The WSB1 Gene Is Involved in Pancreatic Cancer Progression

Pancreatic cancer cells generate metastases because they can survive the stress imposed by the new environment of the host tissue. To mimic this process, pancreatic cancer cells which are not stressed in standard culture conditions are injected into nude mice. Because they develop xenografts, they should have developed adequate stress response. Characterizing that response might provide new strategies to interfere with pancreatic cancer metastasis.In the human pancreatic cancer cell lines Panc-1, Mia-PaCa2, Capan-1, Capan-2 and BxPC3, we used Affymetrix DNA microarrays to compare the expressions of 22.000 genes in vitro and in the corresponding xenografts. We identified 228 genes overexpressed in xenografts and characterized the implication of one of them, WSB1, in the control of apoptosis and cell proliferation. WSB1 generates 3 alternatively spliced transcripts encoding distinct protein isoforms. In xenografts and in human pancreatic tumors, global expression of WSB1 mRNA is modestly increased whereas isoform 3 is strongly overexpressed and isoforms 1 and 2 are down-regulated. Treating Mia-PaCa2 cells with stress-inducing agents induced similar changes. Whereas retrovirus-forced expression of WSB1 isoforms 1 and 2 promoted cell growth and sensitized the cells to gemcitabine- and doxorubicin-induced apoptosis, WSB1 isoform 3 expression reduced cell proliferation and enhanced resistance to apoptosis, showing that stress-induced modulation of WSB1 alternative splicing increases resistance to apoptosis of pancreatic cancer cells.Data on WSB1 regulation support the hypothesis that activation of stress-response mechanisms helps cancer cells establishing metastases and suggest relevance to cancer development of other genes overexpressed in xenografts

Neoadjuvant Docetaxel-Based Chemoradiation for Resectable Adenocarcinoma of the Pancreas

International audienceTo assess the safety and efficacy of a new neoadjuvant chemoradiation (CRT) docetaxel-based regimen in patients with resectable adenocarcinoma of the pancreatic head or body

Novel role of VMP1 as modifier of the pancreatic tumor cell response to chemotherapeutic drugs

We hypothesized that inhibiting molecules that mediate the adaptation response to cellular stress can antagonize the resistance of pancreatic cancer cells to chemotherapeutic drugs. Toward this end, here, we investigated how VMP1, a stress-induced autophagy-associated protein, modulate stress responses triggered by chemotherapeutic agents in PDAC. We find that VMP1 is particularly over-expressed in poorly differentiated human pancreatic cancer. Pharmacological studies show that drugs that work, in part, via the endoplasmic reticulum stress response, induce VMP1 expression. Similarly, VMP1 is induced by known endoplasmic reticulum stress activators. Genetic inactivation of VMP1 using RNAi-based antagonize the pancreatic cancer stress response to antitumoral agents. Functionally, we find that VMP1 regulates both autophagy and chemotherapeutic resistance even in the presence of chloroquin, ATG5 or Beclin 1 siRNAs, or a Beclin 1-binding VMP1 mutant. In addition, VMP1 modulates endoplasmic reticulum stress independently of its coupling to the molecular and cellular autophagy machinery. Preclinical studies demonstrate that xenografts expressing an inducible and tractable form of VMP1 show increased resistance to the gemcitabine treatment. These results underscore a novel role for VMP1 as a potential therapeutic target for combinatorial therapies aimed at sensitizing pancreatic cancer cells to chemotherapeutic agents as well as provide novel molecular mechanisms to better understand this phenomenon.Fil: Gilabert, Mariana. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Vaccaro, Maria Ines. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Bioquímica y Medicina Molecular; ArgentinaFil: Fernandez Zapico, Martín E.. Mayo Clinic Cancer Center; Estados UnidosFil: Calvo, Ezequiel L.. Molecular Endocrinology and Oncology Research Center; CanadáFil: Turrini, Olivier. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Secq, Véronique. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Garcia, Stéphanie. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Moutardier, Vincent. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Lomberk, Gwen. Mayo Clinic; Estados UnidosFil: Dusetti, Nelson. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; FranciaFil: Urrutia, Raul. Mayo Clinic; Estados UnidosFil: Iovanna, Juan L.. Cancer Research Center of Marseille; Francia. Aix-Marseille University; Francia. Centre National de la Recherche Scientifique; Franci

Anti-proliferative and anti-secretory effects of everolimus on human pancreatic neuroendocrine tumors primary cultures: is there any benefit from combination with somatostatin analogs?

