Etude ultrastructurale et cytochimique des cellules du canal semi-circulaire de grenouille. Correlations anatomo-fonctionnelles dans l'epithelium labyrinthique

SIGLEINIST T 74108 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueFRFranc

Etude des propriétés antitumorales de bisphosphonates azotés sur un modèle de carcinome épidermoïde

[Résumé en français] en plus de leur propriétés antirésorptives, les bisphosphonates (BP) exercent des activités antitumorales sur des modèles de myélomes, sarcomes et adénocarcinomes. Dans la présente étude, nous avons montré que 3 BP inhibent in vitro la viabilité des cellules A431 de carcinome épidermoïde vulvaire. Cet effet, en partie lié à une inhibition de la voie du mévalonate, se traduit par de l'apoptose et de la nécrose. Les BP exercent aussi un effet cytostatique sur les A431. In vivo, l'alendronate n'est capable que de retader la croissance de tumeurs A431 implantées chez la souris nude. Cependant, ce BP inhibe l'invasion des cellules A431 in vitro, laissant supposer un éventuel potentiel antimétastatique de celui-ci in vivo. Les 3 BP affectent également in vitro la prolifération de cellules endothéliales, suggérant une activité antiangiogénique de ces molécules. Ainsi, ces BP pourraient être des candidats intéressants en thérapie anticancéreuse adjuvante dans divers types de cancersPARIS13-BU Sciences (930792102) / SudocSudocFranceF

Low molecular weight fucoidan prevents intimal hyperplasia in rat injured thoracic aorta through the modulation of matrix metalloproteinase-2 expression.

International audienceThe therapeutic potential of low molecular-weight fucoidan (LMWF), a sulfated polysaccharide extracted from brown seaweed was investigated on vascular smooth muscle cell (VSMC) and human vascular endothelial cell (HUV-EC-C) proliferation and migration in vitro and in a rat model of intimal hyperplasia. Sprague-Dawley rats were subjected to balloon injury in the thoracic aorta followed by two weeks' treatment with either LMWF (5mg/kg/day) or vehicle. Morphological analysis and proliferating cell nuclear antigen immunostaining at day 14 indicated that LMWF prevented intimal hyperplasia in rat thoracic aorta as compared with vehicle (neo-intima area, 3±0.50 versus 5±0.30mm, <0.01). In situ zymography showed that LMWF significantly decreased the activity of matrix metalloproteinase (MMP)-2 in the neo-intima compared to vehicle. The in vitro study demonstrated that 10μg/ml LMWF increased HUV-EC-C migration by 45±5% but reduced VSMC migration by 40±3%. LMWF also increased MMP-2 mRNA expression in HUV-EC-Cs and reduced it in VSMCs. MMP-2 level in the conditioned medium from cells incubated with 10μg/ml LMWF was 5.4-fold higher in HUV-EC-C, but 6-fold lower in VSMCs than in untreated control cells. Furthermore, decreasing MMP-2 expression in HUV-EC-Cs or VSMCs by RNA interference resulted in reduced LMWF-induced effects on cell migration

Structure-activity relationships of a new class of aromatic bisphosphonates that inhibit tumor cell proliferation in vitro.

International audienceWe previously reported a simple and efficient one-pot procedure for synthesis of 1-hydroxymethylene-1,1-bisphosphonic acids (HMBP). According to this method, we synthesized a series of new aromatic HMBP and investigated structure-activity relationships by evaluating their anti-proliferative activity against A431 human tumor cell line. Our results showed that the introduction of an extra methylene group in a pyridyl-containing R2 side chain increased 100-fold the anti-proliferative activity of the HMBP. In contrast, this chemical modification did not modify the anti-proliferative activity of compounds substituted with a phenyl-containing R2 side chain. Para-substitution of the phenyl ring with various groups markedly influenced the HMBP activity, the order of potency (bromine > chlorine > fluorine = none) closely matching the atomic volume of the substituted group. Moreover, changes in the substitution position of the bromine group also affected the anti-proliferative activity, the more potent activity being obtained with para-substitution of the phenyl ring. In conclusion, this structure-activity study led us to identify the new aromatic HMBP [(4-Bromo-phenyl)-hydroxy-phosphono-methyl]-phosphonic acid as a potent in vitro anti-proliferative molecule against tumor cell lines (IC50 value of 9.5 x 10(-5) M). Interestingly, this compound can be further easily esterified on its phosphonic acid functions according to our chemical method and, thus, represents a potential candidate for the development of new esterified HMBP with enhanced pharmacokinetics

