402 results on '"Agnès Noël"'
Search Results
2. Remodelling of the fibre-aggregate structure of collagen gels by cancer-associated fibroblasts: A time-resolved grey-tone image analysis based on stochastic modelling
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Cedric J. Gommes, Thomas Louis, Isabelle Bourgot, Agnès Noël, Silvia Blacher, and Erik Maquoi
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fibrillar collagen ,cancer ,cancer-associated-fibroblasts (CAFs) ,confocal microscopy ,image analysis ,stochastic modelling ,Immunologic diseases. Allergy ,RC581-607 - Abstract
IntroductionSolid tumors consist of tumor cells associated with stromal and immune cells, secreted factors and extracellular matrix (ECM), which together constitute the tumor microenvironment. Among stromal cells, activated fibroblasts, known as cancer-associated fibroblasts (CAFs) are of particular interest. CAFs secrete a plethora of ECM components including collagen and modulate the architecture of the ECM, thereby influencing cancer cell migration. The characterization of the collagen fibre network and its space and time-dependent microstructural modifications is key to investigating the interactions between cells and the ECM. Developing image analysis tools for that purpose is still a challenge because the structural complexity of the collagen network calls for specific statistical descriptors. Moreover, the low signal-to-noise ratio of imaging techniques available for time-resolved studies rules out standard methods based on image segmentation.MethodsIn this work, we develop a novel approach based on the stochastic modelling of the gel structure and on grey-tone image analysis. The method is then used to study the remodelling of a collagen matrix by migrating breast cancer-derived CAFs in a three-dimensional spheroid model of cellular invasion imaged by time-lapse confocal microscopy.ResultsThe structure of the collagen at the scale of a few microns consists in regions with high fibre density separated by depleted regions, which can be thought of as aggregates and pores. The approach developped captures this two-scale structure with a clipped Gaussian field model to describe the aggregates-and-pores large-scale structure, and a homogeneous Boolean model to describe the small-scale fibre network within the aggregates. The model parameters are identified by fitting the grey-tone histograms and correlation functions of the images. The method applies to unprocessed grey-tone images, and it can therefore be used with low magnification, noisy time-lapse reflectance images. When applied to the CAF spheroid time-resolved images, the method reveals different matrix densification mechanisms for the matrix in direct contact or far from the cells.ConclusionWe developed a novel and multidisciplinary image analysis approach to investigate the remodelling of fibrillar collagen in a 3D spheroid model of cellular invasion. The specificity of the method is that it applies to the unprocessed grey-tone images, and it can therefore be used with noisy time-lapse reflectance images of non-fluorescent collagen. When applied to the CAF spheroid time-resolved images, the method reveals different matrix densification mechanisms for the matrix in direct contact or far from the cells.
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- 2023
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3. Evaluation of an alternative heterotopic transplantation model for ovarian tissue to test pharmaceuticals improvements for fertility restoration
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Carmen Terren, Jules Bindels, Michelle Nisolle, Agnès Noël, and Carine Munaut
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Ovarian tissue transplantation ,Heterotopic transplantation ,Animal model ,Fertility restoration ,Gynecology and obstetrics ,RG1-991 ,Reproduction ,QH471-489 - Abstract
Abstract Background Ovarian tissue cryopreservation and transplantation (OTCTP) is currently the main option available to preserve fertility in prepubertal patients undergoing aggressive cancer therapy treatments. However, a major limitation of OTCTP is follicle loss after transplantation. The mouse is a model of choice for studying ovarian function and follicle development after ovarian tissue grafting in vivo. In these mouse models, ovarian tissue or ovaries can be transplanted to different sites. Our aim was to evaluate a new alternative to heterotopic transplantation models that could be useful to test pharmaceutical improvement for ovarian grafts after OTCTP. Methods Slow frozen murine whole ovaries were transplanted into the mouse ears (between the external ear skin layer and the cartilage). Ovarian transplants were recovered after 3, 14 or 21 days. Grafts were analyzed by immunohistochemistry and follicle density analyses were performed. Results An increase of ovarian vascularization (CD31 and Dextran-FITC positive staining), as well as cellular proliferation (Ki67 staining) were observed 3 weeks after transplantation in comparison to 3 days. Fibrosis density, evaluated after Van Gieson staining, decreased 3 weeks after transplantation. Furthermore, transplantation of cryopreserved ovaries into ovariectomized mice favored follicle activation compared to transplantation into non-ovariectomized mice. Conclusion The present study indicates that surgical tissue insertion in the highly vascularized murine ear is an effective model for ovarian grafting. This model could be helpful in research to test pharmaceutical strategies to improve the function and survival of cryopreserved and transplanted ovarian tissue.
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- 2022
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4. ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in adults for pro-VEGFC activation and lymphatic homeostasis
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Laura Dupont, Loïc Joannes, Florent Morfoisse, Silvia Blacher, Christine Monseur, Christophe F. Deroanne, Agnès Noël, and Alain C.M.A. Colige
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Angiogenesis ,Vascular biology ,Medicine - Abstract
The capacity of ADAMTS3 to cleave pro-VEGFC into active VEGFC able to bind its receptors and to stimulate lymphangiogenesis has been clearly established during embryonic life. However, this function of ADAMTS3 is unlikely to persist in adulthood because of its restricted expression pattern after birth. Because ADAMTS2 and ADAMTS14 are closely related to ADAMTS3 and are mainly expressed in connective tissues where the lymphatic network extends, we hypothesized that they could substitute for ADAMTS3 during adulthood in mammals allowing proteolytic activation of pro-VEGFC. Here, we demonstrated that ADAMTS2 and ADAMTS14 are able to process pro-VEGFC into active VEGFC as efficiently as ADAMTS3. In vivo, adult mice lacking Adamts2 developed skin lymphedema due to a reduction of the density and diameter of lymphatic vessels, leading to a decrease of lymphatic functionality, while genetic ablation of Adamts14 had no impact. In a model of thermal cauterization of cornea, lymphangiogenesis was significantly reduced in Adamts2- and Adamts14-KO mice and further repressed in Adamts2/Adamts14 double-KO mice. In summary, we have demonstrated that ADAMTS2 and ADAMTS14 are as efficient as ADAMTS3 in activation of pro-VEGFC and are involved in the homeostasis of the lymphatic vasculature in adulthood, both in physiological and pathological processes.
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- 2022
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5. ZO-1 Intracellular Localization Organizes Immune Response in Non-Small Cell Lung Cancer
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Déborah Neyrinck-Leglantier, Julien Lesage, Silvia Blacher, Arnaud Bonnomet, Walter Hunziker, Agnès Noël, Valérian Dormoy, Béatrice Nawrocki-Raby, Christine Gilles, and Myriam Polette
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epithelial plasticity ,ZO-1 ,epithelial-mesenchymal transition ,immune infiltrate ,tumor microenvironment ,lung cancer ,Biology (General) ,QH301-705.5 - Abstract
Delocalization of zonula occludens-1 (ZO-1) from tight junctions plays a substantial role in epithelial cell plasticity observed during tumor progression. In vitro, we reported an impact of ZO-1 cyto-nuclear content in modulating the secretion of several pro-inflammatory chemokines. In vivo, we demonstrated that it promotes the recruitment of immune cells in mouse ear sponge assays. Examining lung cancers, we showed that a high density of CD8 cytotoxic T cells and Foxp3 immunosuppressive regulatory T cells in the tumor microenvironment correlated with a cyto-nuclear expression of ZO-1. Taken together, our results support that, by affecting tumor cell secretome, the cyto-nuclear ZO-1 pool may recruit immune cells, which could be permissive for tumor progression.
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- 2021
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6. Tumor Microenvironment Modifications Recorded With IVIM Perfusion Analysis and DCE-MRI After Neoadjuvant Radiotherapy: A Preclinical Study
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François Lallemand, Natacha Leroi, Silvia Blacher, Mohamed Ali Bahri, Evelyne Balteau, Philippe Coucke, Agnès Noël, Alain Plenevaux, and Philippe Martinive
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radiotherapy ,surgery ,cancer ,neoadjuvant ,DW-MRI ,DCE MRI ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
PurposeNeoadjuvant radiotherapy (NeoRT) improves tumor local control and facilitates tumor resection in many cancers. Some clinical studies demonstrated that both timing of surgery and RT schedule influence tumor dissemination, and subsequently patient overall survival. Previously, we developed a pre-clinical model demonstrating the impact of NeoRT schedule and timing of surgery on metastatic spreading. We report on the impact of NeoRT on tumor microenvironment by MRI.MethodsAccording to our NeoRT model, MDA-MB 231 cells were implanted in the flank of SCID mice. Tumors were locally irradiated (PXI X-Rad SmART) with 2x5Gy and then surgically removed at different time points after RT. Diffusion-weighted (DW) and Dynamic contrast enhancement (DCE) MRI images were acquired before RT and every 2 days between RT and surgery. IntraVoxel Incoherent Motion (IVIM) analysis was used to obtain information on intravascular diffusion, related to perfusion (F: perfusion factor) and subsequently tumor vessels perfusion. For DCE-MRI, we performed semi-quantitative analyses.ResultsWith this experimental model, a significant and transient increase of the perfusion factor F [50% of the basal value (n=16, p
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- 2021
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7. Combined Blockade of GARP:TGF-β1 and PD-1 Increases Infiltration of T Cells and Density of Pericyte-Covered GARP+ Blood Vessels in Mouse MC38 Tumors
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Charlotte Bertrand, Pierre Van Meerbeeck, Grégoire de Streel, Noora Vaherto-Bleeckx, Fatima Benhaddi, Loïc Rouaud, Agnès Noël, Pierre G. Coulie, Nicolas van Baren, and Sophie Lucas
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GARP ,TGF-β1 ,cancer immunotherapy ,immunosuppression ,immune checkpoint inhibition ,Immunologic diseases. Allergy ,RC581-607 - Abstract
When combined with anti-PD-1, monoclonal antibodies (mAbs) against GARP:TGF-β1 complexes induced more frequent immune-mediated rejections of CT26 and MC38 murine tumors than anti-PD-1 alone. In both types of tumors, the activity of anti-GARP:TGF-β1 mAbs resulted from blocking active TGF-β1 production and immunosuppression by GARP-expressing regulatory T cells. In CT26 tumors, combined GARP:TGF-β1/PD-1 blockade did not augment the infiltration of T cells, but did increase the effector functions of already present anti-tumor T cells. Here we show that, in contrast, in MC38, combined GARP:TGF-β1/PD-1 blockade increased infiltration of T cells, as a result of increased extravasation of T cells from blood vessels. Unexpectedly, combined GARP:TGF-β1/PD-1 blockade also increased the density of GARP+ blood vessels covered by pericytes in MC38, but not in CT26 tumors. This appears to occur because anti-GARP:TGF-β1, by blocking TGF-β1 signals, favors the proliferation of and expression of adhesion molecules such as E-selectin by blood endothelial cells. The resulting densification of intratumoral blood vasculature probably contributes to increased T cell infiltration and to the therapeutic efficacy of GARP:TGF-β1/PD-1 blockade in MC38. We conclude from these distinct observations in MC38 and CT26, that the combined blockades of GARP:TGF-β1 and PD-1 can exert anti-tumor activity via multiple mechanisms, including the densification and normalization of intratumoral blood vasculature, the increase of T cell infiltration into the tumor and the increase of the effector functions of intratumoral tumor-specific T cells. This may prove important for the selection of cancer patients who could benefit from combined GARP:TGF-β1/PD-1 blockade in the clinics.
