al

Conference (2017, May 19)

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

Conference (2017, May 05)

Our previous studies have shown that an early postnatal exposure to a very low dose of bisphenol A (BPA) disrupts sexual maturation and pubertal timing. However, the long-term effects of such low dose ... [more ▼]

Our previous studies have shown that an early postnatal exposure to a very low dose of bisphenol A (BPA) disrupts sexual maturation and pubertal timing. However, the long-term effects of such low dose exposure as well as the effects of adult exposure have not been studied. One day-old and 90 day-old female rats received daily subcutaneous injections of corn oil (vehicle) or BPA (25ng/kg/d or 5mg/kg/d) for 15 days. The early postnatal exposure to both BPA doses significantly decreased the percentage of females with a regular cycle (BPA-25ng: 51±15%; BPA-5mg: 7±7%; OIL: 86±2%). The estrus cycle alterations were characterized by a decrease in time spent in proestrus (BPA-25ng: 13±3%; BPA-5mg: 12±3%; OIL: 18±3%). During adult exposure, both doses caused a disruption of the estrous cycle characterized by a significant decrease in the average time spent in proestrus (BPA-25ng: 19±2%; BPA-5mg: 17±1%; OIL: 23±1%). This effect was transient as the exposed females showed a regular cycle one month after the last dose of BPA. After adult exposure, we also observed a disruption of folliculogenesis characterized by a significant decrease of antral follicles (BPA-25ng: 21±2%; BPA-5mg: 21±2%; OIL: 36±2%) and increase of atretic follicles (BPA-25ng: 24±4%; BPA-5mg: 26±6%; OIL: 15±1%). GnRH secretion measured ex vivo 24h after adult exposure was moderately affected by BPA. Indeed, GnRH interpulse interval was significantly different when comparing animals exposed to the high or low dose of BPA but not when comparingexposed animals to the control group (BPA-25ng: 42.6±0.5; BPA-5mg: 40.2±0.6%; OIL: 41.1±0,2minutes±SEM). In conclusion, while exposure to BPA produces persistent alterations of the estrous cycle after early postnatal exposure, exposure during adulthood appears to cause activational non-persistent alternations of both the estrous cycle and folliculogenesis. [less ▲]

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See detailDose-dependent effect of Estetrol on Angiogenesis and Tumor Growth
Gallez, Anne ULiege; Blacher, Silvia ULiege; Lenfant, Françoise et al

Poster (2017, April 24)

Hormone replacement therapies (HRT) based on estrogen preparations are the most powerful treatments to prevent menopause symptoms. However, they are associated to an increased risk of breast cancer and ... [more ▼]

Hormone replacement therapies (HRT) based on estrogen preparations are the most powerful treatments to prevent menopause symptoms. However, they are associated to an increased risk of breast cancer and they sustain the development of Estrogen Receptor α-positive tumors (ERα+). In addition, we have previously observed that estradiol (E2) can promote the growth of ERα-negative (ERα-) tumors, by increasing tumor angiogenesis that subsequently improves oxygen and nutrients delivery, thereby preventing hypoxia and necrosis. To identify new and safe drugs for the development of HRT presenting a better benefit/risk ratio, it is therefore necessary to evaluate the potential impact of new candidates on both ERα+ and ERα- tumors. In this context, estetrol (E4), a natural estrogen exclusively produced by the fetal liver, is a promising candidate. [less ▲]

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See detailCancer associated fibroblast-derived integrin α11 regulates PDGFRβ signaling to promote breast cancer progression
Primac, Irina ULiege; Blacher, Silvia ULiege; cimino, Jonathan et al

Conference (2017, April 24)

CAF-specific proteins can provide important prognostic markers and targets for anticancer drugs. Recently, integrin α11 (ITGA11) emerged as a new biomarker of CAFs. ITGA11 is mainly expressed by ... [more ▼]

