Carbohydrate-based peptidomimetics targeting neuropilin-1: synthesis, molecular docking study and in vitro biological activities

International audienceNeuropilin-1 (NRP-1), a transmembrane glycoprotein acting as a co-receptor of VEGF-A, is expressed by cancer and angiogenic endothelial cells and is involved in the angiogenesis process. Taking advantage of functionalities and stereodiversities of sugar derivatives, the design and the synthesis of carbohydrate based peptidomimetics are here described. One of these compounds (56) demonstrated inhibition of VEGF-A165 binding to NRP-1 (IC50 = 39 μM) and specificity for NRP-1 over VEGF-R2. Biological evaluations were performed on human umbilical vein endothelial cells (HUVECs) through activation of downstream proteins (AKT and ERK phosphorylation), viability/proliferation assays and in vitro measurements of anti-angiogenic abilities

Intérêts des films minces multicouches de polyélectrolytes dans la conception de substituts vasculaires

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Intérêts des films minces multicouches de polyélectrolytes dans la conception de substituts vasculaires

NANCY1-SCD Medecine (545472101) / SudocSudocFranceF

Les thérapies ciblées anti-EGFR ont-elles un réel effet anti-angiogénique ? Etude in vitro de l'angiogenèse induite par des cellules cancéreuses des VADS traitées ou non par le Cetuximab

La surexpression du récepteur EGFR a un rôle majeur dans le développement des carcinomes des voies aérodigestives supérieures (VADS) et son inhibition par les anticorps anti-EGFR (cetuximab) induit un effet anti-tumoral mais pourrait également avoir un effet anti-angiogénique. Cependant, les effets de ces agents sur l'angiogenèse et les cellules endothéliales (CE) n'ont pas réellement été évalués. L'objectif de ce travail est d'étudier l'angiogenèse induite par les molécules libérées par les cellules tumorales des VADS (Cal27, FaDu) dans les milieux de culture en présence ou non de cetuximab, appelés milieux conditionnés (CM). Le cetuximab n'a pas d'effet direct significatif sur les CE. Il induit une diminution de la sécrétion de VEGF par les cellules tumorales mais paradoxalement, les CM obtenus induisent un effet pro-angiogénique. L'analyse de la composition des CM ne permet pas d'identifier de molécule clé responsable de cet effet, le cetuximab diminuant à la fois la sécrétion tumorale des facteurs pro- et anti-angiogéniques. Pour expliquer ce paradoxe et en accord avec la littérature, nous avons mis en évidence une libération de microvésicules par nos cellules tumorales (TMV), TMV exprimant EGFR et TF, et une régulation de cette libération et de leur contenu par le cetuximab. Ces TMV peuvent interagir avec les CE et le cetuximab favoriserait cette interaction. La caractérisation de ces TMV et leur rôle dans le processus angiogénique en réponse ou non au cetuximab permettront dans le futur de comprendre la réelle activité des anticorps anti-EGFR sur l'angiogenèseOverexpression of EGFR has a major role in the development of head and neck squamous cell carcinoma (HNSCC) and its inhibition by anti-EGFR antibodies (cetuximab) induced an anti-tumor effect but could also induce an anti-angiogenic effect. However, the effects of these agents onto angiogenesis and endothelial cells (EC) have not really been evaluated. The objective of this work is to study angiogenesis induced by mediators released by head and neck squamous carcinoma cells (Cal27, FaDu) in culture media with or without cetuximab exposure, known as conditioned media (CM). Cetuximab has no significant direct effect on EC. It induces a decrease in the secretion of VEGF by tumor cells but, paradoxically, the CM induces a pro-angiogenic effect. The analysis of the composition of the CM does not allow us to identify a key molecule responsible for this effect because cetuximab decreases the secretion of both pro- and anti-angiogenic factors by tumor cells. To explain this paradox and in agreement with the literature, we highlighted the release of microvesicles by our tumor cells (TMV), TMV which express EGFR and TF, and regulation of this release and the content of TMV after cetuximab exposure. These TMV may interact with the EC and cetuximab increases this interaction. Further characterization of TMV and studying their role in the angiogenic process in response to cetuximab will allow us in the future to understand the real activity of anti-EGFR antibodies onto angiogenesisNANCY1-Bib. numérique (543959902) / SudocSudocFranceF

Natural Killer cells and monoclonal antibodies: Two partners for successful antibody dependent cytotoxicity against tumor cells

