Osteoprotegerin regulates cancer cell migration through SDF-1/CXCR4 axis and promotes tumour development by increasing neovascularization

We previously reported that OPG is involved in ischemic tissue neovascularization through the secretion of SDF-1 by pretreated-OPG endothelial colony-forming cells (ECFCs). As the vascularization is one of the key factor influencing the tumour growth and cancer cell dissemination, we investigated whether OPG was able to modulate the invasion of human MNNG-HOS osteosarcoma and DU145 prostate cancer cell lines in vitro and in vivo. Cell motility was analysed in vitro by using Boyden chambers. Human GFP-labelled MMNG-HOS cells were inoculated in immunodeficient mice and the tumour nodules formed were then injected with OPG and/or FGF-2, AMD3100 or 0.9% NaCl (control group). Tumour growth was manually followed and angiogenesis was assessed by immunohistochemistry. In vitro, SDF-1 released by OPG-pretreated ECFCs markedly attracted both MNNG-HOS and DU145 cells and induced spontaneous migration of cancer cells. In vivo, tumour volumes were significantly increased in OPG-treated group compared to the control group and OPG potentiated the effect of FGF-2. Concomitantly, OPG alone or combined with FGF-2 increased the number of new vasculature compared to the control group. Interestingly AMD3100, an inhibitor of SDF-1, prevented the in vivo effects of OPG induced by SDF-1 This study provides experimental evidence that OPG promotes tumour development trough SDF-1/CXCR4 axis

L'ostéoprotégérine, nouvel acteur dans l'angiogenèse (Rôle dans la formation de nouveaux vaisseaux et mécanisme d'action)

L Osteoprotégérine est une cytokine soluble qui joue un rôle clé dans le métabolisme osseux et est impliquée dans la réponse immunitaire et l hématopoïèse. Elle est associée à la dysfonction endothéliale et semble intervenir dans l angiogenèse. Cette cytokine constituerait en fait, un trait d union entre le tissu osseux et vasculaire. Son rôle dans la formation de la matrice osseuse est aujourd hui bien élucidé mais son implication dans la vascularisation reste à établir. L OPG est rapidement libérée par l endothélium dans des conditions inflammatoires et est donc en mesure d intervenir dans le processus de revascularisation initié par les cellules progénitrices endothéliales (PECs). Au cours de cette étude, nous avons tenté de comprendre le rôle joué par cette cytokines dans la néovascularisation induite in vitro, par une sous population de PECs appelées ECFCs (endothelial colony-forming cells), et sur la formation des néovaisseaux in vivo.Nous avons montré qu elle agit sur la souchitude des cellules CD34+, potentialise les propriétés proangiogènes des ECFCs in vitro, et participe au processus angiogénique in vivo. L OPG agit sur les ECFCs via le syndécanne-1, inhibe leur adhésion à la matrice extracellulaire, favorise leur migration et leur tubulogenèse via la voie SDF-1/CXCR4, et potentialise leur adhésion à l'endothélium activé. Les effets observés sont corrélés à la libération du SDF-1, une activation des voies de signalisation ERK1/2, Akt et mTOR et à une activation de l intégrine aVb3. Par ailleurs, nous avons montré que l'OPG potentialise l effet proangiogène du FGF-2 in vivo. Elle participe également au développement tumoral et à la dissémination des métastases, probablement via l'inhibition de l'apoptose des cellules tumorales, mais aussi par la promotion de l'angiogenèse tumorale.Osteoprotegerin is a key regulator of bone metabolism involved in the immune response, hematopoiesis, and endothelial dysfunction. It seems to be implicated in angiogenesis and may represent a link between bone and vascular system. Although its role in bone is well recognized, its involvement in vasculature remains to be established. In inflammatory conditions, OPG is constitutively released by endothelial cells and smooth muscle cells, and therefore is able to participate in blood vessels formation induced by endothelial progenitor cells (EPCs). In this study we attempted to determine, in vitro the precise role of OPG in angiogenesis process induced by a subpopulation of EPCs called endothelial colony-forming cells (ECFCs), and on neovessel formation in vivo.We found that OPG causes phenotype changes of ECFCs via the activation of different molecular pathways targeting cell clonogenicity, differentiation, proliferation, migration and adhesion. Our results suggest that OPG may interact with ECFCs through its binding to syndecan-1, to induce an anti-adhesive effect and thereby promoting ECFCs migration through a SDF-1/CXCR4 dependant pathway and the ERK1/2, Akt and the mTOR pathways activation. OPG can intervene on the autocrine effect of ECFCs by inducing their adhesion to activated endothelium and their tubulogenesis, and potentiate their paracrine effects by inducing SDF-1 release. Alternatively, it can promote ECFCs survival, probably, in a aVb3 integrin-dependent manner. In vivo, OPG potentiates FGF-2 proangiogenic effects and may participate in tumour growth, invasion and metastasis, possibly through inhibition of tumour cell apoptosis but also by promoting tumour angiogenesis.PARIS5-Bibliotheque electronique (751069902) / SudocSudocFranceF

