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See detailAnalyse des propriétés anti-tumorales des exosomes endothéliaux dans le cancer du sein suite au transfert du microARN miR-503
Bovy, Nicolas ULg

Doctoral thesis (2015)

L’angiogenèse est un processus essentiel au développement tumoral ainsi qu’à la dissémination des métastases. De plus, il a été démontré ces dernières années que les miARN, des ARN non codant d'une ... [more ▼]

L’angiogenèse est un processus essentiel au développement tumoral ainsi qu’à la dissémination des métastases. De plus, il a été démontré ces dernières années que les miARN, des ARN non codant d'une vingtaine de nucléotides régulant l’expression des gènes au niveau post-transcriptionnel, jouent un rôle important dans divers processus tumoraux. Ils ont en outre été détectés dans plusieurs fluides biologiques, protégés de la dégradation dans des microvésicules, les exosomes. Cependant, à l’heure actuelle, aucune information n’est connue sur le rôle des exosomes endothéliaux et des miARN qu’ils contiennent sur la croissance tumorale. Au cours de ce travail, nous avons pour la première fois mis en évidence l’existence d’un transfert de miARN des cellules endothéliales vers les cellules tumorales par l’intermédiaire d’exosomes. Nous avons ensuite identifié un miARN, miR-503, dont l’export dans ces microvésicules est modifié en conditions tumorales. L’analyse de la fonction du miARN dans les cellules tumorales de cancer du sein montre qu’il possède des propriétés anti-tumorales en réduisant la prolifération et l’invasion. Nous avons également observé que le miR-503 d’origine endothéliale génère les mêmes effets. Pour expliquer ces résultats, deux cibles du miARN ont été identifiées, CCND2 et CCND3. De plus, l’inhibition de ces dernières conduit au même phénotype qu’une surexpression de miR-503. Nous avons ensuite voulu déterminer si le niveau plasmatique de ce miARN était modulé chez des patientes atteintes de cancer du sein. Nos analyses révèlent une augmentation du niveau sanguin de miR-503 à la suite d’un traitement par chimiothérapie néoadjuvante. Nous avons de plus observé que des cellules endothéliales soumises aux mêmes agents chimiothérapeutiques sécrètent activement du miR-503 dans leurs exosomes. Il semble également que le changement phénotypique induit par miR-503 sur les cellules tumorales modifie leur production en facteurs angiogènes ce qui mène, en retour, à une inhibition de l’angiogenèse. Ces résultats montrent que miR-503 est un miARN anti-tumoral sécrété dans les exosomes de cellules endothéliales. Celui-ci provoque l’inhibition de la prolifération et de l’invasion de cellules tumorales du cancer du sein en ciblant CCND2 et CCND3. Ce processus pourrait être complémentaire des effets directs générés par la chimiothérapie sur la tumeur et favoriser la réponse de l’hôte dans le traitement de la maladie. [less ▲]

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See detailEndothelial exosomes contribute to the antitumor response during breast cancer neoadjuvant chemotherapy via microRNA transfer.
Bovy, Nicolas ULg; Blomme, Benoît ULg; Freres, Pierre ULg et al

in Oncotarget (2015)

The interaction between tumor cells and their microenvironment is an essential aspect of tumor development. Therefore, understanding how this microenvironment communicates with tumor cells is crucial for ... [more ▼]

The interaction between tumor cells and their microenvironment is an essential aspect of tumor development. Therefore, understanding how this microenvironment communicates with tumor cells is crucial for the development of new anti-cancer therapies. MicroRNAs (miRNAs) are small non-coding RNAs that inhibit gene expression. They are secreted into the extracellular medium in vesicles called exosomes, which allow communication between cells via the transfer of their cargo. Consequently, we hypothesized that circulating endothelial miRNAs could be transferred to tumor cells and modify their phenotype. Using exogenous miRNA, we demonstrated that endothelial cells can transfer miRNA to tumor cells via exosomes. Using miRNA profiling, we identified miR-503, which exhibited downregulated levels in exosomes released from endothelial cells cultured under tumoral conditions. The modulation of miR-503 in breast cancer cells altered their proliferative and invasive capacities. We then identified two targets of miR-503, CCND2 and CCND3. Moreover, we measured increased plasmatic miR-503 in breast cancer patients after neoadjuvant chemotherapy, which could be partly due to increased miRNA secretion by endothelial cells. Taken together, our data are the first to reveal the involvement of the endothelium in the modulation of tumor development via the secretion of circulating miR-503 in response to chemotherapy treatment. [less ▲]