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- 2021
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8. Reciprocal Interplay Between Fibrillar Collagens and Collagen-Binding Integrins: Implications in Cancer Progression and Metastasis
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Isabelle Bourgot, Irina Primac, Thomas Louis, Agnès Noël, and Erik Maquoi
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fibrillar collagens ,extracellular matrix ,integrins ,cancer ,metastasis ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Cancers are complex ecosystems composed of malignant cells embedded in an intricate microenvironment made of different non-transformed cell types and extracellular matrix (ECM) components. The tumor microenvironment is governed by constantly evolving cell-cell and cell-ECM interactions, which are now recognized as key actors in the genesis, progression and treatment of cancer lesions. The ECM is composed of a multitude of fibrous proteins, matricellular-associated proteins, and proteoglycans. This complex structure plays critical roles in cancer progression: it functions as the scaffold for tissues organization and provides biochemical and biomechanical signals that regulate key cancer hallmarks including cell growth, survival, migration, differentiation, angiogenesis, and immune response. Cells sense the biochemical and mechanical properties of the ECM through specialized transmembrane receptors that include integrins, discoidin domain receptors, and syndecans. Advanced stages of several carcinomas are characterized by a desmoplastic reaction characterized by an extensive deposition of fibrillar collagens in the microenvironment. This compact network of fibrillar collagens promotes cancer progression and metastasis, and is associated with low survival rates for cancer patients. In this review, we highlight how fibrillar collagens and their corresponding integrin receptors are modulated during cancer progression. We describe how the deposition and alignment of collagen fibers influence the tumor microenvironment and how fibrillar collagen-binding integrins expressed by cancer and stromal cells critically contribute in cancer hallmarks.
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- 2020
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9. Targeting VEGFR-3/-2 signaling pathways with AD0157: a potential strategy against tumor-associated lymphangiogenesis and lymphatic metastases
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Melissa García-Caballero, Jenny Paupert, Silvia Blacher, Maureen Van de Velde, Ana Rodríguez Quesada, Miguel Angel Medina, and Agnès Noël
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AD0157 ,Lymphangiogenesis ,VEGFR-3/-2 ,Lymph nodes ,Lymphatic metastasis ,Diseases of the blood and blood-forming organs ,RC633-647.5 ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Abstract Background Lymphatic metastasis is one of the leading causes of death in patients with different types of cancer and is the main prognostic factor for the disease survival. The formation of new lymphatic vessels (lymphangiogenesis) in primary tumors facilitates tumor cell dissemination to regional lymph nodes and correlates with distant metastases. Lymphangiogenesis has thus emerged as a suitable therapeutic target to block metastases, but no anti-lymphangiogenic compounds have been approved for clinical use to date. Therefore, new or improved therapies blocking lymphatic metastases are urgently required. Methods We established murine breast tumors to assess the effect of AD0157 on tumor growth, lymphangiogenesis, and lymphatic dissemination. Then, a battery of in vivo (mouse corneal neovascularization and ear sponges), ex vivo (mouse lymphatic rings and rat mesentery explants), and in vitro (proliferation, tubulogenesis, wound-healing, Boyden chambers, and spheroids) assays was used to give insight into the lymphangiogenic steps affected by AD0157. Finally, we investigated the molecular pathways controlled by this drug. Results AD0157 was found to inhibit the growth of human breast cancer xenografts in mice, to strongly reduce tumor-associated lymphangiogenesis and to block metastatic dissemination to both lymph nodes and distant organs. The high anti-lymphangiogenic potency of AD0157 was further supported by its inhibitory activity at low micromolar range in two in vivo pathological models and in two ex vivo assays. In addition, AD0157 inhibited lymphatic endothelial cell proliferation, migration and invasion, cellular sprouting, and tube formation. Mechanistically, this compound induced apoptosis in lymphatic endothelial cells and decreased VEGFR-3/-2, ERK1/2, and Akt phosphorylations. Conclusions These findings demonstrate the suitability of AD0157 to suppress tumor-associated lymphangiogenesis. Beyond discovering a new potent anti-lymphangiogenic drug that is worth considering in future clinical settings, our study supports the interest of designing anti-lymphangiogenic therapies to avoid distant metastatic processes.
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- 2017
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10. MT4-MMP: The GPI-Anchored Membrane-Type Matrix Metalloprotease with Multiple Functions in Diseases
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Cassandre Yip, Pierre Foidart, Agnès Noël, and Nor Eddine Sounni
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MT4-MMP ,cancer ,diseases ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
MT4-MMP (or MMP17) belongs to the Membrane-Type Matrix Metalloproteinase (MT-MMP) family. This family of proteases contributes to extracellular matrix remodeling during several physiological processes, including embryogenesis, organogenesis, tissue regeneration, angiogenesis, wound healing, and inflammation. MT4-MMP (MMP17) presents unique characteristics compared to other members of the family in terms of sequence homology, substrate specificity, and internalization mode, suggesting distinct physiological and pathological functions. While the physiological functions of MT4-MMP are poorly understood, it has been involved in different pathological processes such as arthritis, cardiovascular disease, and cancer progression. The mt4-mmp transcript has been detected in a large diversity of cancers. The contribution of MT4-MMP to tumor development has been further investigated in gastric cancer, colon cancer, head and neck cancer, and more deeply in breast cancer. Given its contribution to different pathologies, particularly cancers, MT4-MMP represents an interesting therapeutic target. In this review, we examine its biological and structural properties, and we propose an overview of its physiological and pathological functions.
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- 2019
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11. A membrane-type-1 matrix metalloproteinase (MT1-MMP)-discoidin domain receptor 1 axis regulates collagen-induced apoptosis in breast cancer cells.
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Delphine Assent, Isabelle Bourgot, Benoît Hennuy, Pierre Geurts, Agnès Noël, Jean-Michel Foidart, and Erik Maquoi
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Medicine ,Science - Abstract
During tumour dissemination, invading breast carcinoma cells become confronted with a reactive stroma, a type I collagen-rich environment endowed with anti-proliferative and pro-apoptotic properties. To develop metastatic capabilities, tumour cells must acquire the capacity to cope with this novel microenvironment. How cells interact with and respond to their microenvironment during cancer dissemination remains poorly understood. To address the impact of type I collagen on the fate of tumour cells, human breast carcinoma MCF-7 cells were cultured within three-dimensional type I collagen gels (3D COL1). Using this experimental model, we have previously demonstrated that membrane type-1 matrix metalloproteinase (MT1-MMP), a proteinase overexpressed in many aggressive tumours, promotes tumour progression by circumventing the collagen-induced up-regulation of BIK, a pro-apoptotic tumour suppressor, and hence apoptosis. Here we performed a transcriptomic analysis to decipher the molecular mechanisms regulating 3D COL1-induced apoptosis in human breast cancer cells. Control and MT1-MMP expressing MCF-7 cells were cultured on two-dimensional plastic plates or within 3D COL1 and a global transcriptional time-course analysis was performed. Shifting the cells from plastic plates to 3D COL1 activated a complex reprogramming of genes implicated in various biological processes. Bioinformatic analysis revealed a 3D COL1-mediated alteration of key cellular functions including apoptosis, cell proliferation, RNA processing and cytoskeleton remodelling. By using a panel of pharmacological inhibitors, we identified discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase specifically activated by collagen, as the initiator of 3D COL1-induced apoptosis. Our data support the concept that MT1-MMP contributes to the inactivation of the DDR1-BIK signalling axis through the cleavage of collagen fibres and/or the alteration of DDR1 receptor signalling unit, without triggering a drastic remodelling of the transcriptome of MCF-7 cells.
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- 2015
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12. Conditioned medium from bone marrow-derived mesenchymal stem cells improves recovery after spinal cord injury in rats: an original strategy to avoid cell transplantation.
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Dorothée Cantinieaux, Renaud Quertainmont, Silvia Blacher, Loïc Rossi, Thomas Wanet, Agnès Noël, Gary Brook, Jean Schoenen, and Rachelle Franzen
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Medicine ,Science - Abstract
Spinal cord injury triggers irreversible loss of motor and sensory functions. Numerous strategies aiming at repairing the injured spinal cord have been studied. Among them, the use of bone marrow-derived mesenchymal stem cells (BMSCs) is promising. Indeed, these cells possess interesting properties to modulate CNS environment and allow axon regeneration and functional recovery. Unfortunately, BMSC survival and differentiation within the host spinal cord remain poor, and these cells have been found to have various adverse effects when grafted in other pathological contexts. Moreover, paracrine-mediated actions have been proposed to explain the beneficial effects of BMSC transplantation after spinal cord injury. We thus decided to deliver BMSC-released factors to spinal cord injured rats and to study, in parallel, their properties in vitro. We show that, in vitro, BMSC-conditioned medium (BMSC-CM) protects neurons from apoptosis, activates macrophages and is pro-angiogenic. In vivo, BMSC-CM administered after spinal cord contusion improves motor recovery. Histological analysis confirms the pro-angiogenic action of BMSC-CM, as well as a tissue protection effect. Finally, the characterization of BMSC-CM by cytokine array and ELISA identified trophic factors as well as cytokines likely involved in the beneficial observed effects. In conclusion, our results support the paracrine-mediated mode of action of BMSCs and raise the possibility to develop a cell-free therapeutic approach.
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- 2013
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13. Differential expression of Vegfr-2 and its soluble form in preeclampsia.
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Carine Munaut, Sophie Lorquet, Christel Pequeux, Capucine Coulon, Jeanne Le Goarant, Frédéric Chantraine, Agnès Noël, Frédéric Goffin, Vassilis Tsatsaris, Damien Subtil, and Jean-Michel Foidart
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Medicine ,Science - Abstract
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.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.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.
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- 2012
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14. MicroRNA-21 exhibits antiangiogenic function by targeting RhoB expression in endothelial cells.
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Céline Sabatel, Ludovic Malvaux, Nicolas Bovy, Christophe Deroanne, Vincent Lambert, Maria-Luz Alvarez Gonzalez, Alain Colige, Jean-Marie Rakic, Agnès Noël, Joseph A Martial, and Ingrid Struman
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Medicine ,Science - Abstract
BackgroundMicroRNAs (miRNAs) are endogenously expressed small non-coding RNAs that regulate gene expression at post-transcriptional level. The recent discovery of the involvement of these RNAs in the control of angiogenesis renders them very attractive in the development of new approaches for restoring the angiogenic balance. Whereas miRNA-21 has been demonstrated to be highly expressed in endothelial cells, the potential function of this miRNA in angiogenesis has never been investigated.Methodology/principal findingsWe first observed in endothelial cells a negative regulation of miR-21 expression by serum and bFGF, two pro-angiogenic factors. Then using in vitro angiogenic assays, we observed that miR-21 acts as a negative modulator of angiogenesis. miR-21 overexpression reduced endothelial cell proliferation, migration and the ability of these cells to form tubes whereas miR-21 inhibition using a LNA-anti-miR led to opposite effects. Expression of miR-21 in endothelial cells also led to a reduction in the organization of actin into stress fibers, which may explain the decrease in cell migration. Further mechanistic studies showed that miR-21 targets RhoB, as revealed by a decrease in RhoB expression and activity in miR-21 overexpressing cells. RhoB silencing impairs endothelial cell migration and tubulogenesis, thus providing a possible mechanism for miR-21 to inhibit angiogenesis. Finally, the therapeutic potential of miR-21 as an angiogenesis inhibitor was demonstrated in vivo in a mouse model of choroidal neovascularization.Conclusions/significanceOur results identify miR-21 as a new angiogenesis inhibitor and suggest that inhibition of cell migration and tubulogenesis is mediated through repression of RhoB.
