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Nantes, France

Chiron D.,French Institute of Health and Medical Research | Chiron D.,University of Nantes | Chiron D.,Equipe labellisee Ligue Nationale Contre le Cancer | Maiga S.,French Institute of Health and Medical Research | And 16 more authors.
Blood Cells, Molecules, and Diseases | Year: 2012

The purpose of this study was to identify the pathways associated with the ability of CD138 + human myeloma cells to form colonies in a serum-free semi-solid human collagen-based assay. Only 26% (7 of 27) of human myeloma cell lines were able to spontaneously form colonies. This spontaneous clonogenic growth correlated with the expression of the NOTCH ligand JAG2 (p<0.001). Blocking JAG-NOTCH interactions with NOTCH-Fc chimeric molecules impaired self-colony formation, indicating a role for JAG-NOTCH pathway in colony formation. In two cell lines, silencing of JAG2 blocked both colony formation and in vivo tumor formation in immunocompromised mice. RT-PCR and flow cytometry analysis revealed that JAG2 is often expressed by CD138 + primary cells. Our results indicate that spontaneous clonogenic growth of myeloma cells requires the expression of JAG2. © 2012 Elsevier Inc. Source

Kervoelen C.,Myelomax | Kervoelen C.,University of Nantes | Menoret E.,Myelomax | Gomez-Bougie P.,University of Nantes | And 6 more authors.
Oncotarget | Year: 2015

Due to its cytotoxic effect in lymphoid cells, dexamethasone is widely used in the treatment of multiple myeloma (MM). However, only a subset of myeloma patients responds to high-dose dexamethasone. Despite the undeniable anti-myeloma benefits of dexamethasone, significant adverse effects have been reported. We re-evaluate the anti-tumor effect of dexamethasone according to the molecular heterogeneity of MM. We demonstrated that the pro-death effect of dexamethasone is related to the genetic heterogeneity of MM because sensitive cell lines were restricted to MAF and MMSET signature subgroups, whereas all CCND1 cell lines (n = 10) were resistant to dexamethasone. We demonstrated that the glucocorticoid receptor expression was an important limiting factor for dexamethasone-induced cell death and we found a correlation between glucocorticoid receptor levels and the induction of glucocorticoidinduced leucine zipper (GILZ) under dexamethasone treatment. By silencing GILZ, we next demonstrated that GILZ is necessary for Dex induced apoptosis while triggering an imbalance between anti- and pro-apoptotic Bcl-2 proteins. Finally, the heterogeneity of the dexamethasone response was further confirmed in vivo using myeloma xenograft models. Our findings suggested that the effect of dexamethasone should be re-evaluated within molecular subgroups of myeloma patients to improve its efficacy and reduce its adverse effects. Source

Tessoulin B.,French Institute of Health and Medical Research | Tessoulin B.,University of Nantes | Tessoulin B.,French National Center for Scientific Research | Descamps G.,French Institute of Health and Medical Research | And 23 more authors.
Blood | Year: 2014

The aim of this study was to assess the efficiency of p53 reactivation and induction of massive apoptosis (PRIMA-1Met) in inducingmyeloma cell death, using 27 human myeloma cell lines (HMCLs) and 23 primary samples. Measuring the lethal dose (LD50) of HMCLs revealed thatHMCLs displayed heterogeneous sensitivity,with an LD50 ranging from4 μM to more than 200 μM. The sensitivity of HMCLs did not correlate with myeloma genomic heterogeneity or TP53 status, and PRIMA-1Met did not induce or increase expression of the p53 target genes CDKN1A or TNFRSF10B/DR5. However, PRIMA-1Met increased expression of NOXA in a p53-independent manner, and NOXA silencing decreased PRIMA1Met-induced cell death. PRIMA-1Met depleted glutathione (GSH) content and induced reactive oxygen species production.The expression of GSH synthetase correlated with PRIMA-1Met LD50 values, and we showed that a GSH decrease mediated by GSH synthetase silencing or by and L-buthionine sulphoximine, an irreversible inhibitor of γ-glutamylcysteine synthetase, increased PRIMA-1Met-induced cell death and overcame PRIMA-1Met resistance. PRIMA-1Met (10 μM) induced cell death in 65% of primary cells independent of the presence of del17p; did not increase DR5 expression, arguing against an activation of p53 pathway; and synergized with L-buthionine sulphoximine in all samples. Finally, we showed in mouse TP53neg JJN3-xenograft model that PRIMA-1Met inhibited myeloma growth and synergized with L-buthionine sulphoximine in vivo. © 2014 by The American Society of Hematology. Source

Potiron V.A.,French Institute of Health and Medical Research | Potiron V.A.,University of Nantes | Potiron V.A.,French National Center for Scientific Research | Abderrahmani R.,French Institute of Health and Medical Research | And 16 more authors.
PLoS ONE | Year: 2013

Although endothelial cell apoptosis participates in the tumor shrinkage after single high-dose radiotherapy, little is known regarding the vascular response after conventionally fractionated radiation therapy. Therefore, we evaluated hypoxia, perfusion and vascular microenvironment changes in an orthotopic prostate cancer model of conventionally fractionated radiation therapy at clinically relevant doses (2 Gy fractions, 5 fractions/week). First, conventionally fractionated radiation therapy decreased tumor cell proliferation and increased cell death with kinetics comparable to human prostate cancer radiotherapy. Secondly, the injection of Hoechst 33342 or fluorescent-dextrans showed an increased tumor perfusion within 14 days in irradiated tumors, which was correlated with a clear reduction of hypoxia. Improved perfusion and decreased hypoxia were not explained by increased blood vessel density, size or network morphology. However, a tumor vascular maturation defined by perivascular desmin+/SMA+ cells coverage was clearly observed along with an increase in endothelial, zonula occludens (ZO)-1 positive, intercellular junctions. Our results show that, in addition to tumor cell killing, vascular maturation plays an uncovered role in tumor reoxygenation during fractionated radiation therapy. © 2013 Potiron et al. Source

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