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See detailNeoadjuvant chemotherapy in breast cancer induces miR-34a and miR-122 expression
FRERES, Pierre ULg; JOSSE, Claire ULg; Bovy, Nicolas ULg et al

in Journal of Cellular Physiology (2014)

Circulating microRNAs (miRNAs) have been extensively studied in cancer as biomarkers but little is known regarding the influence of anti-cancer drugs on their expression levels. In this article, we ... [more ▼]

Circulating microRNAs (miRNAs) have been extensively studied in cancer as biomarkers but little is known regarding the influence of anti-cancer drugs on their expression levels. In this article, we describe the modifications of circulating miRNAs profile after neoadjuvant chemotherapy (NAC) for breast cancer. The expression of 188 circulating miRNAs was assessed in the plasma of 25 patients before and after NAC by RT-qPCR. Two miRNAs, miR- 34a and miR-122, that were significantly increased after NAC, were measured in tumor tissue before and after chemotherapy in 7 patients with pathological partial response (pPR) to NAC. These 2 chemotherapy-induced miRNAs were further studied in the plasma of 22 patients with adjuvant chemotherapy (AC) as well as in 12 patients who did not receive any chemotherapy. Twenty-five plasma miRNAs were modified by NAC. Among these miRNAs, miR-34a and miR-122 were highly upregulated, notably in pPR patients with aggressive breast cancer. Furthermore, miR-34a level was elevated in the remaining tumor tissue after NAC treatment. Studying the kinetics of circulating miR-34a and miR-122 expression during NAC revealed that their levels were especially increased after anthracycline-based chemotherapy. Comparisons of the plasma miRNA profiles after NAC and AC suggested that chemotherapy-induced miRNAs originated from both tumoral and non-tumoral compartments. This study is the first to demonstrate that NAC specifically induces miRNA expression in plasma and tumor tissue, which might be involved in the anti-tumor effects of chemotherapy in breast cancer patients. [less ▲]

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See detailmiRNA cargo within exosome-like vesicle transfer influences metastatic bone colonization.
Valencia, Karmele; Luis-Ravelo, Diego; Bovy, Nicolas ULg et al

in Molecular oncology (2014), 8(3), 689-703

Bone metastasis represents one of the most deleterious clinical consequences arising in the context of many solid tumors. Severe osteolysis results from tumor cell colonization of the bone compartment, a ... [more ▼]

Bone metastasis represents one of the most deleterious clinical consequences arising in the context of many solid tumors. Severe osteolysis results from tumor cell colonization of the bone compartment, a process which entails reciprocal exchange of soluble signals between tumor cells and their osseous microenvironment. Recent evidence indicates that tumor-intrinsic miRNAs are pleiotropic regulators of gene expression. But they are also frequently released in exosome-like vesicles (ELV). Yet the functional relevance of the transference of tumor-derived ELV and their miRNA cargo to the extracellular milieu during osseous colonization is unknown. Comparative transcriptomic profiling using an in vivo murine model of bone metastasis identified a repressed miRNA signature associated with high prometastatic activity. Forced expression of single miRNAs identified miR-192 that markedly appeased osseous metastasis in vivo, as shown by X-ray, bioluminescence imaging and microCT scans. Histological examination of metastatic lesions revealed impaired tumor-induced angiogenesis in vivo, an effect that was associated in vitro with decreased hallmarks of angiogenesis. Isolation and characterization of ELV by flow cytometry, Western blot analysis, transmission electron microscopy and nanoparticle tracking analysis revealed the ELV cargo enrichment in miR-192. Consistent with these findings, fluorescent labeled miR-192-enriched-ELV showed the in vitro transfer and release of miR-192 in target endothelial cells and abrogation of the angiogenic program by repression of proangiogenic IL-8, ICAM and CXCL1. Moreover, in vivo infusion of fluorescent labeled ELV efficiently targeted cells of the osseous compartment. Furthermore, treatment with miR-192 enriched ELV in a model of in vivo bone metastasis pre-conditioned osseous milieu and impaired tumor-induced angiogenesis, thereby reducing the metastatic burden and tumor colonization. Changes in the miRNA-cargo content within ELV represent a novel mechanism heavily influencing bone metastatic colonization, which is most likely relevant in other target organs. Mechanistic mimicry of this phenomenon by synthetic nanoparticles could eventually emerge as a novel therapeutic approach. [less ▲]

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See detailMiR-205 is downregulated in hereditary hemorrhagic telangiectasia and impairs TGF-beta signaling pathways in endothelial cells.
Tabruyn, Sebastien P.; Hansen, Sylvain ULg; Ojeda-Fernandez, Maria-Luisa et al

in Angiogenesis (2013)

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by arteriovenous malformations and hemorrhages. This vascular disease results mainly from mutations in 2 genes ... [more ▼]

