miRNA-30 family members inhibit breast cancer invasion, osteomimicry, and bone destruction by directly targeting multiple bone metastasis–associated genes

miRNAs are master regulators of gene expression that play key roles in cancer metastasis. During bone metastasis, metastatic tumor cells must rewire their biology and express genes that are normally expressed by bone cells (a process called osteomimicry), which endow tumor cells with full competence for outgrowth in the bone marrow. Here, we establish miR-30 family members miR-30a, miR-30b, miR-30c, miR-30d, and miR-30e as suppressors of breast cancer bone metastasis that regulate multiple pathways, including osteomimicry. Low expression of miR-30 in primary tumors from patients with breast cancer were associated with poor relapse-free survival. In addition, estrogen receptor (ER)-negative/progesterone receptor (PR)-negative breast cancer cells expressed lower miR-30 levels than their ER/PR-positive counterparts. Overexpression of miR-30 in ER/PR-negative breast cancer cells resulted in the reduction of bone metastasis burden in vivo. In vitro, miR-30 did not affect tumor cell proliferation, but did inhibit tumor cell invasion. Furthermore, overexpression of miR-30 restored bone homeostasis by reversing the effects of tumor cell–conditioned medium on osteoclastogenesis and osteoblastogenesis. A number of genes associated with osteoclastogenesis stimulation (IL8, IL11), osteoblastogenesis inhibition (DKK-1), tumor cell osteomimicry (RUNX2, CDH11), and invasiveness (CTGF, ITGA5, ITGB3) were identified as targets for repression by miR-30. Among these genes, silencing CDH11 or ITGA5 in ER-/PR-negative breast cancer cells recapitulated inhibitory effects of miR-30 on skeletal tumor burden in vivo. Overall, our findings provide evidence that miR-30 family members employ multiple mechanisms to impede breast cancer bone metastasis and may represent attractive targets for therapeutic intervention. Significance: These findings suggest miR-30 family members may serve as an effective means to therapeutically attenuate metastasis in triple-negative breast cancer

Système catalytique aisément recyclable constitué d'un complexe cationique du rhodium et d'un liquide ionique pour effectuer l'hydrogénation énantiosélective d'énamines

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Le cotonnier à feuilles okra. Synthèse des études réalisées au Cameroun

Les objectifs de cette étude, réalisée par le programme coton de l'IRA (Institut de Recherches Agronomiques du Cameroun), étaient de définir des références techniques pour une expression optimale du potentiel de production des cultivars à feuille okra, évaluer les avantages et les inconvénients de ce type de variété dans les conditions de culture au Nord-Cameroun et tester l'hypothèse d'un effet bénéfique vis-à-vis du phénomène de collage, par une limitation des populations d'insectes piqueurs-suceurs. Pour conduire cette étude, la variété IRMA BOXA, isogénique okra de la variété vulgarisée IRMA 1243, a été utilisée. Les tests okra effectués en milieu réel, comparant ces deux variétés, ne font pas apparaître de rejet vis-à-vis de la culture okra de la part des planteurs. Ils apprécient la facilité de traitement insecticide et ne constatent pas de différence d'enherbement. Sur le plan technologique, les écarts observés sont réduits ou non significatifs. L'étude du potentiel de nutrition indique qu'IRMA 1243 et IRMA BOXA répondent de façon identique à l'azote. Aucun effet de la densité de semis (de 50 000 à 167 000 plants par hectare) n'a pu être mis en évidence sur le rendement en coton-graine de la variété okra : la hausse du nombre de capsules, observée avec l'accroissement de la densité, est compensée par la réduction de la production moyenne par plant et du poids moyen capsulaire. D'importantes différences du nombre de pucerons par feuilles apparaissent, la surface foliaire constituant l'élément limitant (saturation spatiale des limbes). La surface moyenne des feuilles d'IRMA BOXA représente 61 % de celle d'IRMA 1243, ce pourcentage étant identique au rapport du nombre de pucerons par cotonnier. Mais, à l'échelle du plant, le type okra possède un plus grand nombre de feuilles, compensant la différence de surface foliaire : les effectifs de pucerons suivent ainsi la même tendance, et les mesures de collage font apparaître une équivalence entre les deux variétés. (Résumé d'auteur

Combination of Antiangiogenic Therapies Reduces Osteolysis and Tumor Burden in Experimental Breast Cancer Bone Metastasis.

