ISPB

Sainte-Foy-lès-Lyon, France
Sainte-Foy-lès-Lyon, France
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Labidi-Galy S.I.,ISPB | Labidi-Galy S.I.,University of Lyon | Labidi-Galy S.I.,French Institute of Health and Medical Research | Sisirak V.,University of Lyon | And 28 more authors.
Cancer Research | Year: 2011

In ovarian cancer, the immune system fails to eradicate established tumors partly due to the induction of immune tolerance within tumor microenvironment. In this study, we investigated the contribution of plasmacytoid dendritic cells (pDC) in the establishment of immune tolerance in a cohort of 44 ovarian cancer patients. In the tumor and malignant ascites, CD4+CD123 +BDCA2+ pDC were the most abundant dendritic cell subset; however, they were profoundly depleted in peripheral blood. The presence of pDC in primary ovarian cancer, but not ascites, was an independent prognostic factor associated with early relapse. Following chemotherapy, we observed a partial restoration of blood pDC levels in patients in complete remission. These findings show preferential recruitment of pDC into tumors where they express a partially mature phenotype that may reflect an in situ activation. Importantly, compared with pDC found in ascites or blood, tumor-associated pDC (TApDC) produced less IFN-α, TNF-α, IL-6, macrophage inflammatory protein-1β, and RANTES in response to toll-like receptor stimulation, and alterations in pDC functions were mainly mediated through tumor-derived TNF-α and TGF-β. Unlike ascites-derived pDC, TApDC induced IL-10 production from allogeneic naive CD4+ T lymphocytes, suggesting the existence of a paracrine immunosuppressive loop. Taken together, our findings indicate that both local and systemic dysfunction of pDC play a critical role in the progression of ovarian cancer via induction of immune tolerance. ©2011 AACR.


Nguyen N.T.,ISPB | Nguyen N.T.,University of Lyon | Nguyen N.T.,French Institute of Health and Medical Research | Vendrell J.A.,ISPB | And 19 more authors.
Molecular Oncology | Year: 2014

We aimed at highlighting the role of ZNF217, a Krüppel-like finger protein, in Estrogen Receptor-α (ERα)-positive (ER+) and luminal breast cancers. Here we report for the first time that ZNF217 and ERα proteins bind to each other in both breast cancer cells and breast tumour samples, via the ERα hinge domain and the ZNF217 C-terminal domain. ZNF217 enhances the recruitment of ERα to its estrogen response elements (ERE) and the ERα-dependent transcription of the GREB1 estrogen-regulated gene. The prognostic power of ZNF217 mRNA expression levels is most discriminatory in breast cancers classified with a "good prognosis", particularly the Luminal-A subclass. A new immunohistochemistry ZNF217 index, based on nuclear and cytoplasmic ZNF217 staining, also allowed the identification of intermediate/poor relapse-free survivors in the Luminal-A subgroup. ZNF217 confers tamoxifen resistance in ER+ breast cancer cells and is a predictor of relapse under endocrine therapy in patients with ER+ breast cancer. ZNF217 thus allows the re-stratification of patients with ER+ breast cancers considered as cancers with good prognosis where no other biomarkers are currently available and widely used. Here we propose a model in ER+ breast cancer where ZNF217-driven aggressiveness incorporates ZNF217 as a positive enhancer of ERα direct genomic activity and where ZNF217 possesses its highest discriminatory prognostic value. © 2014 Federation of European Biochemical Societies.


Girollet T.,Association nationale des etudiants en pharmacie de France | Beltier M.,Association nationale des etudiants en pharmacie de France | Catala O.,ISPB | Vinciguerra C.,ISPB | Charpiat B.,Service de pharmacie
Annales Pharmaceutiques Francaises | Year: 2013

Pharmacy practice experience (PPE) aims to help trainees to become independent professional practitioners and is a prerequisite for developing skills and competence. In France, it does not exist any study that describes student satisfaction related to preregistration trainings. The aim of this study was to assess student perceptions related to the four PPE types that are planned along the course of study. A questionnaire was sent to each student. Concerning the first and second year introductory PPE, among the 8491 responses, 73% of the students stated that the length was too long regarding their actual knowledge and the objectives were not always achieved. Four thousand and eleven responses regarding third and fourth year PPE were analyzed. Sixty-two percent of the students did not deliver drugs related to the practice's subject and 57% declared doing similar task assigned during the first year PPE especially storage one's. One thousand six hundred and seven questionnaires regarding hospital practices were received. Forty-one percent of the trainees were not asked to perform task that were related to their actual knowledge. Additional comments focused on overmuch shadowing. Among the 853 responses related to the 6th year PPE, 88% of the students considered that they were overall satisfied of the training. Although 30% felt they acquired insufficient skills and professionalism and declared they were not ready to integrate the work world. Those results should prompt decision makers to modify in depth PPE programs in France in order to improve trainees' professionalism and skills acquisition. Promoting and developing researches in the field of PPE is urgently needed. © 2013 Elsevier Masson SAS.


