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Julien Bollard,
Christophe Couderc,
Martine Blanc,
Gilles Poncet, Florian Lepinasse,
Valérie Hervieu,
Géraldine Gouysse,
Carole Ferraro-Peyret,
Noura Benslama,
Thomas Walter,
Jean-Yves Scoazec,
Colette Roche
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ABSTRACT: Background/Aims: While the range of therapeutic options for well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP NETs) has recently increased with the emergence of targeted therapies, such as mTOR inhibitors, there is no recent progress in the treatment of poorly differentiated neuroendocrine carcinomas (PDNECs). Since PDNECs have been shown to strongly express mTOR pathway components, the aim of the present study was to assess the antitumor effect of the mTOR inhibitor everolimus in preclinical models of PDNECs. Methods: Thee expression of mTOR pathway components and their response to everolimus were assessed in two neuroendocrine cell lines: STC-1 and GluTag. A xenograft model of intra-hepatic dissemination in the nude mouse, based on the intrasplenic injection of either STC-1 and GluTag tumor cells, was used. Animals were started on everolimus treatment 3 days after injection. The effects of treatment on tumor growth, proliferative capacities, apoptosis and in situ expression of mTOR pathway components were assessed. Results: The expression of mTOR pathway components was comparable in STC-1 and GluTag cells and in human PDNECs and could be inhibited in vitro by everolimus. In vivo, the tumor volume of STC-1 and GluTag xenografts was significantly reduced in treated animals (6.05% ± 1.84 as compared to 21.76 ± 3.88% in controls). Everolimus treatment also induced a significant decrease in Ki67 index and in the phosphorylation levels of the two major effectors of mTOR, p70S6K and 4E-BP1. Conclusion: Our experimental data suggest that mTOR inhibition could be considered a therapeutic option for high grade GEP NETs.
Neuroendocrinology 01/2013; · 2.38 Impact Factor
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Christophe Couderc,
Gilles Poncet,
Karine Villaume,
Martine Blanc,
Nicolas Gadot,
Thomas Walter, Florian Lepinasse,
Valérie Hervieu,
Martine Cordier-Bussat,
Jean-Yves Scoazec,
Colette Roche
[show abstract]
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ABSTRACT: The mammalian target of rapamycin (mTOR) inhibitors, such as rapalogues, are a promising new tool for the treatment of metastatic gastroenteropancreatic endocrine tumors. However, their mechanisms of action remain to be established. We used two murine intestinal endocrine tumoral cell lines, STC-1 and GLUTag, to evaluate the antitumor effects of rapamycin in vitro and in vivo in a preclinical model of liver endocrine metastases. In vitro, rapamycin inhibited the proliferation of cells in the basal state and after stimulation by insulin-like growth factor-1. Simultaneously, p70S6 kinase and 4EBP1 phosphorylation was inhibited. In vivo, rapamycin substantially inhibited the intrahepatic growth of STC-1 cells, irrespectively of the timing of its administration and even when the treatment was administered after cell intrahepatic engraftment. In addition, treated animals had significantly prolonged survival (mean survival time: 47.7 days in treated animals versus 31.8 days in controls) and better clinical status. Rapamycin treatment was associated with a significant decrease in mitotic index and in intratumoral vascular density within STC-1 tumors. Furthermore, the antitumoral effect obtained after treatment with a combination of rapamycin and phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 was more significant than with rapamycin alone in both cell lines. Our results suggest that the antitumor efficacy of rapamycin in neuroendocrine tumors results from a combination of antiproliferative and antiangiogenic effects. Interestingly, a more potent antitumor efficiency could be obtained by simultaneously targeting several levels of the PI3K/mTOR pathway.
American Journal Of Pathology 01/2011; 178(1):336-44. · 4.89 Impact Factor
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David F Vincent,
Kai-Ping Yan,
Isabelle Treilleux,
Fabien Gay,
Vanessa Arfi,
Bastien Kaniewski,
Julien C Marie, Florian Lepinasse,
Sylvie Martel,
Sophie Goddard-Leon,
Juan L Iovanna,
Pierre Dubus,
Stéphane Garcia,
Alain Puisieux,
Ruth Rimokh,
Nabeel Bardeesy,
Jean-Yves Scoazec,
Régine Losson,
Laurent Bartholin
PLoS Genetics 09/2009; 5(8). · 8.69 Impact Factor
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David F Vincent,
Kai-Ping Yan,
Isabelle Treilleux,
Fabien Gay,
Vanessa Arfi,
Bastien Kaniewski,
Bastien Kaniewsky,
Julien C Marie, Florian Lepinasse,
Sylvie Martel,
Sophie Goddard-Leon,
Juan L Iovanna,
Pierre Dubus,
Stéphane Garcia,
Alain Puisieux,
Ruth Rimokh,
Nabeel Bardeesy,
Jean-Yves Scoazec,
Régine Losson,
Laurent Bartholin
[show abstract]
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ABSTRACT: Inactivation of the Transforming Growth Factor Beta (TGFbeta) tumor suppressor pathway contributes to the progression of Pancreatic Ductal AdenoCarcinoma (PDAC) since it is inactivated in virtually all cases of this malignancy. Genetic lesions inactivating this pathway contribute to pancreatic tumor progression in mouse models. Transcriptional Intermediary Factor 1 gamma (TIF1gamma) has recently been proposed to be involved in TGFbeta signaling, functioning as either a positive or negative regulator of the pathway. Here, we addressed the role of TIF1gamma in pancreatic carcinogenesis. Using conditional Tif1gamma knockout mice (Tif1gamma(lox/lox)), we selectively abrogated Tif1gamma expression in the pancreas of Pdx1-Cre;Tif1gamma(lox/lox) mice. We also generated Pdx1-Cre;LSL-Kras(G12D);Tif1gamma(lox/lox) mice to address the effect of Tif1gamma loss-of-function in precancerous lesions induced by oncogenic Kras(G12D). Finally, we analyzed TIF1gamma expression in human pancreatic tumors. In our mouse model, we showed that Tif1gamma was dispensable for normal pancreatic development but cooperated with Kras activation to induce pancreatic tumors reminiscent of human Intraductal Papillary Mucinous Neoplasms (IPMNs). Interestingly, these cystic lesions resemble those observed in Pdx1-Cre;LSL-Kras(G12D);Smad4(lox/lox) mice described by others. However, distinctive characteristics, such as the systematic presence of endocrine pseudo-islets within the papillary projections, suggest that SMAD4 and TIF1gamma don't have strictly redundant functions. Finally, we report that TIF1gamma expression is markedly down-regulated in human pancreatic tumors by quantitative RT-PCR and immunohistochemistry supporting the relevance of these findings to human malignancy. This study suggests that TIF1gamma is critical for tumor suppression in the pancreas, brings new insight into the genetics of pancreatic cancer, and constitutes a promising model to decipher the respective roles of SMAD4 and TIF1gamma in the multifaceted functions of TGFbeta in carcinogenesis and development.
PLoS Genetics 08/2009; 5(7):e1000575. · 8.69 Impact Factor
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David F Vincent,
Kai-Ping Yan,
Isabelle Treilleux,
Fabien Gay,
Vanessa Arfi,
Bastien Kaniewski,
Julien C Marie, Florian Lepinasse,
Sylvie Martel,
Sophie Goddard-Leon,
Juan L Iovanna,
Pierre Dubus,
Stéphane Garcia,
Alain Puisieux,
Ruth Rimokh,
Nabeel Bardeesy,
Jean-Yves Scoazec,
Régine Losson,
Laurent Bartholin