Introduction: The clinical efficacy of anti-angiogenic monotherapies in metastatic breast cancer is less than originally anticipated and it is not clear what the response of bone metastases to anti-angiogenic therapies is. Moreover, the evaluation of the combined use of antiangiogenic agents is still in its infancy. Therefore, we examined here the impact of neutralizing tumor-derived VEGF and/or VEGF receptor activity in a mouse model of breast cancer bone metastasis. Methods: VEGF expression in human MDA-MB-231/B02 breast cancer cells, which metastasize to bone, was invalidated using RNA interference strategy. The effects of VEGF silencing in B02 cells (Sh-VEGF) were compared with that of mock-transfected cells (Sc-VEGF) using in vitro cell migration and invasion assays and a model of tumor angiogenesis following subcutaneous implantation of Sh-VEGF and Sc-VEGF transfectants in nude mice. The effects of VEGF receptor tyrosine kinase inhibitor vatalanib were also investigated on bone metastasis formation caused by Sh-VEGF and Sc-VEGF transfectants. Additionally, the effects of vatalanib and VEGF-neutralizing antibody bevacizumab, used as single agents or in combination, were studied in the mouse model of bone metastasis caused by parental B02 breast cancer cells. Bone destruction was measured by radiography and histomorphometry. Skeletal tumor burden was measured by bioluminescence imaging and histomorphometry. All statistical tests were two-sided. Results : VEGF silencing severely impaired the motility and invasiveness of B02 breast cancer cells in vitro and decreased tumor angiogenesis in vivo, leading to growth inhibition of subcutaneous tumor xenografts in animals. VEGF silencing in B02 cells did not however inhibit the formation and progression of experimental bone metastases. Similarly, vatalanib did not inhibit bone metastasis formation caused by Sc-VEGF transfectants. By contrast, it did inhibit bone metastasis formation in animals bearing Sh-VEGF tumors. Moreover, B02 tumor-bearing mice treated with vatalanib + bevacizumab showed a decreased bone destruction and a reduced tumor burden compared with vehicle, whereas a single agent therapy had no effect. Conclusion: A combined therapy targeting both VEGF and its receptors efficiently reduces not only bone destruction but also skeletal tumor growth in a mouse model of breast cancer bone metastasis. Keywords Breast, cancer, bone, metastasis, tumor angiogenesis, VEGF, bevacizumab, PTK787, vatalani

Severe postoperative complications decrease overall and disease free survival in pancreatic ductal adenocarcinoma after pancreaticoduodenectomy

International audienceBACKGROUND:Postoperative complications influence overall and disease free survival after pancreaticoduodenectomy for pancreatic ductal adenocarcinoma is still a matter of debate and controversy.METHODS:The outcome of 942 consecutive patients, from the multicentric study of the French Association of Surgery, between January 2004 and December 2009 was analyzed. Perioperative data, including severe complications (grade III and above), were used in univariate and multivariate analysis to assess their influence on overall and disease free survival. Recurrence and its location were investigated as well.RESULTS:Median overall and disease free survival were 24 and 19 months respectively. Postoperative complications occurred in 444 patients (47%) with 18.3% of severe complications. On multivariate analysis, severe complications, positive lymph node status and R1-R2 resection were independent prognostic factors for both overall and disease free survival. The median overall survival decreased from 25 to 22 months (p = 0.005) and disease free survival from 21 to 16 months (p = 0.02) if severe complications occurred. Severe complications were independent prognostic factor of recurrence (p < 0.001).CONCLUSIONS:Severe complications significantly alter both overall and disease free survival and are an independent factor of recurrence

Immune-mediated thrombotic thrombocytopenic purpura plasma induces calcium- and IgG-dependent endothelial activation: correlations with disease severity

International audienceImmune-mediated thrombotic thrombocytopenic purpura (iTTP) is characterized by a severe ADAMTS13 deficiency due to the presence of anti-ADAMTS13 auto-antibodies, with subsequent accumulation of circulating ultra-large von Willebrand factor (VWF) multimers. The role of endothelial cell activation as a trigger of the disease has been suggested in animal models but remains to be demonstrated in humans. We prospectively obtained plasma from the first plasma exchange of 25 patients during iTTP acute phase. iTTP but not control plasma, induced a rapid VWF release and P-selectin exposure on the surface of dermal human micro-vascular endothelial cell (HMVEC-d), associated with angiopoietin-2 and endothelin-1 secretion, consistent with Weibel-Palade bodies exocytosis. Calcium (Ca2+) blockade significantly decreased VWF release, whereas iTTP plasma induced a rapid and sustained Ca2+ flux in HMVEC-d which correlated in retrospect, with disease severity and survival in 62 iTTP patients. F(ab)’2 fragments purified from the immunoglobulin G fraction of iTTP plasma mainly induced endothelial cell activation with additional minor roles for circulating free heme and nucleosomes, but not for complement. Furthermore, two anti-ADAMTS13 monoclonal antibodies purified from iTTP patients’ B cells, but not serum from hereditary TTP, induced endothelial Ca2+ flux associated with Weibel-Palade bodies exocytosis in vitro, whereas inhibition of endothelial ADAMTS13 expression using small intering RNA, significantly decreased the stimulating effects of iTTP immunoglobulin G. In conclusion, Ca2+-mediated endothelial cell activation constitutes a “second hit” of iTTP, is correlated with the severity of the disease and may constitute a possible therapeutic target

Targeting soluble CD146 with a neutralizing antibody inhibits vascularization, growth and survival of CD146-positive tumors

International audienceCD146 (MUC-18, MCAM) expression on cancer cells correlates with cancer progression and a bad prognosis in several tumors, including melanoma and pancreatic tumors. Deciphering the mechanism mediating the CD146 role in cancer is essential for generating new therapeutic strategies. We found that CD146 expression in cancer cells is associated with a secretion of soluble CD146 (sCD146) that constitutes an active player in tumor development. Indeed, sCD146 induces the overexpression of its binding protein, angiomotin, on both endothelial and cancer cells and promotes both paracrine effects on angiogenesis and autocrine effects on cancer cells proliferation and survival. These last effects are mediated in part through the induction and phosphorylation of c-myc in cancer cells. In mice models xenografted with human CD146-positive melanoma or pancreatic cancer cells, administration of a novel monoclonal antibody specifically targeting sCD146, but not its membrane form, successfully suppresses tumor vascularization and growth. Our findings demonstrate that sCD146 secreted by CD146-positive tumors mediates important pro-angiogenic and pro-tumoral effects. Targeting sCD146 with a novel neutralizing antibody could thus constitute an innovative therapeutic strategy for the treatment of CD146-positive tumors