CAF-specific proteins can provide important prognostic markers and targets for anticancer drugs. Recently, integrin α11 (ITGA11) emerged as a new biomarker of CAFs. ITGA11 is mainly expressed by mesenchymal cells and is correlated with fibroblast activation and matrix reorganization. While the role of ITGA11 in wound healing has been well described, only a very limited number of reports have assessed its role in the cancer disease. This research project aims to investigate the role of stromal ITGA11 in breast cancer. To analyze the in vivo effects of ITGA11 on tumor insurgence, growth and metastasis, we crossed the oncogenic MMTv-PyMT mice with the ITGA11 KO/WT mice, which develop spontaneously breast tumors. ITGA11 deletion strongly delayed tumor growth and metastasis in PyMT mouse model. ITGA11 was poorly expressed at early stages of the tumor progression and its expression was strongly increased in the late stage invasive carcinomas. Importantly, a reduced angiogenesis and collagen content was observed in tumors lacking of ITGA11. Furthermore, a strong co-localization between ITGA11 and PDGFRb, but not other CAF markers such as alpha smooth actin, was also observed within the tumor stroma, suggesting that ITGA11 defines a subpopulation of CAFs, which is not represented by myofibroblasts, but rather PDGFRb+ CAFs. For mechanistic investigation, CAFs and breast cancer cells were isolated from the PyMT model. ITGA11 co-immunoprecipitated with PDGFRb in the isolated CAFs and regulated its phosphorylation. Interestingly, ITGA11-deficient CAFs failed to promote CAF and cancer cell invasion, in contrast to WT CAFs in a spheroid invasion assay. A high throughput comparative proteomics analysis on CAF spheroids in 3D a system was next performed. Proteomics data identified several proteins with relevance in the cancer disease which were significantly modulated in CAFs through ITGA11 down-regulation. The top-ranking candidates are under validation and molecular pathways, which may link these targets and ITGA11 will be further analyzed in the in vitro models. Overall, these in vivo and in vitro data show that ITGA11 defines a PDGFRβ+ subpopulation of CAFs distinct from α-SMA+ myofibroblasts that promote tumor cell invasion and angiogenesis at late stages of carcinoma evolution. ITGA11 is a promising target within the stroma of breast cancer and further investigations of its molecular signaling pathways will be of great relevance. [less ▲]

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See detailZonula occludens-1/NF-κB/CXCL8: a new regulatory axis for tumor angiogenesis.
Lesage, Julien; Suarez-Carmona, Meggy; Neyrinck-Leglantier, Deborah et al

in FASEB Journal (2017), 31(4), 1678-1688

Zonula occludens-1 (ZO-1) is a submembrane scaffolding protein that may display proinvasive functions when it relocates from tight junctions into the cytonuclear compartment. This article examines the ... [more ▼]

Zonula occludens-1 (ZO-1) is a submembrane scaffolding protein that may display proinvasive functions when it relocates from tight junctions into the cytonuclear compartment. This article examines the functional involvement of ZO-1 in CXCL8/IL-8 chemokine expression in lung and breast tumor cells. ZO-1 small interfering RNA and cDNA transfection experiments emphasized regulation of CXCL8/IL-8 expression via a cytonuclear pool of ZO-1. Luciferase reporter assays highlighted a 173-bp region of CXCL8/IL-8 promoter that responded to ZO-1. Moreover, by using mutated promoter constructs, we identified a NF-κB site as critical in this activation. Furthermore, NF-κB pathway signaling analysis revealed both IκBα and p65 phosphorylation in ZO-1-overexpressing cells, and subsequent p65 silencing validated its requirement for CXCL8/IL-8 induction. Investigation of the functional implication of this regulatory axis next showed the proangiogenic activity of ZO-1 in both ex vivo and in vivo angiogenesis assays. Finally, we found that non-small-cell lung carcinoma that presented a cytonuclear ZO-1 pattern was significantly more angiogenic that that without detectable cytonuclear ZO-1 expression. Taken together, our results demonstrate that ZO-1 regulates CXCL8/IL-8 expression via the NF-κB signaling pathway and its p65 subunit, which subsequently modulates the transcription of IL-8. We also provide evidence of a newly identified regulatory pathway that could promote angiogenesis. Thus, our results support the concept that the ZO-1 shuttle from the cell junction to the cytonuclear compartment may affect both the intrinsic invasive properties of tumor cells and the establishment of the protumoral microenvironment. [less ▲]