Important Determinants for Fucoidan Bioactivity: A Critical Review of Structure-Function Relations and Extraction Methods for Fucose-Containing Sulfated Polysaccharides from Brown Seaweeds

Seaweeds—or marine macroalgae—notably brown seaweeds in the class Phaeophyceae, contain fucoidan. Fucoidan designates a group of certain fucose-containing sulfated polysaccharides (FCSPs) that have a backbone built of (1→3)-linked α-l-fucopyranosyl or of alternating (1→3)- and (1→4)-linked α-l-fucopyranosyl residues, but also include sulfated galactofucans with backbones built of (1→6)-β-d-galacto- and/or (1→2)-β-d-mannopyranosyl units with fucose or fuco-oligosaccharide branching, and/or glucuronic acid, xylose or glucose substitutions. These FCSPs offer several potentially beneficial bioactive functions for humans. The bioactive properties may vary depending on the source of seaweed, the compositional and structural traits, the content (charge density), distribution, and bonding of the sulfate substitutions, and the purity of the FCSP product. The preservation of the structural integrity of the FCSP molecules essentially depends on the extraction methodology which has a crucial, but partly overlooked, significance for obtaining the relevant structural features required for specific biological activities and for elucidating structure-function relations. The aim of this review is to provide information on the most recent developments in the chemistry of fucoidan/FCSPs emphasizing the significance of different extraction techniques for the structural composition and biological activity with particular focus on sulfate groups

In vitro and in vivo evaluation of a dextran-graft-polybutylmethacrylate copolymer coated on CoCr metallic stent

International audienceIntroduction: The major complications of stent implantation are restenosis and late stent thrombosis. PBMA polymers are used for stent coating because of their mechanical properties. We previously synthesized and characterized Dextrangraft-polybutylmethacrylate copolymer (Dex-PBMA) as a potential stent coating. In this study, we evaluated the haemocompatibility and biocompatibility properties of Dex-PBMA in vitro and in vivo.Methods: Here, we investigated: (1) the effectiveness of polymer coating under physiological conditions and its ability to release Tacrolimus®, (2) the capacity of Dex-PBMA to inhibit Staphylococcus aureus adhesion, (3) the thrombin generation and the human platelet adhesion in static and dynamic conditions, (4) thebiocompatibility properties in vitro on human endothelial colony forming cells (ECFC) and on mesenchymal stem cells (MSC) and in vivo in rat models, and (5) we implanted Dex-PBMA and Dex-PBMA TAC coated stents in neointimal hyperplasia restenosis rabbit model. Results: Dex-PBMA coating efficiently prevented bacterial adhesion and release Tacrolimus®. Dex-PBMA exhibit haemocompatibility properties under flow and ECFC and MSC compatibility. In vivo, no pathological foreign body reaction was observed neither after intramuscular nor intravascular aortic implantation. After Dex-PBMA and Dex-PBMATAC coated stents 30 days implantation in a restenosis rabbit model, an endothelial cell coverage was observed and the lumenpatency was preserved.Conclusion: Based on our findings, Dex-PBMA exhibited vascular compatibility and can potentially be used as a coating for metallic coronary stents

Effect of precipitated extracellular marennine on angiogenesis and tumour cell proliferation

Angiogenesis is a fundamental biological process involved in the formation of new blood vessels from the pre-existing vascular network. In addition to physiological processes, angiogenesis is also implicated in pathological conditions such as tumour growth and metastatic progression. Research on marennine, a water-soluble blue-green pigment produced by the marine diatom Haslea ostrearia, has highlighted various promising biological activities. In vivo studies have suggested the potential of marennine in cancer treatment. However, these studies were conducted with crude extracts, the exact composition of which remained poorly defined. In this context, our study aimed to explore the effects of marennine on angiogenesis and tumour proliferation by using a Precipitated Extracellular Marennine (PEMn) extract. Our results confirmed the antiproliferative properties of PEMn on several cancer cell lines associated with angiogenic tumours. We then analysed its impact on the key steps of the angiogenic process, including Endothelial Colony-Forming Cells (ECFCs) proliferation, migration, and tubulogenesis. In parallel, we investigated the underlying mechanisms of its action, notably by assessing its effects on cell cycle regulation, senescence, and apoptosis. PEMn significantly inhibited tumour cell proliferation, induced ECFC senescence and apoptosis, impaired migration and tubulogenesis, and downregulated VEGFR-1 expression, highlighting its potential as a novel marine-derived antiangiogenic compound. These findings provide deeper insights into the mechanisms of action of marennine, identifying this bioactive natural compound as a novel bioactive compound in cancer treatment