Therapeutic management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) is challenging. The mammalian target of rapamycin (mTOR) inhibitor everolimus recently obtained approval from the Food and Drug Administration for the treatment of patients with advanced pancreatic neuroendocrine tumors (pNETs). Despite its promising antitumor efficacy observed in cell lines, clinical benefit for patients is unsatisfactory. The limited therapeutic potential of everolimus in cancer cells has been attributed to Akt activation due to feedback loops relief following mTOR inhibition. Combined inhibition of Akt might then improve everolimus antitumoral effect. In this regard, the somatostatin analog (SSA) octreotide has been shown to repress the PI3K/Akt pathway in some tumor cell lines. Moreover, SSAs are well tolerated and routinely used to reduce symptoms caused by peptide release in patients carrying functional GEP-NETs. We have recently established and characterized primary cultures of human pNETs and demonstrated the anti-proliferative effects of both octreotide and pasireotide. In this study, we aim at determining the antitumor efficacy of everolimus alone or in combination with the SSAs octreotide and pasireotide in primary cultures of pNETs. Everolimus reduced both Chromogranin A secretion and cell viability and upregulated Akt activity in single treatment. Its anti-proliferative and anti-secretory efficacy was not improved combined with the SSAs. Both SSAs did not overcome everolimus-induced Akt upregulation. Furthermore, caspase-dependent apoptosis induced by SSAs was lost in combined treatments. These molecular events provide the first evidence supporting the lack of marked benefit in patients co-treated with everolimus and SSA

Gene expression profiling of patient‐derived pancreatic cancer xenografts predicts sensitivity to the BET bromodomain inhibitor JQ1: implications for individualized medicine efforts

Abstract c‐MYC controls more than 15% of genes responsible for proliferation, differentiation, and cellular metabolism in pancreatic as well as other cancers making this transcription factor a prime target for treating patients. The transcriptome of 55 patient‐derived xenografts show that 30% of them share an exacerbated expression profile of MYC transcriptional targets (MYC‐high). This cohort is characterized by a high level of Ki67 staining, a lower differentiation state, and a shorter survival time compared to the MYC‐low subgroup. To define classifier expression signature, we selected a group of 10 MYC target transcripts which expression is increased in the MYC‐high group and six transcripts increased in the MYC‐low group. We validated the ability of these markers panel to identify MYC‐high patient‐derived xenografts from both: discovery and validation cohorts as well as primary cell cultures from the same patients. We then showed that cells from MYC‐high patients are more sensitive to JQ1 treatment compared to MYC‐low cells, in monolayer, 3D cultured spheroids and in vivo xenografted tumors, due to cell cycle arrest followed by apoptosis. Therefore, these results provide new markers and potentially novel therapeutic modalities for distinct subgroups of pancreatic tumors and may find application to the future management of these patients within the setting of individualized medicine clinics

Analyse multivariée des facteurs de risque hémorragique après duodénopancréatectomie céphalique

BUT DU TRAVAIL: Une diminution de la mortalité postopératoire a été observée ces dernières années après duodenopancréatectomie céphalique (DPC). En revanche, la morbidité postopératoire reste élevée, notamment hémorragique. Le but de cette étude est de déterminer les facteurs de risque d'hémorragie. METHODES: Il s'agit d'une étude multicentrique rétrospective, incluant l'ensemble des DPC réalisées entre janvier 2005 et décembre 2012. L'évaluation portait sur des critères démographiques et des données pré, per et postopératoires. RESULTATS: Quatre-vingt douze patients ont eu une hémorragie postopératoire parmi les 606 analysés (15,2%). En analyse univariée, les facteurs de risque étaient l'ictère (p=0,036), l'indice de masse corporelle > 25 (p=0,006), la collection intra-abdominale (p<0,001), le sepsis clinique et biologique (p<0,001) et la fistule pancréatique (p<0,001). Chez les patients ictériques, le drainage biliaire préopératoire (DBP) était un facteur protecteur (p=0,042) et ce que l'ictère ait disparu au moment de l'intervention ou non.Les patients n'ayant pas eu de DBP malgré un ictère avaient un risque accru d'hémorragie (p=0,032). En analyse multivariée, on retrouve la fistule pancréatique (odd-ratio (OR)=3,7; p<0,001), la collection intra-abdominale (OR=2,3; p=0,005) et l'ictère (OR=1,9; p=0,028). En revanche, le taux de complications majeures (Dindo III, IV, V) n'était pas augmenté chez les patients drainés. CONCLUSION: Cette étude montre que l'ictère est un facteur de risque hémorragique post-DPC et plaide en faveur du DBP chez ces patients. Il permettrait de diminuer le risque d'hémorragie sans augmenter la morbi-mortalité port opératoireAIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Tumeur endocrine du pancréas (analyse multivariée des facteurs pronostiques de survie)