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- 2011
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15. Enhanced activity of meprin-α, a pro-migratory and pro-angiogenic protease, in colorectal cancer.
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Daniel Lottaz, Christoph A Maurer, Agnès Noël, Silvia Blacher, Maya Huguenin, Alexandra Nievergelt, Verena Niggli, Alexander Kern, Stefan Müller, Frank Seibold, Helmut Friess, Christoph Becker-Pauly, Walter Stöcker, and Erwin E Sterchi
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Medicine ,Science - Abstract
Meprin-α is a metalloprotease overexpressed in cancer cells, leading to the accumulation of this protease in a subset of colorectal tumors. The impact of increased meprin-α levels on tumor progression is not known. We investigated the effect of this protease on cell migration and angiogenesis in vitro and studied the expression of meprin-α mRNA, protein and proteolytic activity in primary tumors at progressive stages and in liver metastases of patients with colorectal cancer, as well as inhibitory activity towards meprin-α in sera of cancer patient as compared to healthy controls. We found that the hepatocyte growth factor (HGF)-induced migratory response of meprin-transfected epithelial cells was increased compared to wild-type cells in the presence of plasminogen, and that the angiogenic response in organ-cultured rat aortic explants was enhanced in the presence of exogenous human meprin-α. In patients, meprin-α mRNA was expressed in colonic adenomas, primary tumors UICC (International Union Against Cancer) stage I, II, III and IV, as well as in liver metastases. In contrast, the corresponding protein accumulated only in primary tumors and liver metastases, but not in adenomas. However, liver metastases lacked meprin-α activity despite increased expression of the corresponding protein, which correlated with inefficient zymogen activation. Sera from cancer patients exhibited reduced meprin-α inhibition compared to healthy controls. In conclusion, meprin-α activity is regulated differently in primary tumors and metastases, leading to high proteolytic activity in primary tumors and low activity in liver metastases. By virtue of its pro-migratory and pro-angiogenic activity, meprin-α may promote tumor progression in colorectal cancer.
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- 2011
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16. The Pbx interaction motif of Hoxa1 is essential for its oncogenic activity.
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Stéphanie Delval, Arnaud Taminiau, Juliette Lamy, Cécile Lallemand, Christine Gilles, Agnès Noël, and René Rezsohazy
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Medicine ,Science - Abstract
Hoxa1 belongs to the Hox family of homeodomain transcription factors involved in patterning embryonic territories and governing organogenetic processes. In addition to its developmental functions, Hoxa1 has been shown to be an oncogene and to be overexpressed in the mammary gland in response to a deregulation of the autocrine growth hormone. It has therefore been suggested that Hoxa1 plays a pivotal role in the process linking autocrine growth hormone misregulation and mammary carcinogenesis. Like most Hox proteins, Hoxa1 can interact with Pbx proteins. This interaction relies on a Hox hexapeptidic sequence centred on conserved Tryptophan and Methionine residues. To address the importance of the Hox-Pbx interaction for the oncogenic activity of Hoxa1, we characterized here the properties of a Hoxa1 variant with substituted residues in the hexapeptide and demonstrate that the Hoxa1 mutant lost its ability to stimulate cell proliferation, anchorage-independent cell growth, and loss of contact inhibition. Therefore, the hexapeptide motif of Hoxa1 is required to confer its oncogenic activity, supporting the view that this activity relies on the ability of Hoxa1 to interact with Pbx.
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- 2011
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17. Does plasminogen activator inhibitor-1 drive lymphangiogenesis?
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Françoise Bruyère, Laurence Melen-Lamalle, Silvia Blacher, Benoît Detry, Anne Masset, Julie Lecomte, Vincent Lambert, Catherine Maillard, Gunilla Høyer-Hansen, Leif R Lund, Jean-Michel Foidart, and Agnès Noël
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Medicine ,Science - Abstract
The purpose of this study is to explore the function of plasminogen activator inhibitor-1 (PAI-1) during pathological lymphangiogenesis. PAI-1, the main physiological inhibitor of plasminogen activators is involved in pathological angiogenesis at least by controlling extracellular proteolysis and by regulating endothelial cell survival and migration. Protease system's role in lymphangiogenesis is unknown yet. Thus, based on its important pro-angiogenic effect, we hypothesized that PAI-1 may regulate lymphangiogenesis associated at least with metastatic dissemination of cancer cells. To address this issue, we studied the impact of PAI-1 deficiency in various murine models of tumoral lymphangiogenesis. Wild-type PAI-1 proficient mice were used as controls. We provide for the first time evidence that PAI-1 is dispensable for tumoral lymphangiogenesis associated with breast cancers either induced by mammary carcinoma cell injection or spontaneously appearing in transgenic mice expressing the polyomavirus middle T antigen (PymT) under the control of a mouse mammary tumor virus long-terminal repeat promoter (MMTV-LTR). We also investigated inflammation-related lymphatic vessel recruitment by using two inflammatory models. PAI-1 deficiency did neither affect the development of lymphangioma nor burn-induced corneal lymphangiogenesis. These novel data suggest that vascular remodelling associated with lymphangiogenesis and angiogenesis involve different molecular determinants. PAI-1 does not appear as a potential therapeutic target to counteract pathological lymphangiogenesis.
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- 2010
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18. Design, Synthesis, and Evaluation of Novel Pyruvate Dehydrogenase Kinase Inhibitors
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Bernard Pirotte, Deniz Arslan, Matthieu Schoumacher, Sébastien Dilly, Benaïssa Elmoualij, Danièle Zorzi, Pascale Quatresooz, Vincent Lambert, Agnès Noël, and Pascal de Tullio
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Drug Discovery - Abstract
Aims: The present work describes the synthesis and the biological evaluation of novel compounds acting as pyruvate dehydrogenase kinase (PDK) inhibitors. These drugs should become a new therapeutic approach for the treatment of pathologies improved by the control of the blood lactate level. Methods: Four series of compounds belonging to N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2- methylpropanamides and 1,2,4-benzothiadiazine 1,1-dioxides were prepared and evaluated as PDK inhibitors. Results: The newly synthesized N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-methylpropanamides structurally related to previously reported reference compounds 4 and 5 were found to be potent PDK inhibitors (i.e. 10d: IC50 = 41 nM). 1,2,4-Benzothiadiazine 1,1-dioxides carrying a (methyl/ trifluoromethyl)-propanamide moiety at the 6-position were also designed as conformationally restricted ring-closed analogues of N-(4-(N-alkyl/aralkylsulfamoyl)phenyl)-2-hydroxy-2-methylpropanamides. Most of them were found to be less potent than their ring-opened analogues. Interestingly, the best choice of hydrocarbon side chain at the 4-position was the benzyl chain, providing 11c (IC50 = 3.6 μM) belonging to “unsaturated” 1,2,4-benzothiadiazine 1,1-dioxides, and 12c (IC50 = 0.5 μM) belonging to “saturated’ 1,2,4-benzothiadiazine 1,1-dioxides. Conclusion: This work showed that ring-closed analogues of N-(4-(N-alkyl/aralkylsulfamoyl) phenyl)- 2-hydroxy-2-methylpropanamides were less active as PDK inhibitors than their corresponding ring-opened analogues. However, the introduction of a bulkier substituent at the 4-position of the 1,2,4-benzothiadiazine 1,1-dioxide core structure, such as a benzyl or a phenethyl side chain, was allowed, opening the way to the design of new inhibitors with improved PDK inhibitory activity.
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- 2023
19. Supplementary Data from Expression of MT4-MMP, EGFR, and RB in Triple-Negative Breast Cancer Strongly Sensitizes Tumors to Erlotinib and Palbociclib Combination Therapy
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Guy Jerusalem, Nor Eddine Sounni, Agnès Noël, Elisabetta Marangoni, Véronique Jossa, Michel Coibion, Joëlle Collignon, Sophie Château-Joubert, Elodie Montaudon, Erik Maquoi, Laetitia Montero-Ruiz, Mehdi Lienard, Silvia Blacher, Jean Radermacher, Cassandre Yip, and Pierre Foidart
- Abstract
Supplemental data include a Supplemental Table-1, Supplemental Figure 1, Supplemental Figure 2, Supplemental Figure 3, Supplemental Figure 4, Supplemental Figure 5 and Supplemental Figure 6. Supplemental Table-1 is related to Figure 1 Supplemental Figure 1 is related to Figure 2 Supplemental Figure 2 is related to Figure 5 Supplemental Figures 3-5 are related to Figure 6 Supplemental Figure 6 is related to Figure 1 and Figure 5
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- 2023
20. Data from Expression of MT4-MMP, EGFR, and RB in Triple-Negative Breast Cancer Strongly Sensitizes Tumors to Erlotinib and Palbociclib Combination Therapy
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Guy Jerusalem, Nor Eddine Sounni, Agnès Noël, Elisabetta Marangoni, Véronique Jossa, Michel Coibion, Joëlle Collignon, Sophie Château-Joubert, Elodie Montaudon, Erik Maquoi, Laetitia Montero-Ruiz, Mehdi Lienard, Silvia Blacher, Jean Radermacher, Cassandre Yip, and Pierre Foidart
- Abstract
Purpose:Here, we investigated the clinical relevance of an unprecedented combination of three biomarkers in triple-negative breast cancer (TNBC), both in human samples and in patient-derived xenografts of TNBC (PDX-TNBC): EGFR, its recently identified partner (MT4-MMP), and retinoblastoma protein (RB).Experimental Design: IHC analyses were conducted on human and PDX-TNBC samples to evaluate the production of the three biomarkers. The sensitivity of cancer cells expressing or not MT4-MMP to anti-EGFR (erlotinib) or anti-CDK4/6 inhibitor (palbociclib) was evaluated in vitro in 2D and 3D proliferation assays and in vivo using xenografts and PDX-TNBC displaying different RB, MT4-MMP, and EGFR status after single (erlotinib or palbociclib) or combined (erlotinib + palbociclib) treatments.Results:EGFR and MT4-MMP were coexpressed in >70% of TNBC samples and PDX-TNBC, among which approximately 60% maintained RB expression. Notably, approximately 50% of all TNBC and PDX-TNBC expressed the three biomarkers. Single erlotinib and palbociclib treatments drastically reduced the in vitro proliferation of cells expressing EGFR and MT4-MMP when compared with control cells. Both TNBC xenografts and PDX expressing MT4-MMP, EGFR, and RB, but not PDX-TNBC with RB loss, were sensitive to erlotinib and palbociclib with an additive effect of combination therapy. Moreover, this combination was efficient in another PDX-TNBC expressing the three biomarkers and resistant to erlotinib alone.Conclusions:We defined a new association of three biomarkers (MT4-MMP/EGFR/RB) expressed together in 50% of TNBC and demonstrated its usefulness to predict the TNBC response to anti-EGFR and anti-CDK4/6 drugs used in single or combined therapy.