Antioxidant activities of sulfated polysaccharides from brown and red seaweeds

The in vitro antioxidant activities of the following six sulfated polysaccharides were investigated: iota, kappa and lambda carrageenans, which are widely used in the food industry, fucoidan (homofucan) from the edible seaweed Fucus vesiculosus and fucans (heterofucans) F0.5 and F1.1 from the seaweed Padina gymnospora. With respect to the inhibition of superoxide radical formation, fucoidan had an IC50 (the half maximal inhibitory concentration) of 0.058 mg·mL−1, while the IC50 for the kappa, iota and lambda carrageenans were 0.112, 0.332 and 0.046 mg·mL−1, respectively. All of the samples had an inhibitory effect on the formation of hydroxyl radicals. The results of peroxidation tests showed that fucoidan had an IC50 of 1.250 mg·mL−1 and that the kappa, iota and lambda carrageenans had an IC50 of 2.753 and 2.338 and 0.323 mg·mL−1, respectively. Fucan fractions showed low antioxidant activity relative to fucoidan. These results clearly indicate the beneficial effect of algal polysaccharides as antioxidants

Critical role of interleukin (IL)-17 in inflammatory and immune disorders: An updated review of the evidence focusing in controversies

Interleukin 17 (IL-17) is a proinflammatory cytokine that has been the focus of intensive research because of its crucial role in the pathogenesis of different diseases across many medical specialties. In this context, the present review in which a panel of 13 experts in immunology, dermatology, rheumatology, neurology, hematology, infectious diseases, hepatology, cardiology, ophthalmology and oncology have been involved, puts in common the mechanisms through which IL-17 is considered a molecular target for the development of novel biological therapies in these different fields. A comprehensive review of the literature and analysis of the most outstanding evidence have provided the basis for discussing the most relevant data related to IL-17A blocking agents for the treatment of different disorders, such as psoriasis, psoriatic arthritis, rheumatoid arthritis, ankylosing spondylitis, cardiovascular disorders, non alcoholic fatty liver disease, multiple sclerosis, inflammatory bowel disease, uveitis, hematological and solid cancer. Current controversies are presented giving an opening line for future research.This work was supported by Novartis Pharmaceuticals Spain

Broadband multi-wavelength properties of M87 during the 2018 EHT campaign including a very high energy flaring episode

Context. The nearby elliptical galaxy M87 contains one of only two supermassive black holes whose emission surrounding the event horizon has been imaged by the Event Horizon Telescope (EHT). In 2018, more than two dozen multi-wavelength (MWL) facilities (from radio to γ-ray energies) took part in the second M87 EHT campaign. Aims. The goal of this extensive MWL campaign was to better understand the physics of the accreting black hole M87*, the relationship between the inflow and inner jets, and the high-energy particle acceleration. Understanding the complex astrophysics is also a necessary first step towards performing further tests of general relativity. Methods. The MWL campaign took place in April 2018, overlapping with the EHT M87* observations. We present a new, contemporaneous spectral energy distribution (SED) ranging from radio to very high-energy (VHE) γ-rays as well as details of the individual observations and light curves. We also conducted phenomenological modelling to investigate the basic source properties. Results. We present the first VHE γ-ray flare from M87 detected since 2010. The flux above 350 GeV more than doubled within a period of ≈36 hours. We find that the X-ray flux is enhanced by about a factor of two compared to 2017, while the radio and millimetre core fluxes are consistent between 2017 and 2018. We detect evidence for a monotonically increasing jet position angle that corresponds to variations in the bright spot of the EHT image. Conclusions. Our results show the value of continued MWL monitoring together with precision imaging for addressing the origins of high-energy particle acceleration. While we cannot currently pinpoint the precise location where such acceleration takes place, the new VHE γ-ray flare already presents a challenge to simple one-zone leptonic emission model approaches, and it emphasises the need for combined image and spectral modelling