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by arteriovenous malformations and hemorrhages. This vascular disease results mainly from mutations in 2 genes involved in the TGF-beta pathway (ENG and ALK1) that are exclusively expressed by endothelial cells. The present study identified miR-27a and miR-205 as two circulating miRNAs differentially expressed in HHT patients. The plasma levels of miR-27a are elevated while those of miR-205 are reduced in both HHT1 and HHT2 patients compared to healthy controls. The role of miR-205 in endothelial cells was further investigated. Our data indicates that miR-205 expression displaces the TGF-beta balance towards the anti-angiogenic side by targeting Smad1 and Smad4. In line, overexpression of miR-205 in endothelial cells reduces proliferation, migration and tube formation while its inhibition shows opposite effects. This study not only suggests that detection of circulating miRNA (miR-27a and miR-205) could help for the screening of HHT patients but also provides a functional link between the deregulated expression of miR-205 and the HHT phenotype. [less ▲]

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See detailPhenotyping and outcome on contemporary management in a German cohort of patients with peripartum cardiomyopathy.
Haghikia, A.; Podewski, E.; Libhaber, E. et al

in Basic Research in Cardiology (2013), 108(4), 366

Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease developing towards the end of pregnancy or in the months following delivery in previously healthy women in terms of cardiac disease ... [more ▼]

Peripartum cardiomyopathy (PPCM) is a life-threatening heart disease developing towards the end of pregnancy or in the months following delivery in previously healthy women in terms of cardiac disease. Enhanced oxidative stress and the subsequent cleavage of the nursing hormone Prolactin into an anti-angiogenic 16 kDa subfragment emerged as a potential causal factor of the disease. We established a prospective registry with confirmed PPCM present in 115 patients (mean baseline left ventricular ejection fraction, LVEF: 27 +/- 9 %). Follow-up data (6 +/- 3 months) showed LVEF improvement in 85 % and full recovery in 47 % while 15 % failed to recover with death in 2 % of patients. A positive family history of cardiomyopathy was present in 16.5 %. Pregnancy-associated hypertension was associated with a better outcome while a baseline LVEF </= 25 % was associated with a worse outcome. A high recovery rate (96 %) was observed in patients obtaining combination therapy with beta-blocker, angiotensin-converting enzyme (ACE) inhibitors/angiotensin-receptor-blockers (ARBs) and bromocriptine. Increased serum levels of Cathepsin D, the enzyme that generates 16 kDa Prolactin, miR-146a, a direct target of 16 kDa Prolactin, N-terminal-pro-brain-natriuretic peptide (NT-proBNP) and asymmetric dimethylarginine (ADMA) emerged as biomarkers for PPCM. In conclusion, low baseline LVEF is a predictor for poor outcome while pregnancy-induced hypertensive disorders are associated with a better outcome in this European PPCM cohort. The high recovery rate in this collective is associated with a treatment concept using beta-blockers, ACE inhibitors/ARBs and bromocriptine. Increased levels of Cathepsin D activity, miR-146a and ADMA in serum of PPCM patients support the pathophysiological role of 16 kDa Prolactin for PPCM and may be used as a specific diagnostic marker profile. [less ▲]

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See detailMiR-146a: an angiostatic miRNA with tumor-suppressive properties
Halkein, Julie ULg; Bovy, Nicolas ULg; Castermans, Karolien et al

Poster (2011, February)

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See detailmicroRNA-21 Exhibits Anti-Angiogenic Function by Targeting RhoB Expression in Endothelial Cells
Sabatel, Céline; Malvaux, Ludovic; Bovy, Nicolas ULg et al

Poster (2011, February)

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See detailMicroRNA-21 Exhibits Antiangiogenic Function by Targeting RhoB Expression in Endothelial Cells.
Sabatel, Céline; Malvaux, Ludovic ULg; Bovy, Nicolas ULg et al

in PLoS ONE (2011), 6(2), 16979

BACKGROUND: MicroRNAs (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 ... [more ▼]

BACKGROUND: MicroRNAs (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 FINDINGS: We 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/SIGNIFICANCE: Our results identify miR-21 as a new angiogenesis inhibitor and suggest that inhibition of cell migration and tubulogenesis is mediated through repression of RhoB. [less ▲]

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See detailStudy of the role of miR-21 in the regulation of angiogenesis
Sabatel, Céline; Malvaux, Ludovic; Bovy, Nicolas ULg et al

Poster (2010, May)

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See detailStudy of the role of miR-21 in the regulation of angiogenesis
Sabatel, Céline; Malvaux, Ludovic; Bovy, Nicolas ULg et al

Poster (2010, March)

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