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- 2023
21. Data from Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells
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Christine Gilles, Myriam Polette, Cécile Oury, Agnès Noël, Brett G. Hollier, Silvia Blacher, Marc Thiry, Geert Berx, Guy Jérusalem, Erik W. Thompson, Nicolas Skrypek, Céline Delierneux, Hélène Schroeder, Marie-Emilie Francart, Justine Lambert, Meggy Suarez-Carmona, and Morgane Bourcy
- Abstract
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 CTCs with enhanced colonizing properties. Here we report that EMT induces tissue factor (TF), a major cell-associated initiator of coagulation and related procoagulant properties in the blood. TF blockade by antibody or shRNA diminished the procoagulant 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 that triggers local activation of coagulation pathways to support metastatic colonization of EMT-positive CTCs. Cancer Res; 76(14); 4270–82. ©2016 AACR.
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- 2023
22. Supplementary Figure 4 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
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Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux
- Abstract
PDF file - 140K, Vessel stabilization
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- 2023
23. Supplementary Methods, Table 1 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
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Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux
- Abstract
PDF file - 156K
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- 2023
24. Supplementary Figure 7 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
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Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux
- Abstract
PDF file - 139, ER� is efficiently suppressed in BM and BM-derived cells using chimeric hematopoietic approach
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- 2023
25. Supplementary Figure 2 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
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Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux
- Abstract
PDF file - 364K, B16K1, LL2 and 4T1 characterization
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- 2023
26. Supplementary Figure 1 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
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Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux
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PDF file - 162K, Vessel diameter quantification by granulometry
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- 2023
27. Supplementary Figure 3 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
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Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux
- Abstract
PDF file - 122K, B16K1 time- and size-dependent tumor harvesting
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- 2023
28. Supplementary Materials and Methods from Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells
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Christine Gilles, Myriam Polette, Cécile Oury, Agnès Noël, Brett G. Hollier, Silvia Blacher, Marc Thiry, Geert Berx, Guy Jérusalem, Erik W. Thompson, Nicolas Skrypek, Céline Delierneux, Hélène Schroeder, Marie-Emilie Francart, Justine Lambert, Meggy Suarez-Carmona, and Morgane Bourcy
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Supplementary Materials and Methods
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- 2023
29. Supplementary Table 1 to 4 from Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells
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Christine Gilles, Myriam Polette, Cécile Oury, Agnès Noël, Brett G. Hollier, Silvia Blacher, Marc Thiry, Geert Berx, Guy Jérusalem, Erik W. Thompson, Nicolas Skrypek, Céline Delierneux, Hélène Schroeder, Marie-Emilie Francart, Justine Lambert, Meggy Suarez-Carmona, and Morgane Bourcy
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Supplementary Table 1: list of siRNA used. Supplementary Table 2: list of primers used. Supplementary Table 3: list of antibodies used in different applications. Supplementary Table 4: list of patients and donors information
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- 2023
30. Supplementary Figure Legends from Tissue Factor Induced by Epithelial–Mesenchymal Transition Triggers a Procoagulant State That Drives Metastasis of Circulating Tumor Cells
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Christine Gilles, Myriam Polette, Cécile Oury, Agnès Noël, Brett G. Hollier, Silvia Blacher, Marc Thiry, Geert Berx, Guy Jérusalem, Erik W. Thompson, Nicolas Skrypek, Céline Delierneux, Hélène Schroeder, Marie-Emilie Francart, Justine Lambert, Meggy Suarez-Carmona, and Morgane Bourcy
- Abstract
Supplementary Figure Legends
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- 2023
31. Data from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
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Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux
- Abstract
Estrogens directly promote the growth of breast cancers that express the estrogen receptor α (ERα). However, the contribution of stromal expression of ERα in the tumor microenvironment to the protumoral effects of estrogen has never been explored. In this study, we evaluated the molecular and cellular mechanisms by which 17β-estradiol (E2) impacts the microenvironment and modulates tumor development of ERα-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 ERα-deficient mice, showing a critical role of host ERα. Notably, E2 did not accelerate tumor growth when ERα was deficient in Tie2-positive cells, even in mice grafted with wild-type bone marrow. These results were extended by clinical evidence of ERα-positive stromal cell labeling in the microenvironment of human breast cancers. Together, our findings therefore show that E2 promotes the growth of ERα-negative cancer cells through the activation of stromal ERα (extra-hematopoietic Tie-2 positive cells), which normalizes tumor angiogenesis and allows an adaptation of blood supply to tumors, thereby preventing hypoxia and necrosis. These findings significantly deepen mechanistic insights into the impact of E2 on tumor development with potential consequences for cancer treatment. Cancer Res; 72(12); 3010–9. ©2012 AACR.
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- 2023
32. Supplementary Figure 6 from Stromal Estrogen Receptor-α Promotes Tumor Growth by Normalizing an Increased Angiogenesis
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Françoise Lenfant, Jean-François Arnal, Laurent Brouchet, Pierre Chambon, Andrée Krust, Jean-Michel Foidart, Agnès Noël, Philippe Rochaix, Marie-José Fouque, Marine Adlanmerini, Frédéric Boudou, Silvia Blacher, Isabelle Raymond-Letron, and Christel Péqueux
- Abstract
PDF file - 204K, B16K1 Tumor necrosis in C57BL/6 mice
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- 2023
33. Kidney-targeted irradiation triggers renal ischemic preconditioning in mice
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Badr Khbouz, François Lallemand, Arianna Cirillo, Pascal Rowart, David Legouis, Nor Eddine Sounni, Agnès Noël, Pascal De Tullio, Sophie de Seigneux, and François Jouret
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Male ,Mice, Inbred C57BL ,Vascular Endothelial Growth Factor A ,Mice ,Physiology ,Ischemia ,Reperfusion Injury ,Animals ,Acute Kidney Injury ,Ischemic Preconditioning ,Kidney - Abstract
Renal ischemia-reperfusion (I/R) causes acute kidney injury (AKI). Ischemic preconditioning (IPC) attenuates I/R-associated AKI. Whole body irradiation induces renal IPC in mice. Still, the mechanisms remain largely unknown. Furthermore, the impact of kidney-centered irradiation on renal resistance against I/R has not been studied. Renal irradiation (8.5 Gy) was done in male 8- to 12-wk-old C57bl/6 mice using a small animal radiation therapy device. Left renal I/R was performed by clamping the renal pedicles for 30 min, with simultaneous right nephrectomy, at 7, 14, and 28 days postirradiation. The renal reperfusion lasted 48 h. Following I/R, blood urea nitrogen (BUN) and serum creatinine (SCr) levels were lower in preirradiated mice compared with controls; so was the histological Jablonski score of AKI. The metabolomics signature of renal I/R was attenuated in preirradiated mice. The numbers of proliferating cell nuclear antigen (PCNA)-, cluster of differentiation molecule 11b (CD11b)-, and cell surface glycoprotein F4/80-positive cells in the renal parenchyma post-I/R were reduced in preirradiated versus control groups. Such IPC was significantly observed as early as
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- 2022
34. Regulation of Tissue Factor by CD44 Supports Coagulant Activity in Breast Tumor Cells
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Amélie V. Villard, Anthony Genna, Justine Lambert, Marianna Volpert, Agnès Noël, Brett Hollier, Myriam Polette, Aline M. Vanwynsberghe, Christine Gilles, GIGA [Université Liège], Université de Liège, University of Queensland [Brisbane], Pathologies Pulmonaires et Plasticité Cellulaire - UMR-S 1250 (P3CELL), Université de Reims Champagne-Ardenne (URCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire de Reims (CHU Reims), and dormoy, valerian
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[SDV] Life Sciences [q-bio] ,Cancer Research ,Oncology ,[SDV]Life Sciences [q-bio] ,tissue factor ,CD44 ,epithelial-mesenchymal transitions ,metastasis ,coagulation - Abstract
International audience; Previous work identified Tissue Factor (TF), a key activator of the coagulation cascade, as a gene induced in cellular contexts of Epithelial-Mesenchymal Transitions (EMTs), providing EMT+ Circulating Tumor Cells (CTCs) with coagulant properties that facilitate their metastatic seeding. Deciphering further molecular aspects of TF regulation in tumor cells, we report here that CD44 and TF coexpress in EMT contexts, and that CD44 acts as a regulator of TF expression supporting procoagulant properties and metastatic seeding. A transcriptional regulatory mechanism bridging CD44 to TF expression was further evidenced. Comparing different TF –promoter luciferase reporter constructs, we indeed found that the shortest -111 pb TF promoter fragment harboring three Specificity Protein 1 (Sp1) binding sites is still responsive to CD44 silencing. The observation that (i) mutation within Sp1 binding sites decreased the basal activity of the -111 pb TF promoter construct, (ii) CD44 silencing decreased Sp1 protein and mRNA levels and (iii) Sp1 silencing diminished TF expression further points to Sp1 as a key mediator linking CD44 to TF regulation. All together, these data thus report a transcriptional regulatory mechanism of TF expression by CD44 supporting procoagulant activity and metastatic competence of CTCs.
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- 2022
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35. uPARAP/Endo180: a multifaceted protein of mesenchymal cells
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Fabrice Gucciardo, Sébastien Pirson, Louis Baudin, Alizée Lebeau, and Agnès Noël
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Vascular Endothelial Growth Factor A ,Pharmacology ,Cellular and Molecular Neuroscience ,Mannose-Binding Lectins ,Membrane Glycoproteins ,Receptors, Mitogen ,Molecular Medicine ,Collagen ,Cell Biology ,Carrier Proteins ,Molecular Biology - Abstract
The urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180) is already known to be a key collagen receptor involved in collagen internalization and degradation in mesenchymal cells and some macrophages. It is one of the four members of the mannose receptor family along with a macrophage mannose receptor (MMR), a phospholipase lipase receptor (PLA2R), and a dendritic receptor (DEC-205). As a clathrin-dependent endocytic receptor for collagen or large collagen fragments as well as through its association with urokinase (uPA) and its receptor (uPAR), uPARAP/Endo180 takes part in extracellular matrix (ECM) remodeling, cell chemotaxis and migration under physiological (tissue homeostasis and repair) and pathological (fibrosis, cancer) conditions. Recent advances that have shown an expanded contribution of this multifunctional protein across a broader range of biological processes, including vascular biology and innate immunity, are summarized in this paper. It has previously been demonstrated that uPARAP/Endo180 assists in lymphangiogenesis through its capacity to regulate the heterodimerization of vascular endothelial growth factor receptors (VEGFR-2 and VEGFR-3). Moreover, recent findings have demonstrated that it is also involved in the clearance of collectins and the regulation of the immune system, something which is currently being studied as a biomarker and a therapeutic target in a number of cancers.