Vilquin P.,ISPB | Vilquin P.,University of Lyon | Vilquin P.,French Institute of Health and Medical Research | Donini C.F.,ISPB | And 17 more authors.
Breast Cancer Research | Year: 2015

Introduction: Increasing evidence indicates that microRNAs (miRNAs) are important players in oncogenesis. Considering the widespread use of aromatase inhibitors (AIs) in endocrine therapy as a first-line treatment for postmenopausal estrogen receptor α-positive breast cancer patients, identifying deregulated expression levels of miRNAs in association with AI resistance is of utmost importance. Methods: To gain further insight into the molecular mechanisms underlying the AI resistance, we performed miRNA microarray experiments using a new model of acquired resistance to letrozole (Res-Let cells), obtained by long-term exposure of aromatase-overexpressing MCF-7 cells (MCF-7aro cells) to letrozole, and a model of acquired anastrozole resistance (Res-Ana cells). Three miRNAs (miR-125b, miR-205 and miR-424) similarly deregulated in both AI-resistant cell lines were then investigated in terms of their functional role in AI resistance development and breast cancer cell aggressiveness and their clinical relevance using a cohort of 65 primary breast tumor samples. Results: We identified the deregulated expression of 33 miRNAs in Res-Let cells and of 18 miRNAs in Res-Ana cells compared with the sensitive MCF-7aro cell line. The top-ranked Kyoto Encyclopedia of Genes and Genomes pathways delineated by both miRNA signatures converged on the AKT/mTOR pathway, which was found to be constitutively activated in both AI-resistant cell lines. We report for the first time, to our knowledge, that ectopic overexpression of either miR-125b or miR-205, or the silencing of miR-424 expression, in the sensitive MCF-7aro cell line was sufficient to confer resistance to letrozole and anastrozole, to target and activate the AKT/mTOR pathway and to increase the formation capacity of stem-like and tumor-initiating cells possessing self-renewing properties. Increasing miR-125b expression levels was also sufficient to confer estrogen-independent growth properties to the sensitive MCF-7aro cell line. We also found that elevated miR-125b expression levels were a novel marker for poor prognosis in breast cancer and that targeting miR-125b in Res-Let cells overcame letrozole resistance. Conclusion: This study highlights that acquisition of specific deregulated miRNAs is a newly discovered alternative mechanism developed by AI-resistant breast cancer cells to achieve constitutive activation of the AKT/mTOR pathway and to develop AI resistance. It also highlights that miR-125b is a new biomarker of poor prognosis and a candidate therapeutic target in AI-resistant breast cancers. © Vilquin et al.


Philippe I.,French Institute of Health and Medical Research | Philippe I.,University of Caen Lower Normandy | Hubert L.,ISPB | Hubert L.,University of Lyon | Hubert L.,French Institute of Health and Medical Research
Drug Resistance Updates | Year: 2016

Proliferating cells reduce their oxidative metabolism and rely more on glycolysis, even in the presence of O2 (Warburg effect). This shift in metabolism reduces citrate biosynthesis and diminishes intracellular acidity, both of which promote glycolysis sustaining tumor growth. Because citrate is the donor of acetyl-CoA, its reduced production favors a deacetylation state of proteins favoring resistance to apoptosis and epigenetic changes, both processes contributing to tumor aggressiveness. Citrate levels could be monitored as an indicator of cancer aggressiveness (as already shown in human prostate cancer) and/or could serve as a biomarker for response to therapy. Strategies aiming to increase cytosolic citrate should be developed and tested in humans, knowing that experimental studies have shown that administration of citrate and/or inhibition of ACLY arrest tumor growth, inhibit the expression of the key anti-apoptotic factor Mcl-1, reverse cell dedifferentiation and increase sensibility to cisplatin. © 2016 Elsevier Ltd


Icard P.,Ecole Polytechnique - Palaiseau | Icard P.,French Institute of Health and Medical Research | Icard P.,University of Caen Lower Normandy | Vallantin T.,French Institute of Health and Medical Research | And 7 more authors.
Oncologie | Year: 2015

Cancer tumors behave as metabolic parasites that draw on reserves of the host to feed their biosynthesis, and they secrete waste products (NO, polyamines, ammoniac, lactate, etc.) that promote tumor growth and an acidic microenvironment favoring invasion and proliferation. In the metabolism of cancer cells, citrate plays a major role, being both the gauge of cellular energy (with ATP), and the acetyl donor for the synthesis of fatty acids and/or acetylation of proteins. Therefore, the rate of citrate should be very low in cancer cells, a hypothesis recently confirmed in prostatic cancer biopsies. Strategies to restore a normal rate of citrate in cancer cells could be promising as we have shown in our laboratory. © 2015, Springer-Verlag France.


Cohen P.A.,ISPB | Cohen P.A.,University of Lyon | Cohen P.A.,French Institute of Health and Medical Research | Donini C.F.,ISPB | And 11 more authors.
Oncotarget | Year: 2015

The recently described oncogene ZNF217 belongs to a chromosomal region that is frequently amplified in human cancers. Recent findings have revealed that alternative mechanisms such as epigenetic regulation also govern the expression of the encoded ZNF217 protein. Newly discovered molecular functions of ZNF217 indicate that it orchestrates complex intracellular circuits as a new key regulator of tumorigenesis. In this review, we focus on recent research on ZNF217-driven molecular functions in human cancers, revisiting major hallmarks of cancer and highlighting the downstream molecular targets and signaling pathways of ZNF217. We also discuss the exciting translational medicine investigating ZNF217 expression levels as a new powerful biomarker, and ZNF217 as a candidate target for future anti-cancer therapies.


PubMed | ISPB
Type: Journal Article | Journal: Oncotarget | Year: 2015

The recently described oncogene ZNF217 belongs to a chromosomal region that is frequently amplified in human cancers. Recent findings have revealed that alternative mechanisms such as epigenetic regulation also govern the expression of the encoded ZNF217 protein. Newly discovered molecular functions of ZNF217 indicate that it orchestrates complex intracellular circuits as a new key regulator of tumorigenesis. In this review, we focus on recent research on ZNF217-driven molecular functions in human cancers, revisiting major hallmarks of cancer and highlighting the downstream molecular targets and signaling pathways of ZNF217. We also discuss the exciting translational medicine investigating ZNF217 expression levels as a new powerful biomarker, and ZNF217 as a candidate target for future anti-cancer therapies.

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