Membrane Microvesicles as Actors in the Establishment of a Favorable Prostatic Tumoral Niche: A Role for Activated Fibroblasts and CX3CL1-CX3CR1 Axis

Tumor microenvironment is enriched in plasma membrane microvesicles (MV) shed from all cell types that constitute the tumor mass, reflecting the antigenic profile of the cells they originate from. Fibroblasts and tumor cells mutually communicate within tumor microenvironment. Recent evidences suggest that tumor-derived MVs (TMV) exert a broad array of biological functions in cell-to-cell communication. To elucidate their role in cancer-to-fibroblast cell communication, TMV obtained from two prostate carcinoma cell lines with high and weak metastatic potential (PC3 and LnCaP, respectively) have been characterized. TMV exhibit matrix metalloproteinases (MMP) and extracellular MMP inducer at their surface, suggesting a role in extracellular matrix degradation. Moreover, TMV not only induce the activation of fibroblasts assessed through extracellular signal-regulated kinase 1/2 phosphorylation and MMP-9 up-regulation, increase motility and resistance to apoptosis but also promote MV shedding from activated fibroblasts able in turn to increase migration and invasion of highly metastatic PC3 cells but not LnCaP cells. PC3 cell chemotaxis seems, at least partially, dependent on membrane-bound CX3CL1/fractalkine ligand for chemokine receptor CX3CR1. The present results highlight a mechanism of mutual communication attributable not only to soluble factors but also to determinants harbored by MV, possibly contributing to the constitution of a favorable niche for cancer development. [Cancer Res 2009;69(3):785–93

Medium-chain triglycerides supplementation exacerbates peritonitis-induced septic shock in rats: role on cell membrane remodeling

International audienc

Lipid emulsions differentially affect LPS-induced acute monocytes inflammation: in vitro effects on membrane remodeling and cell viability

International audienc

Studies of Circulating Microparticle Release in Peripheral Blood After Pancreatic Islet Transplantation

International audienc

Transpl Int

Instant Blood-Mediated Inflammatory Reaction (IBMIR) occurs at the vicinity of transplanted islets immediately after intraportal infusion and is characterized by cytokine secretion, tissue factor (TF) expression, and ss cell loss. Microparticles (MPs) are cellular effectors shed from the plasma membrane of apoptotic cells. Modulation of the properties of ss cell-derived MPs by liraglutide was assessed in a cellular model designed to mimic IBMIR oxidative and inflammatory conditions. Rin-m5f rat beta cells were stimulated by H2 O2 or a combination of IL-1beta and TNF-alpha. Cell-derived MPs were applied to naive Rin-m5f for 24 h. Apoptosis, MP release, TF activity, P-IkappaB expression, and MP-mediated apoptosis were measured in target cells. Direct protection by liraglutide was shown by a significant decrease in the oxidative stress-induced apoptosis (18.7% vs. 7.6%, P < 0.0001 at 1 mum liraglutide) and cellular TF activity (-40% at 100 nm liraglutide). Indirect cytoprotection led to 20% reduction in MP generation, thereby lowering MP-mediated apoptosis (6.3% vs. 3.7%, P = 0.022) and NF-kappaB activation (-50%) in target cells. New cytoprotective effects of liraglutide were evidenced, limiting the expression of TF activity by ss cells and the generation of noxious MPs. Altogether, these data suggest that liraglutide could target pro-apoptotic and pro-inflammatory MPs in transplanted islets

J Cardiovasc Electrophysiol

BACKGROUND: Thrombi form mainly in the left rather than the right atria of patients with atrial fibrillation (AF), the reason of this predilection being unknown. OBJECTIVE: The purpose of this study was to investigate whether atrial-specific differences in endothelial damage, leukocyte activation, platelet stimulation, and tissue factor activity occur in patients with AF. METHODS: Twenty-two patients (16 men, 6 women; age 56 +/- 8 years; 16 paroxysmal AF, 6 persistent AF) with AF undergoing pulmonary vein isolation were investigated. Blood samples from the left and the right atrium were obtained at the start of the procedure. Microparticles (MPs) released by apoptotic/stimulated cells were measured by capture assays. Their procoagulant abilities were quantified by functional prothrombinase and tissue factor assays and their cellular origin were determined (endothelium, platelet, leukocyte). Platelet reactivity was evaluated by whole blood flow cytometry for expression of platelet P-selectin (CD62P), active glycoprotein IIb/IIIa receptor (PAC-1). Platelet aggregation was evaluated using ADP, TRAP and collagen-induced whole blood aggregometry. RESULTS: There were no atrial-specific differences in the levels of total procoagulant MPs, leukocyte-derived-MPs or platelet-derived MPs. Conversely, endothelial-derived MPs and tissue factor activity and collagen-induced platelet aggregation were slightly elevated in the right atrium (P < 0.05). CONCLUSIONS: Our data show no evidence for increased thrombogenic status in the left atrium that would account for its greater propensity for thrombus formation in patients with AF

Medium-chain triglyceride supplementation exacerbates peritonitis-induced septic shock in rats: role on cell membrane remodeling:

BACKGROUND AND AIMS: Lipid emulsions for parenteral nutrition interfere with immunity and may alter the cell plasma membrane and microparticle release, thus modulating their biological effects. Our aim was to evaluate the effect of two lipid emulsions for parenteral nutrition containing either a mixture of long- and medium-chain triglycerides (LCTs and MCTs) or LCTs only, to assess their role on microparticle release and acute inflammation during septic shock in rats. METHODS AND RESULTS: Septic rats (cecal ligation and puncture) and sham rats were infused with 5% dextrose or a lipid emulsion during 22 h. After 18 h, rats were resuscitated during 4 h and hemodynamic parameters monitored. Circulating microparticles and their phenotype were measured by prothrombinase assay; heart and aorta were collected for Western blotting and electron paramagnetic resonance measurements. No significant effect of lipid emulsions was observed in sham rats. In septic rats, norepinephrine requirements were increased in MCT/LCT-infused rats compared with 5% dextrose- or LCT-infused rats (2.7 +/- 0.2 vs. 1.9 +/- 0.8 and 1.2 +/- 0.3 mug/kg per minute, respectively; P < 0.05) with increased procoagulant microparticle generation (38.6 +/- 5.8 vs. 18.8 +/- 3.1 and 19.2 +/- 3.0 nM equivalent phosphatidylserine [Eq PhtdSer]; P < 0.05), leukocyte- (17.4 +/- 3.5 vs. 7.7 +/- 1.8 and 6.0 +/- 1.1 nM Eq PhtdSer; P < 0.05), platelet- (13.9 +/- 2.5 vs. 4.4 +/- 0.7 and 5.4 +/- 1.3 nM Eq PhtdSer; P < 0.05), and endothelial-derived microparticles (16.9 +/- 3.6 vs. 6.4 +/- 1.4 and 5.6 +/- 0.8 nM Eq PhtdSer; P < 0.05). The mixture of MCTs/LCTs significantly increased cardiac and vascular nitric oxide and superoxide anion production, phosphorylated IkappaB, and cyclooxygenase 2 expression compared with the lipid emulsion containing only LCTs. CONCLUSIONS: Compared with 5% dextrose, MCT/LCT supplementation during septic shock in rats induced deleterious effects with increased inflammation and cell activation, associated to vascular hyporeactivity. During septic shock, LCT supplementation seemed to be neutral compared with 5% dextrose infusion