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- 2022
36. Prenatal exposure to ozone triggers development of lung diseases in offspring
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Alison Gillard, Agnès Noël, and Didier Cataldo
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- 2022
37. Pyruvate dehydrogenase kinase/lactate axis: a therapeutic target for neovascular age-related macular degeneration identified by metabolomics
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Bénédicte Locht, Jean-Marie Rakic, Matthieu Schoumacher, André Gothot, Pascal De Tullio, Michael Herfs, Julie Lecomte, Pierre Blaise, Pascale Hubert, Agnès Noël, Cassandre Yip, Bernadette Govaerts, Edouard Duchateau, Vincent Lambert, Michèle Thys, Oriane Carnet, Etienne Cavalier, Sylvain Hansen, Silvia Blacher, and Justine Leenders
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Pyruvate dehydrogenase kinase ,genetic structures ,Angiogenesis ,Angiogenesis Inhibitors ,Dichloroacetic acid ,Inflammation ,Pharmacology ,Pathogenesis ,Macular Degeneration ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Drug Discovery ,Humans ,Metabolomics ,Medicine ,Lactic Acid ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,Genetics (clinical) ,business.industry ,Disease Management ,Pyruvate Dehydrogenase Acetyl-Transferring Kinase ,Macular degeneration ,medicine.disease ,Choroidal Neovascularization ,eye diseases ,Choroidal neovascularization ,chemistry ,Metabolome ,Molecular Medicine ,sense organs ,medicine.symptom ,business ,Biomarkers ,Metabolic Networks and Pathways ,Signal Transduction ,030215 immunology ,Lipoprotein - Abstract
Neovascular age-related macular degeneration (nAMD) is the leading cause of blindness in aging populations. Here, we applied metabolomics to human sera of patients with nAMD during an active (exudative) phase of the pathology and found higher lactate levels and a shift in the lipoprotein profile (increased VLDL-LDL/HDL ratio). Similar metabolomics changes were detected in the sera of mice subjected to laser-induced choroidal neovascularization (CNV). In this experimental model, we provide evidence for two sites of lactate production: first, a local one in the injured eye, and second a systemic site associated with the recruitment of bone marrow-derived inflammatory cells. Mechanistically, lactate promotes the angiogenic response and M2-like macrophage accumulation in the eyes. The therapeutic potential of our findings is demonstrated by the pharmacological control of lactate levels through pyruvate dehydrogenase kinase (PDK) inhibition by dichloroacetic acid (DCA). Mice treated with DCA exhibited normalized lactate levels and lipoprotein profiles, and inhibited CNV formation. Collectively, our findings implicate the key role of the PDK/lactate axis in AMD pathogenesis and reveal that the regulation of PDK activity has potential therapeutic value in this ocular disease. The results indicate that the lipoprotein profile is a traceable pattern that is worth considering for patient follow-up. KEY MESSAGES: Lactate and lipoprotein profile are associated with the active phase of AMD and CNV development. Lactate is a relevant and functional metabolite correlated with AMD progression. Modulating lactate through pyruvate dehydrogenase kinase led to a decrease of CNV progression. Pyruvate dehydrogenase kinase is a new therapeutic target for neovascular AMD.
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- 2020
38. Cancer-associated fibroblasts in desmoplastic tumors: emerging role of integrins
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Pugazendhi Erusappan, Cédric Zeltz, Agnès Noël, Irina Primac, Jahedul Alam, and Donald Gullberg
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0301 basic medicine ,Integrins ,Cancer Research ,Stromal cell ,Cancer-associated fibroblast ,TME-Mediated chemoresistance ,Angiogenesis ,Integrin ,Biology ,Collagen receptor ,Extracellular matrix ,03 medical and health sciences ,Paracrine signalling ,0302 clinical medicine ,Cell Transformation, Neoplastic -- genetics -- metabolism ,Cancer-Associated Fibroblasts ,Biomarkers, Tumor ,Tumor Microenvironment ,Animals ,Humans ,Neoplasms, Connective Tissue ,Tumor microenvironment ,Sciences bio-médicales et agricoles ,Fibroblasts ,Fibrosis ,3. Good health ,Cell biology ,Integrins -- metabolism ,Cell Transformation, Neoplastic ,030104 developmental biology ,Organ Specificity ,030220 oncology & carcinogenesis ,Tumor Microenvironment -- genetics ,biology.protein ,Neoplasms, Connective Tissue -- etiology -- metabolism -- pathology ,Disease Susceptibility ,Cancer-Associated Fibroblasts -- metabolism -- pathology - Abstract
The tumor microenvironment (TME) is a complex meshwork of extracellular matrix (ECM) macromolecules filled with a collection of cells including cancer-associated fibroblasts (CAFs), blood vessel associated smooth muscle cells, pericytes, endothelial cells, mesenchymal stem cells and a variety of immune cells. In tumors the homeostasis governing ECM synthesis and turnover is disturbed resulting in abnormal blood vessel formation and excessive fibrillar collagen accumulations of varying stiffness and organization. The disturbed ECM homeostasis opens up for new types of paracrine, cell-cell and cell-ECM interactions with large consequences for tumor growth, angiogenesis, metastasis, immune suppression and resistance to treatments. As a main producer of ECM and paracrine signals the CAF is a central cell type in these events. Whereas the paracrine signaling has been extensively studied in the context of tumor-stroma interactions, the nature of the numerous integrin-mediated cell-ECM interactions occurring in the TME remains understudied. In this review we will discuss and dissect the role of known and potential CAF interactions in the TME, during both tumorigenesis and chemoresistance-induced events, with a special focus on the "interaction landscape" in desmoplastic breast, lung and pancreatic cancers. As an example of the multifaceted mode of action of the stromal collagen receptor integrin α11β1, we will summarize our current understanding on the role of this CAF-expressed integrin in these three tumor types., info:eu-repo/semantics/published
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- 2020
39. Periostin in lymph node pre-metastatic niches governs lymphatic endothelial cell functions and metastatic colonization
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Lionel Gillot, Alizée Lebeau, Louis Baudin, Charles Pottier, Thomas Louis, Tania Durré, Rémi Longuespée, Gabriel Mazzucchelli, Christophe Nizet, Silvia Blacher, Frédéric Kridelka, and Agnès Noël
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Pharmacology ,Proteomics ,Vascular Endothelial Growth Factor C ,Endothelial Cells ,Uterine Cervical Neoplasms ,Cell Biology ,Cellular and Molecular Neuroscience ,Mice ,Lymphatic Metastasis ,Molecular Medicine ,Animals ,Humans ,Female ,Lymph Nodes ,Molecular Biology ,Cell Adhesion Molecules - Abstract
Although lymph node (LN) metastasis is an important prognostic parameter in cervical cancer, the tissue remodeling at a pre-metastatic state is poorly documented in LNs. We here identified periostin (POSTN) as a component of non-metastatic LNs by applying proteomic analyses and computerized image quantifications on LNs of patients with cervical cancer. We provide evidence for remarkable modifications of POSTN and lymphatic vessel distributions and densities in non-metastatic sentinel and metastatic human LNs, when compared to distant non-metastatic LNs. POSTN deposition at a pre-metastatic stage was demonstrated in a pre-clinical murine model (the ear sponge assay). Its expression by fibroblastic LN cells was assessed by in situ hybridization and in vitro cultures. In vitro, POSTN promoted lymphatic endothelial cell functions and tumor cell proliferation. Accordingly, the in vivo injection of recombinant POSTN together with VEGF-C boosted the lymphangiogenic response, while the metastatic potential of tumor cells was drastically reduced using a POSTN blocking antibody. This translational study also supports the existence of an unprecedented dialog “in cascade”, between the primary tumor and the first pelvic nodal relay in early cervical cancer, and subsequently from pelvic LN to para-aortic LNs in locally advanced cervical cancers. Collectively, this work highlights the association of POSTN deposition with lymphangiogenesis in LNs, and provides evidence for a key contribution of POSTN in promoting VEGF-C driven lymphangiogenesis and the seeding of metastatic cells.
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- 2021
40. Multi- and Transgenerational Outcomes of an Exposure to a Mixture of Endocrine-Disrupting Chemicals (EDCs) on Puberty and Maternal Behavior in the Female Rat
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David Lopez-Rodriguez, Arlette Gerard, Anne-Simone Parent, Delphine Franssen, Marion Martin, Marzia Campanile, Alejandro Lomniczi, Ezio Tirelli, Silvia Blacher, Virginia Delli, Agnès Noël, Carlos F. Aylwin, and Elena Sevrin
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Transgenerational epigenetics ,Research ,Health, Toxicology and Mutagenesis ,media_common.quotation_subject ,Public Health, Environmental and Occupational Health ,Physiology ,Endocrine system ,Fertility ,Environmental Exposure ,Biology ,Hazardous Substances ,media_common - Abstract
Background: The effects of endocrine-disrupting chemicals (EDCs) on fertility and reproductive development represent a rising concern in modern societies. Although the neuroendocrine control of sexual maturation is a major target of EDCs, little is known about the potential role of the hypothalamus in puberty and ovulation disruption transmitted across generations. Objectives: We hypothesized that developmental exposure to an environmentally relevant dose of EDC mixture could induce multi- and/or transgenerational alterations of sexual maturation and maternal care in female rats through epigenetic reprograming of the hypothalamus. We investigated the transmission of a disrupted reproductive phenotype via the maternal germline or via nongenomic mechanisms involving maternal care. Methods: Adult female Wistar rats were exposed prior to and during gestation and until the end of lactation to a mixture of the following 13 EDCs: di-n-butyl phthalate (DnBP), di(2-ethylhexyl) phthalate (DEHP), bisphenol A (BPA), vinclozolin, prochloraz, procymidone, linuron, epoxynaxole, dichlorodiphenyldichloroethylene, octyl methoxynimmate, 4-methylbenzylidene camphor (4-MBC), butylparaben, and acetaminophen. Perinatally exposed offspring (F1) were mated with unexposed males to generate germ cell (F2) and transgenerationally exposed (F3 and F4) females. Sexual maturation, maternal behavior, and hypothalamic targets of exposure were studied across generations. Results: Germ cell (F2) and transgenerationally (F3) EDC-exposed females, but not F1, displayed delayed pubertal onset and altered folliculogenesis. We reported a transgenerational alteration of key hypothalamic genes controlling puberty and ovulation (Kiss1, Esr1, and Oxt), and we identified the hypothalamic polycomb group of epigenetic repressors as actors of this mechanism. Furthermore, we found a multigenerational reduction of maternal behavior (F1–F3) induced by a loss in hypothalamic dopaminergic signaling. Using a cross-fostering paradigm, we identified that the reduction in maternal phenotype was normalized in EDC-exposed pups raised by unexposed dams, but no reversal of the pubertal phenotype was achieved. Discussion: Rats developmentally exposed to an EDC mixture exhibited multi- and transgenerational disruption of sexual maturation and maternal care via hypothalamic epigenetic reprogramming. These results raise concerns about the impact of EDC mixtures on future generations. https://doi.org/10.1289/EHP8795
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- 2021
41. ADAMTS2 and ADAMTS14 can substitute for ADAMTS3 in adults for pro-VEGFC activation and lymphatic homeostasis
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Laura Dupont, Loïc Joannes, Florent Morfoisse, Silvia Blacher, Christine Monseur, Christophe F. Deroanne, Agnès Noël, and Alain C.M.A. Colige
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Mammals ,Mice ,ADAMTS Proteins ,Animals ,Homeostasis ,General Medicine ,Lymphedema ,Lymphangiogenesis ,Lymphatic Vessels - Abstract
The capacity of ADAMTS3 to cleave pro-VEGFC into active VEGFC able to bind its receptors and to stimulate lymphangiogenesis has been clearly established during embryonic life. However, this function of ADAMTS3 is unlikely to persist in adulthood because of its restricted expression pattern after birth. Because ADAMTS2 and ADAMTS14 are closely related to ADAMTS3 and are mainly expressed in connective tissues where the lymphatic network extends, we hypothesized that they could substitute for ADAMTS3 during adulthood in mammals allowing proteolytic activation of pro-VEGFC. Here, we demonstrated that ADAMTS2 and ADAMTS14 are able to process pro-VEGFC into active VEGFC as efficiently as ADAMTS3. In vivo, adult mice lacking Adamts2 developed skin lymphedema due to a reduction of the density and diameter of lymphatic vessels, leading to a decrease of lymphatic functionality, while genetic ablation of Adamts14 had no impact. In a model of thermal cauterization of cornea, lymphangiogenesis was significantly reduced in Adamts2- and Adamts14-KO mice and further repressed in Adamts2/Adamts14 double-KO mice. In summary, we have demonstrated that ADAMTS2 and ADAMTS14 are as efficient as ADAMTS3 in activation of pro-VEGFC and are involved in the homeostasis of the lymphatic vasculature in adulthood, both in physiological and pathological processes.