Angiogenic properties of the chemokine RANTES/CCL5

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Robustness and drivers of the Northern Hemisphere extratropical atmospheric circulation response to a CO2-induced warming in CNRM-CM6-1

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A novel non-containing-nitrogen bisphosphonate inhibits both in vitro and in vivo angiogenesis

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Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells

International audienceThe aim of our study was to investigate whether myofibroblasts and the chemokine monocyte chemoattractant protein‐1 (MCP‐1)/CCL2 may play a role in hepatocellular carcinoma progression. We observed that hepatic myofibroblast LI90 cells express MCP‐1/CCL2 mRNA and secrete this chemokine. Moreover, myofibroblast LI90 cell‐conditioned medium (LI90‐CM) induces human hepatoma Huh7 cell migration and invasion. These effects are strongly reduced when a MCP‐1/CCL2‐depleted LI90‐CM was used. We showed that MCP‐1/CCL2 induces Huh7 cell migration and invasion through its G‐protein–coupled receptor CCR2 and, to a lesser extent, through CCR1 only at high MCP‐1/CCL2 concentrations. MCP‐1/CCL2's chemotactic activities rely on tyrosine phosphorylation of focal adhesion components and depend on matrix metalloproteinase (MMP)‐2 and MMP‐9. Furthermore, we observed that Huh7 cell migration and invasion induced by the chemokine are strongly inhibited by heparin, by β‐D‐xyloside treatment of cells and by anti‐syndecan‐1 and ‐4 antibodies. Finally, we developed a 3‐dimensional coculture model of myofibroblast LI90 and Huh7 cells and demonstrated that MCP‐1/CCL2 and its membrane partners, CCR1 and CCR2, may be involved in the formation of mixed hepatoma‐myofibroblast spheroids. In conclusion, our data show that human liver myofibroblasts act on hepatoma cells in a paracrine manner to increase their invasiveness and suggest that myofibroblast‐derived MCP‐1/CCL2 could be involved in the pathogenesis of hepatocellular carcinoma

Syndecan-1 and syndecan-4 are involved in RANTES/CCL5-induced migration and invasion of human hepatoma cells

International audienceBackgroundWe previously demonstrated that the CC-chemokine Regulated upon Activation, Normal T cell Expressed and Secreted (RANTES)/CCL5 exerts pro-tumoral effects on human hepatoma Huh7 cells through its G protein-coupled receptor, CCR1. Glycosaminoglycans play major roles in these biological events.MethodsIn the present study, we explored 1/ the signalling pathways underlying RANTES/CCL5-mediated hepatoma cell migration or invasion by the use of specific pharmacological inhibitors, 2/ the role of RANTES/CCL5 oligomerization in these effects by using a dimeric RANTES/CCL5, 3/ the possible involvement of two membrane heparan sulfate proteoglycans, syndecan-1 (SDC-1) and syndecan-4 (SDC-4) in RANTES/CCL5-induced cell chemotaxis and spreading by pre-incubating cells with specific antibodies or by reducing SDC-1 or -4 expression by RNA interference.Results and conclusionThe present data suggest that focal adhesion kinase phosphorylation, phosphoinositide 3-kinase-, mitogen-activated protein kinase- and Rho kinase activations are involved in RANTES/CCL5 pro-tumoral effects on Huh7 cells. Interference with oligomerization of the chemokine reduced RANTES/CCL5-mediated cell chemotaxis. This study also indicates that SDC-1 and -4 may be required for HepG2, Hep3B and Huh7 human hepatoma cell migration, invasion or spreading induced by the chemokine. These results also further demonstrate the involvement of glycosaminoglycans as the glycosaminoglycan-binding deficient RANTES/CCL5 variant, in which arginine 47 was replaced by lysine, was devoid of effect.General significanceThe modulation of RANTES/CCL5-mediated cellular effects by targeting the chemokine-syndecan interaction could represent a new therapeutic approach for hepatocellular carcinoma