Targeting the PI3K/mTOR pathway in murine endocrine cell lines: in vitro and in vivo effects on tumor cell growth
| Autor: | Couderc , Christophe, Poncet , Gilles, Villaume , Karine, Blanc , Martine, Gadot , Nicolas, Walter , Thomas, Lepinasse , Florian, Hervieu , Valérie, Cordier-Bussat , Martine, Scoazec , Jean-Yves, Roche , Colette |
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| Přispěvatelé: | Centre de Recherche en Cancérologie de Lyon ( CRCL ), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Unité de Chirurgie Colorectale, CHU Grenoble, Anipath, UFR Médecine Lyon-RTH Laennec, DOCOMO Euro-Labs, DOCOMO Communications Laboratories Europe GmbH, Laboratoire Central d'Anatomie et de Cytologie Pathologiques [Hôpital Edouard Herriot - HCL], Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon ( HCL ) -Hospices Civils de Lyon ( HCL ), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL) |
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
MESH: Cell Line
Tumor MESH: Carcinoma Neuroendocrine MESH : Antineoplastic Combined Chemotherapy Protocols Morpholines MESH: Morpholines [SDV.CAN]Life Sciences [q-bio]/Cancer [ SDV.CAN ] Life Sciences [q-bio]/Cancer Mice MESH : Phosphorylation Cell Line Tumor MESH: Cell Proliferation Antineoplastic Combined Chemotherapy Protocols Intestinal Neoplasms MESH : Mice MESH : Cell Proliferation Animals MESH: Protein Kinase Inhibitors MESH : Intestinal Neoplasms MESH: Animals Phosphorylation MESH: Antibiotics Antineoplastic MESH: Intestinal Neoplasms Protein Kinase Inhibitors MESH: Mice MESH: TOR Serine-Threonine Kinases Cell Proliferation Phosphoinositide-3 Kinase Inhibitors Sirolimus Antibiotics Antineoplastic MESH: Phosphorylation MESH : Cell Line Tumor TOR Serine-Threonine Kinases MESH : Sirolimus MESH : Phosphatidylinositol 3-Kinases Regular Article MESH : Protein Kinase Inhibitors MESH : Antibiotics Antineoplastic Carcinoma Neuroendocrine MESH: Antineoplastic Combined Chemotherapy Protocols MESH: Chromones Chromones MESH: Phosphatidylinositol 3-Kinases MESH : TOR Serine-Threonine Kinases MESH: Sirolimus MESH : Animals MESH : Carcinoma Neuroendocrine MESH : Chromones MESH : Morpholines |
| Zdroj: | American Journal of Pathology American Journal of Pathology, American Society for Investigative Pathology, 2011, 178 (1), pp.336-44. 〈10.1016/j.ajpath.2010.11.023〉 American Journal of Pathology, American Society for Investigative Pathology, 2011, 178 (1), pp.336-44. ⟨10.1016/j.ajpath.2010.11.023⟩ |
| ISSN: | 0002-9440 1525-2191 |
| DOI: | 10.1016/j.ajpath.2010.11.023〉 |
| Popis: | International audience; 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. |
| Databáze: | OpenAIRE |
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