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- 2021
42. MO332THE IRRADIATION-INDUCED RENAL ISCHEMIC PRECONDITIONING IS BLUNTED BY THE ORAL ADMINISTRATION OF THE ANTI-ANGIOGENIC AGENT, SUNITINIB
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François Lallemand, Pascal Rowart, Agnès Noël, Badr Khbouz, Nor Eddine Sounni, Laurence Poma, Jean-Marie Krzesinski, and François Jouret
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Transplantation ,Sunitinib ,business.industry ,Angiogenesis ,Anti angiogenic ,Ischemia ,Pharmacology ,medicine.disease ,Nephrology ,Oral administration ,Renal physiology ,medicine ,Ischemic preconditioning ,Signal transduction ,business ,medicine.drug - Abstract
Background and Aims Whole-body irradiation has been suggested to induce renal ischemic preconditioning (RIP) in rodent models, possibly via neo-angiogenesis. First, we comprehensively investigate the pathways involved in kidney-centered irradiation. Next, we assess the functional and structural impact of kidney-centered irradiation applied before ischemia/reperfusion (I/R) injury. Finally, we test whether Sunitinib-mediated inhibition of the neo-angiogenesis prevents irradiation-associated RIP. Method Experiment 1: Unilateral irradiation of the left kidney (8.56 Gy) was performed in male 10-week-old wild-type C57bl/6 mice (n=10). One month later, total kidney RNA was extracted from irradiated and control (n=5) mice for comparative high-throughput RNA-Seq (using BaseSpace Sequence Hub Illumina). Functional enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). Experiment 2: Two x-ray beams (225Kv, 13mA) specifically targeted both kidneys for a total dose of 8.56Gy. The right kidneys were removed and harvested, and the left kidneys undergo 30-minute ischemia followed by 48-hour reperfusion (n=8) at Days 7-14-21-28 post irradiation. Experiment 3: Following the same protocol of renal I/R at Day14, 3 groups of male 10-week-old wild-type C57bl/6 mice were compared (n=8 per group): 1/ bilateral pre-irradiation; 2/ bilateral pre-irradiation and gavage with Sunitinib from Day2 to Day13; 3/ control group without irradiation or gavage. Results Experiment 1: Comparative transcriptomics showed a significant up-regulation of various signaling pathways, including angiogenesis (HMOX1) and stress response (HSPA1A, HSPA1B). Expressions of angiogenesis markers (CD31, TGFb1, HMOX1) showed an increase at both mRNA (real-time qPCR) and protein (immuno-staining) levels in irradiated kidneys compared to controls (p Experiment 2: Following I/R, the blood urea nitrogen (BUN) and serum creatinine (SCr) levels were significantly lower in the irradiated animals compared to controls: (BUN: 86.2±6.8 vs. 454.5±27.2mg/dl; SCr: 0.1±0.01 vs. 1.7±0.2mg/dl, p Experiment 3: One-way analysis of variance followed by Tukey’s test showed that, following I/R, the serum levels of BUN and SCr were lower in irradiated group compared to controls (BUN: 106.1±33.6 vs. 352.2±54.3mg/dl; SCr: 0.3±0.13 vs. 1±0.2mg/dl), and in irradiated group compared to the irradiated-exposed group to Sunitinib (BUN: 106.1±33.6 vs. 408.4±54.9mg/dl; SCr: 0.3±0.12 vs. 1.5±0.3mg/dl; p Conclusion Renal irradiation induces the activation of signaling pathways involved in angiogenesis in mice. Renal pre-irradiation leads to RIP, with preserved renal function and attenuated inflammation post I/R. Exposure to the anti-angiogenic drug Sunitinib post-irradiation prevents the irradiation-induced RIP.
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- 2021
43. Lymph/angiogenesis contributes to sex differences in lung cancer through oestrogen receptor alpha signalling
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Céline Gérard, Charline Dubois, Silvia Blacher, Agnès Noël, Natacha Rocks, Françoise Lenfant, Didier Cataldo, Anne Gallez, Irina Primac, Laurent Brouchet, Melissa García-Caballero, and Christel Pequeux
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Male ,0301 basic medicine ,Cancer Research ,Angiogenesis ,Endocrinology, Diabetes and Metabolism ,Cell Culture Techniques ,angiogenesis ,Carcinoma, Lewis Lung ,Mice ,0302 clinical medicine ,Endocrinology ,gender ,Sex Characteristics ,tamoxifen ,Sciences bio-médicales et agricoles ,Middle Aged ,respiratory system ,Estrogen Receptor alpha -- physiology ,oestrogen receptor ,Lymphangiogenesis ,lymphangiogenesis ,medicine.anatomical_structure ,Lymphatic system ,Oncology ,030220 oncology & carcinogenesis ,Adenocarcinoma ,Female ,Lymph ,Signal Transduction ,medicine.drug ,Adult ,Carcinoma, Lewis Lung -- epidemiology ,Transfection ,03 medical and health sciences ,medicine ,sex ,Animals ,Humans ,Lung cancer ,Cell Proliferation ,Lung ,business.industry ,Estrogen Receptor alpha ,medicine.disease ,microenvironment ,lung cancer ,030104 developmental biology ,Cancer research ,business ,Tamoxifen - Abstract
Oestrogen signalling pathways are emerging targets for lung cancer therapy. Unravelling the contribution of oestrogens in lung cancer development is a pre-requisite to support the development of sex-based treatments and identify patients who could potentially benefit from anti-oestrogen treatments. In this study, we highlight the contribution of lymphatic and blood endothelia in the sex-dependent modulation of lung cancer. The orthotopic graft of syngeneic lung cancer cells into immunocompetent mice showed that lung tumours grow faster in female mice than in males. Moreover, oestradiol (E2) promoted tumour development, increased lymph/angiogenesis and VEGFA and bFGF levels in lung tumours of females through an oestrogen receptor (ER) alpha-dependent pathway. Furthermore, while treatment with ERb antagonist was inefficient, ERa antagonist (MPP) and tamoxifen decreased lung tumour volumes, altered blood and lymphatic vasculature and reduced VEGFA and bFGF levels in females, but not in males. Finally, the quantification of lymphatic and blood vasculature of lung adenocarcinoma biopsies from patients aged between 35 and 55 years revealed more extensive lymphangiogenesis and angiogenesis in tumour samples issued from women than from men. In conclusion, our findings highlight an E2/ERa-dependent modulation of lymphatic and blood vascular components of lung tumour microenvironment. Our study has potential clinical implication in a personalised medicine perspective by pointing to the importance of oestrogen status or supplementation on lung cancer development that should be considered to adapt therapeutic strategies., info:eu-repo/semantics/published
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- 2019
44. Le médicament anti-angiogénique sunitinib contrarie le conditionnement ischémique rénal induit par l’irradiation
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Badr Khbouz, François Lallemand, J.M. Krzesinski, Pascal Rowart, Agnès Noël, François Jouret, Laurence Poma, and Nor Eddine Sounni
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Gynecology ,medicine.medical_specialty ,Nephrology ,business.industry ,Sunitinib ,Medicine ,business ,medicine.drug - Abstract
Introduction L’irradiation corporelle induit un conditionnement ischemique renal (CIR) chez la souris. Les mecanismes cellulaires sont meconnus, hormis un possible role de la neo-angiogenese. Description Dans cette etude, nous etudions les voies impliquees dans l’irradiation renale. Ensuite, nous analysons l’impact fonctionnel sur les reins avant ischemie renale/reperfusion (I/R). Enfin, nous testons si l’inhibition de l’angiogenese par le Sunitinib empeche le CIR associe a l’irradiation. Methodes Exp1. Une irradiation renale(8 Gy) est realisee chez des C57bl/6 mâles (n = 10). Un mois plus tard, l’ARN renal total est extrait pour un RNAseq comparatif. Exp2. A 7–14–28 jours post-irradiation renale, les reins droits sont nephrectomises et les reins gauches subissent une ischemie (30 min)/reperfusion (48 h) (n = 8/timing). Exp3. Suivant le meme protocole d’I/R a j14, 3 groupes sont compares (n = 8/groupe) : – irradiation ; – irradiation et gavage au sunitinib de j2 a j13 ; – groupe temoin sans irradiation ni gavage. Resultats Exp1. RNAseq montre une up-regulation des voies de l’angiogenese. L’expression de VEGF et CD31 est significativement augmentee au niveau ARNm et proteique dans les reins irradies. Exp2. Apres I/R a j14 post-irradiation, les taux seriques d’uree (BUN) et de creatinine (SCr) sont plus faibles chez les souris irradiees par rapport aux temoins (BUN : 86,2 ± 6,8 vs 454,5 ± 27,2 mg/dL ; SCr : 0,1 ± 0,01 vs 1,7 ± 0,2 mg/dL, p Fig. 1 ). Conclusion L’irradiation renale induit l’activation de l’angiogenese chez la souris et est associee a un CIR, avec fonction renale preservee et inflammation attenuee post-I/R. L’exposition au sunitinib post-irradiation empeche ce CIR.