International audienceMonoclonal antibodies targeting tumors are one of the most important discoveries in the field of cancer. Although several effective antibodies have been developed, a relapse may occur. One of their mechanisms of action is Antibody Dependent Cell Cytotoxicity (ADCC), by engaging the Fc γ receptor CD16 expressing Natural Killer cells, innate lymphoid cells involved in cancer immunosurveillance and able to kill tumor cells. A lack of NK cells observed in many cancers may therefore be a cause of the low efficacy of antibodies observed in some clinical situations. Here we review clear evidences of the essential partnership between NK cells and antibodies showed in vitro, in vivo, and in clinical trials in different indications, describe the hurdles and ways to enhance ADCC and the evolution of monoclonal antibody therapy. NK cell adoptive immunotherapy combined with monoclonal antibodies may overcome the resistance to the treatment and enhance their efficac

Effect of cetuximab treatment on induction of angiogenesis by HNSCC cell line depending on PTEN expression

International audienceOur work aimed to identify the ability of the HNSCC cell line Cal 27 to induce angiogenesis, regarding PTEN expression and anti-EGFR treatment. Cal 27, a human HNSCC cell line expressing PTEN has been transfected by a PTEN-siRNA and exposed to cetuximab for 48 hours. The culture media were then collected to be used as conditionned media for HUVEC and aortic rings culture. Aortic rings sprouting and tubular structures from HUVEC have been investigated by microscopy and quantified by AngioQuant software. The conditioned media have been also characterized by an analysis of key factors involved in angiogenesis regulation using Proteome Profiler Array. The anti-angiogenic effect of cetuximab in HNSCC seems to result from a direct effect of the anti-EGFR on endothelial cells rather than an effect mediated by tumoral cells, despite a VEGF concentration significantly lower due to cetuximab exposure. PTEN is involved in the regulation of vasculature in HNSCC. But surprisingly, loss of PTEN expression in Cal 27 leads to a reduction of the tumoral cells ability to induce angiogenesis. This process is not linked to the VEGF concentration changes but is mediated by a global change in the molecular constitution of conditioned media

In vitro impact of physiological shear stress on endothelial cells gene expression profile

International audienceIn the vascular system, the shear applied to the vascular wall activates mechano-sensors located on endothelial cells (ECs) leading to a modification in the gene expression profile. We applied laminar shear stress at 1 Pa on ECs for 6 h and measured by quantitative real time PCR the expression modulation of genes implied in inflammation (ICAM-1 and E-selectin), oxidative stress sensing (HO-1) and vascular tone modulation (eNOS). We showed that all these genes are shear stress inducible. ICAM-1 is more up-regulated than E-selectin suggesting different levels of implication in inflammatory responses and different modes of induction (SSRE, cytokine). Laminar shear stress induces an oxidative stress translated into HO-1 up-regulation, and a possible vasodilatation through the induction of eNOS. Our laminar shear stress system opens a novel and interesting frame in the evaluation of the impact on ECs and blood cells of new pharmacological substances injected in the bloodstream

Tumor vascular responses to antivascular and antiangiogenic strategies: looking for suitable models

International audienceAntiangiogenic and vascular disrupting agents are in the current cancer therapeutic armamentarium. A better understanding of the intricate mechanisms ruling neovessel survival within tumors during or after treatment is needed. Refinement of imaging and a growing knowledge of molecular biology of tumor vascularization provide new insights. It is necessary to define suitable methods for monitoring tumor response and appropriate tools to analyze data. This review compares most commonly used preclinical models, considering their recent improvements, and describes promising new approaches such as microfluidics, real-time electrical impedance based technique and noninvasive imaging techniques. The advantages and limitations of the in vitro, ex vivo and in vivo models are discussed. This review also provides a critical summary of emerging approaches using mathematical modeling

Storage, managment and analysis of morphological data: Xper3 and its utilisation in palaeobotany

International audienceClassifying and naming taxa is crucial in all biological sciences, and palaeontology is no exception. With the advent of computer sciences and digitized information, Computer Aided Identification systems are of particular interest to paleo-taxonomists dealing with large fossil collections or sampling. Computer-stored and managed knowledge databases allow the exploration of morphological data themselves, but also their relation with ecological or distribution information. Thus, these databases have plentiful applications in systematics, palaeoecology or palaeoclimatology. Among all tools available, Xper2 is a user-friendly application, which can be used to store, edit, analyse and distribute structured descriptive data. Lately, an online interface (Xper3) was introduced to develop online collaboration and diffusion of knowledge databases. Our contribution aims to introduce this tool and to illustrate its helpfulness in several aspects and issues in palaeontology, by giving relevant examples of applications for palaeobotany: (i) an Icacinaceae database and its application in phylogenetic studies, (ii) PalmID, an online identification tool for modern and fossil palms, (iii) ABIeS, an ongoing project proposing a tool for fossil softwoods identification and (iv) the potential use of Xper2 and Xper3 in paleoclimatic studies based on fossil leaves. Additionally, the relevance of Xper3 in teaching applications and knowledge transfer to the public will be discussed

Evaluation de la cytotoxicité des cellules Natural Killer envers le medulloblastome, in vitro et in vivo

International audienc