Article

Targeting the PI3K/mTOR Pathway in Murine Endocrine Cell Lines In Vitro and in Vivo Effects on Tumor Cell Growth

INSERM, U865, Faculté Laënnec, Université Claude Bernard Lyon 1, Lyon, France.
American Journal Of Pathology (Impact Factor: 4.59). 01/2011; 178(1):336-44. DOI: 10.1016/j.ajpath.2010.11.023
Source: PubMed

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.

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    • "There is clear evidence that mTOR is dysregulated in pancreatic neuroendocrine tumors (NETs). The mTORC1 inhibitor rapamycin inhibits growth of NET cells in vitro (Couderc et al. 2011), and one of its analogs, everolimus, was found to have significant activity in a clinical trial of patients with pancreatic NETs (Yao et al. 2011). MTC cells arise from C cells and therefore derive from a neuroendocrine lineage. "
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    • "The deregulation of PI3K leads to elevated PIP3 levels and the downstream activation of AKT [7]. Mammalian target of rapamycin (mTOR), a serine/threonine protein kinase, also regulates cell growth, cell cycle progression and angiogenesis by the activation of the downstream translational regulators p70S6 kinase (p70S6K) and eukaryotic initiation factor (eIF) 4E binding protein 1 (4EBP1) [8]. Indeed, the activation of the MAPK/mTOR signaling pathway in endothelial cells increases their survival when cultured in vitro and in the tumor vasculature in vivo [9,10]. "
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