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- 2021
45. In Vitro, In Vivo, and In Silico Models of Lymphangiogenesis in Solid Malignancies
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Sophie Bekisz, Louis Baudin, Florence Buntinx, Agnès Noël, and Liesbet Geris
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Cancer Research ,Science & Technology ,in silico methods ,TUMOR LYMPHANGIOGENESIS ,VEGF-D PROMOTES ,metastatic dissemination ,INTERSTITIAL FLOW ,GROWTH-FACTOR RECEPTOR-3 ,lymphangiogenesis ,BLOOD-VESSELS ,lymphatic endothelial cells ,ANIMAL-MODELS ,Oncology ,computational models ,NODE METASTASIS ,LYMPHATIC ENDOTHELIAL-CELLS ,cancer ,in vivo models ,Life Sciences & Biomedicine ,VASCULAR DEVELOPMENT ,in vitro models ,MATHEMATICAL-MODEL - Abstract
Lymphangiogenesis (LA) is the formation of new lymphatic vessels by lymphatic endothelial cells (LECs) sprouting from pre-existing lymphatic vessels. It is increasingly recognized as being involved in many diseases, such as in cancer and secondary lymphedema, which most often results from cancer treatments. For some cancers, excessive LA is associated with cancer progression and metastatic dissemination to the lymph nodes (LNs) through lymphatic vessels. The study of LA through in vitro, in vivo, and, more recently, in silico models is of paramount importance in providing novel insights and identifying the key molecular actors in the biological dysregulation of this process under pathological conditions. In this review, the different biological (in vitro and in vivo) models of LA, especially in a cancer context, are explained and discussed, highlighting their principal modeled features as well as their advantages and drawbacks. Imaging techniques of the lymphatics, complementary or even essential to in vivo models, are also clarified and allow the establishment of the link with computational approaches. In silico models are introduced, theoretically described, and illustrated with examples specific to the lymphatic system and the LA. Together, these models constitute a toolbox allowing the LA research to be brought to the next level. ispartof: CANCERS vol:14 issue:6 ispartof: location:Switzerland status: published
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- 2022
46. Potential role of ADAM (A Disintegrin And Metalloprotease) in malignant pleural mesothelioma resistance to chemotherapy
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Ahmed Debit, Bernard Duysinx, Alison Gillard, Agnès Noël, Christelle Sepult, Marine Bellefroid, Christophe Poulet, Didier Cataldo, and Céline Vanwinge
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Cisplatin ,Metalloproteinase ,biology ,business.industry ,Transfection ,medicine.disease ,In vitro ,Cell culture ,Disintegrin ,biology.protein ,Cancer research ,Medicine ,Mesothelioma ,business ,ADAM8 ,medicine.drug - Abstract
Malignant pleural mesothelioma (MPM) standard therapy is a cisplatin-pemetrexed combination. Unfortunately, MPM cells become very rapidly therapy-resistant in most of cases. Numerous ADAMs (A Disintegrin And Metalloprotease) have been recognized as key contributors to resistance to chemotherapy. The aim of the study was to unveil mechanisms of MPM resistance to treatment and assess the possible implication of ADAM proteases. A measurement of ADAMs expression showed that ADAM8 mRNA is overexpressed as compared to control pleura in human MPM samples and in a mouse model of MPM. In vitro, the mesothelioma cell line AB12 transfected with shRNAs targeting ADAM8 and subsequently exposed to cisplatin displayed a decreased survival as compared to control-ShRNA treated counterparts. Several cisplatin-resistant mesothelioma cell lines were generated by exposing different MPM cell lines to increasing concentrations of cisplatin. A RNA sequencing was performed in order to compare cisplatin-resistant cells to matching parental cells. Surprisingly, a striking overexpression of ADAM8 was observed in cell lines rendered resistant to cisplatin. Moreover, in vivo experiments showed that tumors developed when these cisplatin-resistant cells were injected into the flanks of mice were growing faster and displayed a significant overexpression of ADAM8 mRNA as compared to tumors developed after parental cells injection. In conclusion, our results unveil ADAM8 as a key factor of cisplatin resistance in mesothelioma. Our future researches will focus on the downstream molecular pathways implicating ADAM8 in order to understand how it might affect MPM cisplatin resistance.
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- 2020
47. Multi- and transgenerational disruption of maternal behavior and female puberty by Endocrine Disrupting Chemical (EDC) mixture exposure
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Virginia Delli, Silvia Blacher, Arlette Gerard, Marion Martin, Marzia Campanile, Anne-Simone Parent, Alejandro Lomniczi, Delphine Franssen, Elena Sevrin, Ezio Tirelli, Carlos F. Aylwin, David Lopez Rodriguez, and Agnès Noël
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medicine.medical_specialty ,Endocrinology ,Mechanism (biology) ,Hypothalamus ,Internal medicine ,Dopaminergic ,medicine ,Endocrine system ,Epigenetics ,Biology ,Phenotype ,Estrogen receptor alpha ,Germline - Abstract
Female reproductive development and maternal behavior are two intertwined phenotypes centrally controlled by the hypothalamus. Endocrine disrupting chemicals (EDC) can alter these processes especially when animals are exposed during development. We propose the concept that developmental exposure to a low environmentally relevant dose of EDC mixture induces a transgenerational alteration of female rat pubertal timing and ovarian physiology throughout epigenetic reprograming of hypothalamicKiss1, Esr1andOxt1loci. Such exposure also caused a multigenerational reduction of maternal behavior induced by the loss in hypothalamic dopaminergic signaling. Our results identify the hypothalamic Polycomb Group of epigenetic repressors as actors of this mechanism of transgenerational reproductive disruption. Using a cross-fostering approach, we identified that while the reduction in maternal phenotype was normalized in EDC exposed pups raised by unexposed dams, no reversal of the pubertal phenotype was achieved, suggesting a germline transmission of the reproductive phenotype.
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- 2020
48. Role of ADAM8 Protease in Malignant Pleural Mesothelioma Chemoresistance
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Alison Gillard, Erik Maquoi, Agnès Noël, Bernard Duysinx, Christophe Poulet, Didier Cataldo, Céline Vanwinge, Ahmed Debit, Marine Bellefroid, and Christelle Sepult
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Protease ,Pleural mesothelioma ,business.industry ,medicine.medical_treatment ,Cancer research ,medicine ,business ,ADAM8 - Published
- 2020
49. BRCAness, SLFN11, and RB1 loss predict response to topoisomerase I inhibitors in triple-negative breast cancers
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Petra ter Brugge, Laetitia Fuhrmann, Fabien Reyal, Rania El-Botty, Thibaut Larcher, Laura Sourd, Sophie Château-Joubert, Agnès Noël, Jean-Luc Servely, Léa Huguet, Ivan Bièche, Pierre Foidart, Jos Jonkers, Philippe La Rosa, Pierre Painsec, Sophie Leboucher, Ludivine Morisset, Fariba Nemati, Georges Lucotte, Elodie Montaudon, Didier Decaudin, Christopher R. Mueller, Florence Coussy, Ahmed Dahmani, Marc-Henri Stern, Marie-France Poupon, Nor Eddine Sounni, Sophie Vacher, Adrien Briaux, Yves Pommier, Anne Vincent Salomon, Elisabetta Marangoni, Cécile Reyes, Tatiana Popova, Translational Research Department,Medical Oncology Department, Genetics Department, Institut Curie, Translational Research Department, BioPôle Alfort, École nationale vétérinaire d'Alfort (ENVA), PSL Research University, UMR3306, Département Physiologie Animale et Systèmes d'Elevage (PHASE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Physiopathologie Animale et bioThérapie du muscle et du système nerveux (PAnTher), Ecole Nationale Vétérinaire, Agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Genetics Department, University of Santiago de Compostela, Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), U830, Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratory of Tumor and Developmental Biology, Groupe Interdisciplinaire de Génoprotéomique Appliqué-Cancer (GIGA-Cancer), Université de Liège, Translational Research Department, Medical Oncology Department, Department of Pathology, University of Veterinary and Animal Sciences, Lahore, Surgery Department, CRLCC Paul Strauss, U932, Immunity and Cancer, Queen's cancer reserach institute, Queen's University, Division of Molecular Pathology and Cancer Genomics Centre Netherlands, Netherlands Cancer Institute, Developmental Therapeutics Branch and Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, ProdInra, Archive Ouverte, École nationale vétérinaire - Alfort (ENVA), École nationale vétérinaire, agroalimentaire et de l'alimentation Nantes-Atlantique (ONIRIS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Universidade de Santiago de Compostela [Spain] (USC ), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Biologie du développement et reproduction (BDR), École nationale vétérinaire d'Alfort (ENVA)-Institut National de la Recherche Agronomique (INRA)-Centre National de la Recherche Scientifique (CNRS), Développement et Pathologie du Tissu Musculaire (DPTM), Ecole Nationale Vétérinaire de Nantes-Institut National de la Recherche Agronomique (INRA), PSL Research University, U900, and Institut National de la Recherche Agronomique (INRA)-Ecole Nationale Vétérinaire de Nantes
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Anthracycline ,DNA repair ,Ubiquitin-Protein Ligases ,[SDV]Life Sciences [q-bio] ,Triple Negative Breast Neoplasms ,Topoisomerase-I Inhibitor ,Irinotecan ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,CHEK1 ,skin and connective tissue diseases ,030304 developmental biology ,0303 health sciences ,biology ,Retinoblastoma ,business.industry ,Topoisomerase ,Nuclear Proteins ,General Medicine ,medicine.disease ,eye diseases ,3. Good health ,[SDV] Life Sciences [q-bio] ,Retinoblastoma Binding Proteins ,030220 oncology & carcinogenesis ,Cancer research ,biology.protein ,Topoisomerase I Inhibitors ,business ,Schlafen family member 11 ,medicine.drug - Abstract
Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.