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See detailAccurate Control of 17beta-Estradiol Long-Term Release Increases Reliability and Reproducibility of Preclinical Animal Studies.
Gérard, Céline ULiege; Gallez, Anne ULiege; Dubois, Charline ULiege et al

in Journal of Mammary Gland Biology & Neoplasia (2017), 22(1), 1-11

Estrogens are the subject of intensive researches aiming to elucidate their mechanism of action on the various tissues they target and especially on mammary gland and breast cancer. The use of ready-to ... [more ▼]

Estrogens are the subject of intensive researches aiming to elucidate their mechanism of action on the various tissues they target and especially on mammary gland and breast cancer. The use of ready-to-use slow releasing devices to administer steroids, especially estrogens, to small experimental animals remains the method of choice in terms of animal well-being and of safety for both the researcher and the animal. In this study, we evaluated and compared, in vitro and in vivo, the release kinetic of estradiol (E2) over sixty days from two different slow-releasing systems: the matrix pellet (MP) and the reservoir implant (RI). We compared the impact of these systems in three E2-sensitive mouse models : mammary gland development, human MCF7 adenocarcinoma xenograft and mouse melanoma progression. The real amount of E2 that is released from both types of devices could differ from manufacturer specifications due to inadequate release for MP and initial burst effect for RI. Compared to MP, the interindividual variability was reduced with RI thanks to a superior control of the E2 release. Depending on the dose-dependent sensitivity of the physiological or pathological readout studied, this could lead to an improvement of the statistical power of in vivo experiments and thus to a reduction of the required animal number. Altogether, our data draw attention on the importance to adequately select the slow-releasing device that is the most appropriated to a specific experiment to better fulfill the 3Rs rule (Replacement, Reduction, Refinement) related to animal welfare and protection. [less ▲]

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See detailImproved computer-assisted analysis of the global lymphatic network in human cervical tissues.
BALSAT, Cédric ULiege; Signolle, N; Goffin, Frédéric ULiege et al

in Modern Pathology : An Official Journal of the United States & Canadian Academy of Pathology, Inc (2017), 30(2), 313

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See detailA specific immune and lymphatic profile characterizes the pre-metastatic state of the sentinel lymph node in patients with early cervical cancer
Balsat, Cédric ULiege; Blacher, Silvia ULiege; Herfs, Michael ULiege et al

in Oncoimmunology (2017), 6(2), 1265718

The lymph node (LN) pre-metastatic niche is faintly characterized in lymphophilic human neoplasia, although LN metastasis is considered as the strongest prognostic marker of patient survival. Due to its ... [more ▼]

The lymph node (LN) pre-metastatic niche is faintly characterized in lymphophilic human neoplasia, although LN metastasis is considered as the strongest prognostic marker of patient survival. Due to its specific dissemination through a complex bilateral pelvic lymphatic system, early cervical cancer is a relevant candidate for investigating the early nodal metastatic process. In the present study, we analyzed in-depth both the lymphatic vasculature and the immune climate of pre-metastatic sentinel LN (SLN), in 48 cases of FIGO stage IB1 cervical neoplasms. An original digital image analysis methodology was used to objectively determine whole slide densities and spatial distributions of immunostained structures. We observed a marked increase in lymphatic vessel density (LVD) and a specific capsular and subcapsular distribution in pre-metastatic SLN when compared with non-sentinel counterparts. Such features persisted in the presence of nodal metastatic colonization. The inflammatory profile attested by CD8+, Foxp3, CD20 and PD-1expression was also significantly increased in pre-metastatic SLN. Remarkably, the densities of CD20+ B cells and PD-1 expressing germinal centers were positively correlated with LVD. All together, these data strongly support the existence of a pre-metastatic dialog between the primary tumor and the first nodal relay. Both lymphatic and immune responses contribute to the elaboration of a specific pre-metastatic microenvironment in human SLN. Moreover, this work provides evidence that, in the context of early cervical cancer, a pre-metastatic lymphangiogenesis occurs within the SLN (pre-metastatic niche) and is associated with a specific humoral immune response. [less ▲]

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