INTRODUCTION: Etude multicentrique des facteurs cliniques, radiologiques et histologiques associés à la survie et à la récidive des patients atteints d'une tumeur neuroendocrine du pancréas (TNEP). METHODES: Entre le 1er janvier 1991 et le 31 décembre 2011, 127 patient ont eu une pancréatectomie (duodéno-pancréatectomie (DP), pancréatectomie gauche (PG) ou énucléation) pour TNEP. Les patients ayant des métastases extra-hépatiques ont été exclus. Soixante quatre patients (50,4%) présentaient une TNEP sans métastases hépatiques (groupe contrôle), 48 (37,8%) avaient des métastases hépatiques métachrones (groupe métachrone). Les variables étudiées par analyses uni ou multivariés étaient: l'âge, le sexe, le traitement médical, la date de la chirurgie, la taille de la tumeur, le type histologie, le nombre de mitoses, le Ki67 ( 10%), les marges de résections, le statut ganglionnaire et métastatique, l'envahissement périneurale et vasculaire. RESULTATS: Cent trois patients présentaient une TNEP non fonctionnelle (81,1%) et 24 (18,19%) avaient une TNEP fonctionnelle. Soixante quatre patients (50,3%) ont eu une LP, 53 patients (41,7%) une PD et 10 patients (8%) une énucléation. Six patients ont nécessité une résection de la veine portale (RVP) et 19 patients (15%) une résection élargie en bloc d'organes adjacents. La morbidité et mortalité étaient de 48% et 2,3% respectivement. La survie à 1,3 et 5 ans était respectivement de 94%n 84% et 74%. En analyse multivariée, les facteurs pronostiques indépendants du survie étaient la présence de métastases synchrones (p=0,02) et a RVP (p 10%), resection margins, node and metastasis stage, perineural and vascular invasion were examined by uni and multivariate analyses. RESULTS: One hundred three patients had nonfunctional tumors (81.1%) and 24 (18.19%) had hormone-producing PNET. Sixty-four patients (50.3%) underwent LP, 53 (41.7%) PD and 10 (8%) enucleation. Six patients (4,7%) required portal vein resection (PVR) and 19 (15%) elarged "en bloc" resection of adjacent organs. Overall morbidity and mortality rates were 48% and 2.3% respectively. The 1-,3- and 5- year overall survival rates of all patients were 94%, 84% and 74% respectively. In multivariate analyses, synchronous livers metastases (p = 0.02) and portal vein resection (p <.0,01) were independent prognostic factors of survival. CONCLUSIONS: In our large multicentric study, synchronous liver metastasis and portal vein resection were found to be independent factors influencing survival.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Adénocarcinomes de la tête pancréatique résécables (que peut-on attendre de l'association radiochimiothérapie néoadjuvante et chirurgie ?)

AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Disease-free survival following resection in non-ductal periampullary cancers: A retrospective multicenter analysis

International audienceBACKGROUND:Predictors of recurrence following pancreaticoduodenectomy are well described for ductal periampullary cancers but lack reliability for non-ductal tumors. The purpose of this study is to analyze the disease-free survival (DFS) and to define the predictors of recurrence following resection for ampullary (AC), bile duct (BDC) and duodenal cancers (DC).MATERIALS AND METHODS:Clinico-pathological data of patients operated on between 2001 and 2011 were retrospectively reviewed. The effect of lymphatic invasion was specified using the lymph node ratio (LNR) and the number of positive nodes (NPN), with thresholds calculated with the likelihood ratio. Kaplan-Meier disease-free survival (DFS) curves were compared for all covariates by a log-rank test. Multivariate logistic regression analyses were performed to identify predictors of recurrence.RESULTS:135 patients were identified. Mean follow-up was 49 ± 35 months. Median DFS was not reached for AC and was 36 and 18 months for DC and BDC, respectively. Five-year DFS was 52%, 43% and 32% for AC, DC and BDC, respectively. Predictors of recurrence were T4 tumors, neural invasion and preoperative biliary drainage for DC, ≥3 positive nodes and ≥4% loss of BMI for AC, and T3-T4 tumors for BDC.CONCLUSION:Loss of BMI ≥4% is a strong predictor of recurrence in AC, and the recurrence risk increases with the total number of lymph nodes invaded (0; 1-3; ≥4). Only T stage influences recurrence for BDC. Considering DC, the adverse effect of preoperative biliary drainage should be validated in randomized series