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- 2020
50. Consensus guidelines for the use and interpretation of angiogenesis assays
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Marcus Fruttiger, Mark J. Post, Andrey Anisimov, Robert S. Kerbel, Jan Kitajewski, Federico Bussolino, Sarah-Maria Fendt, Neil Dufton, Dai Fukumura, Agnès Noël, Raghu Kalluri, Johannes Waltenberger, Roberto Pili, Anna Dimberg, David O. Bates, Koen Marien, Victor W.M. van Hinsbergh, Peter Carmeliet, Andreas Bikfalvi, Curzio Rüegg, Hong Xin, Rakesh K. Jain, Hellmut G. Augustin, Robert Auerbach, Anna M. Randi, Jimmy Stalin, Bahar Yetkin-Arik, Gabriele Bergers, Stefan Schulte-Merker, Napoleone Ferrara, Paul H.A. Quax, Elisabeth Kuczynski, M. Luisa Iruela-Arispe, Judy R. van Beijnum, R. Hugh F. Bender, Elizabeth Allen, Ruud P.M. Dings, Anca Maria Cimpean, Joanna Kalucka, Andrew C. Dudley, Brant M. Weinstein, Lance L. Munn, Barbara C. Böck, Yan Gong, Jonathan W. Song, Lois E.H. Smith, Alfred C. Aplin, Steven A. Stacker, Jussi Nurro, Nan W. Hultgren, Anna-Karin Olsson, Bart Ghesquière, Peter C. Brooks, Adrian L. Harris, Joyce Bischoff, Juan M. Melero-Martin, Reinier O. Schlingemann, Hynda K. Kleinmann, Amber N. Stratman, Gabriel A. Rabinovich, Pieter Koolwijk, Patrycja Nowak-Sliwinska, Robert J. Griffin, Marius Raica, Mervin C. Yoder, Daniel Castranova, Roberto F. Nicosia, Seppo Ylä-Herttuala, Bertan Cakir, Peter B. Vermeulen, George E. Davis, Christopher C.W. Hughes, Tatiana V. Petrova, Maureen Van de Velde, George Coukos, Jeffrey W. Pollard, Kari Alitalo, Valentin Djonov, Kristian Pietras, Ondine Cleaver, Domenico Ribatti, Melita Irving, Brenda R. Kwak, Arjan W. Griffioen, Michele De Palma, Ingeborg Klaassen, British Heart Foundation, Imperial College Healthcare Charity, Rosetrees Trust, and Kwak, Brenda
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0301 basic medicine ,Tumor angiogenesis ,Cancer Research ,Physiology ,Angiogenesis ,Computer science ,Cell- och molekylärbiologi ,Clinical Biochemistry ,Proliferation ,ddc:616.07 ,Regenerative Medicine ,Neovascularization ,Mice ,Plug assay ,Blood vessels ,ENDOTHELIAL CELLS ,Neoplasms ,AORTIC RING MODEL ,Intussusceptive angiogenesis ,Zebrafish ,Recombinant proteins ,ddc:615 ,Neovascularization, Pathologic ,Angiogenesis assays ,purl.org/becyt/ford/3.1 [https] ,Pharmacology and Pharmaceutical Sciences ,TUBULAR NETWORKS ,Bioquímica y Biología Molecular ,3. Good health ,Medicina Básica ,Retinal vasculature ,purl.org/becyt/ford/3 [https] ,Biological Assay ,Tip cells ,medicine.symptom ,1115 Pharmacology and Pharmaceutical Sciences ,Life Sciences & Biomedicine ,Hindlimb ischemia ,VASCULAR-PERMEABILITY FACTOR ,CIENCIAS MÉDICAS Y DE LA SALUD ,EMBRYO CHORIOALLANTOIC MEMBRANE ,Clinical Sciences ,Guidelines as Topic ,Chorioallantoic membrane ,Endothelial cell migration ,Computational biology ,Aortic ring ,Guidelines ,Article ,ENDOTHELIAL-GROWTH-FACTOR ,03 medical and health sciences ,In vivo ,LIVING CAPILLARY NETWORKS ,medicine ,VASCULAR BIOLOGY METHODS ,Animals ,Humans ,Oncology & Carcinogenesis ,Chorioallantoic membrane (CAM) ,ETS TRANSCRIPTION FACTORS ,Organ regeneration ,Pathologic ,OXYGEN-INDUCED RETINOPATHY ,Science & Technology ,PERIPHERAL ARTERIAL-DISEASE ,1103 Clinical Sciences ,030104 developmental biology ,Corneal angiogenesis ,Vascular network ,Peripheral Vascular Disease ,Microfluidic ,Myocardial angiogenesis ,Vessel co-option ,Cardiovascular System & Cardiology ,Human medicine ,PANCREATIC NEUROENDOCRINE TUMORS ,Biological Assay/instrumentation ,Biological Assay/methods ,Neoplasms/blood supply ,Neoplasms/metabolism ,Neoplasms/pathology ,Neovascularization, Pathologic/metabolism ,Neovascularization, Pathologic/pathology ,Ex vivo ,Cell and Molecular Biology - Abstract
The formation of new blood vessels, or angiogenesis, is a complex process that plays important roles in growth and development, tissue and organ regeneration, as well as numerous pathological conditions. Angiogenesis undergoes multiple discrete steps that can be individually evaluated and quantified by a large number of bioassays. These independent assessments hold advantages but also have limitations. This article describes in vivo, ex vivo, and in vitro bioassays that are available for the evaluation of angiogenesis and highlights critical aspects that are relevant for their execution and proper interpretation. As such, this collaborative work is the first edition of consensus guidelines on angiogenesis bioassays to serve for current and future reference. Fil: Nowak Sliwinska, Patrycja. Université of Lausanne; Suiza. Univeristé of Geneve; Suiza Fil: Alitalo, Kari. Katholikie Universiteit Leuven; Bélgica Fil: Allen, Elizabeth. Katholikie Universiteit Leuven; Bélgica Fil: Anisimov, Andrey. Katholikie Universiteit Leuven; Bélgica Fil: Aplin, Alfred C.. University of Washington; Estados Unidos Fil: Auerbach, Robert. University of Wisconsin; Estados Unidos Fil: Augustin, Hellmut G.. Heidelberg University; Alemania. German Cancer Consortium; Alemania Fil: Bates, David O.. University of Nottingham; Reino Unido Fil: Beijnum, Judy R. van. Cancer Center Amsterdam; Países Bajos Fil: Bender, R. Hugh F.. University of California; Estados Unidos Fil: Bergers, Gabriele. Katholikie Universiteit Leuven; Bélgica Fil: Bikfalvi, Andreas. Universite de Bordeaux; Francia Fil: Bischoff, Joyce. Harvard Medical School; Estados Unidos Fil: Böck, Barbara C.. Heidelberg University; Alemania. German Cancer Consortium; Alemania Fil: Brooks, Peter C.. Maine Medical Center Research Institute; Estados Unidos Fil: Bussolino, Federico. Università di Torino; Italia. Candiolo Cancer Institute; Italia Fil: Cakir, Bertan. Harvard Medical School; Estados Unidos Fil: Carmeliet, Peter. Katholikie Universiteit Leuven; Bélgica Fil: Castranova, Daniel. Harvard Medical School; Estados Unidos Fil: Cimpean, Anca M.. Victor Babes University of Medicine and Pharmacy; Rumania Fil: Cleaver, Ondine. University Of Texas At Brownsville; Estados Unidos Fil: Coukos, George. Universida de Lausanne; Suiza Fil: Davis, George E.. University of Missouri; Estados Unidos Fil: De Palma, Michele. Swiss Federal Institute of Technology; Suiza Fil: Dimberg, Anna. Uppsala University; Suiza Fil: Dings, Ruud P. M.. University of Arkansas for Medical Sciences; Estados Unidos Fil: Djonov, Valentin. University of Bern; Suiza Fil: Dudley, Andrew C.. University of Virginia; Estados Unidos Fil: Dufton, Neil P.. Imperial College London; Reino Unido Fil: Fendt, Sarah-Maria. VIB Center for Cancer Biology; Bélgica Fil: Ferrara, Napoleone. University of California at San Diego; Estados Unidos Fil: Fruttiger, Marcus. University College London; Estados Unidos Fil: Fukumura, Dai. Harvard Medical School; Estados Unidos Fil: Ghesquière, Bart. Harvard Medical School; Estados Unidos Fil: Gong, Yan. Harvard Medical School; Estados Unidos Fil: Griffin, Robert J.. VIB Center for Cancer Biology; Bélgica Fil: Harris, Adrian L.. University of Oxford; Reino Unido Fil: Hughes, Christopher C. W.. University of California at Irvine; Estados Unidos Fil: Hultgren, Nan W.. University of California at Irvine; Estados Unidos Fil: Iruela-Arispe, M. Luisa. University of California at Los Angeles; Estados Unidos Fil: Irving, Melita. Universida de Lausanne; Suiza Fil: Maidana, Agostina Jainen. Harvard Medical School; Estados Unidos Fil: Kalluri, Raghu. Texas A&M University; Estados Unidos Fil: Kalucka, Joanna. Katholikie Universiteit Leuven; Bélgica Fil: Kerbel, Robert S.. University of Toronto; Canadá Fil: Kitajewski, Jan. University of Illinois; Estados Unidos Fil: Klaassen, Ingeborg. University of Amsterdam; Países Bajos Fil: Kleinmann, Hynda K.. The George Washington University; Estados Unidos Fil: Koolwijk, Pieter. Fondation Asile des Aveugles; Suiza. Universida de Lausanne; Suiza Fil: Kuczynski, Elisabeth. University of Toronto; Canadá Fil: Kwak, Brenda R.. University of Geneva; Suiza Fil: Koen, Marien. HistoGeneX; Bélgica Fil: Melero Martin, Juan M.. University of Liège; Bélgica Fil: Munn, Lance L.. Harvard Medical School; Estados Unidos Fil: Nicosia, Roberto F.. VA Puget Sound Health Care System; Estados Unidos Fil: Noel, Agnes. University of Liège; Bélgica Fil: Nurro, Jussi. University of Eastern Finland; Finlandia Fil: Olsson, Anna-Karin. Uppsala University; Suiza Fil: Petrova, Tatiana V.. Ludwig Institute for Cancer Research Lausanne; Suiza Fil: Pietras, Kristian. Division of Translational Cancer Research; Suecia Fil: Pili, Roberto. Indiana University Simon Cancer Center; Estados Unidos Fil: Pollard, Jeffrey W.. University of Edinburgh; Reino Unido Fil: Post, Mark J.. Maastricht University; Países Bajos Fil: Quax, Paul H. A.. Einthoven Laboratory for Experimental Vascular Medicine; Países Bajos Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental. Fundación de Instituto de Biología y Medicina Experimental. Instituto de Biología y Medicina Experimental; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Química Biológica; Argentina Fil: Raica, Marius. Victor Babes University of Medicine and Pharmacy; Rumania Fil: Randi, Anna M.. Imperial College London; Reino Unido Fil: Ribatti, Domenico. Università degli Studi di Bari; Italia Fil: Ruegg, Curzio. University of Fribourg; Suiza Fil: Schlingemann, Reinier O.. University of Amsterdam; Países Bajos Fil: Schulte Merker, Stefan. Institute of Cardiovascular Organogenesis and Regeneration; Alemania Fil: Smith, Lois E. H.. Harvard Medical School; Estados Unidos Fil: Song, Jonathan W.. Ohio State University; Estados Unidos Fil: Stacker, Steven A.. University of Melbourne; Australia Fil: Stalin, Jimmy. Institute of Cardiovascular Organogenesis and Regeneration; Alemania Fil: Stratman, Amber N.. National Institutes of Health; Estados Unidos Fil: Van de Velde, Maureen. University of Liège; Bélgica Fil: van Hinsbergh, Victor W. M.. Universida de Lausanne; Suiza Fil: Vermeulen, Peter B.. HistoGeneX; Bélgica. University of Antwerp; Bélgica Fil: Waltenberger, Johannes. University of Münster; Alemania Fil: Weinstein, Brant M.. National Institutes of Health; Estados Unidos Fil: Xin, Hong. University of California at San Diego; Estados Unidos Fil: Yetkin Arik, Bahar. University of Amsterdam; Países Bajos Fil: Yla Herttuala, Seppo. University of Eastern Finland; Finlandia Fil: Yoder, Mervin C.. Indiana University; Estados Unidos Fil: Griffioen, Arjan W.. VU University Medical Center; Países Bajos
- Published
- 2018
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