Abstract
Although the inhibition of mTOR is a promising treatment for neuroendocrine tumors, several questions are still open for cell specificity and resistance. With the newly characterized gastric neuroendocrine tumor mouse model (CEA424-SV40 T antigen transgenic mice), the anti-tumor efficiency of RAD001 (Everolimus) was tested both in vitro and in vivo. Tumor samples were analyzed for the expression of RNA by cDNA microarrays and also signaling pathways to get more details on the local surviving or selected cells. RAD001 treatment dramatically slowed down tumor growth and prolonged the animals' survival. This inhibitory effect has a preference for tumor cells since gastrointestinal hormone and neuroendocrine tumor specific markers were more reduced than the epithelial ones. While phosphorylation of p70S6K was almost completely blocked both in vitro and in vivo, the phosphorylation of 4EBP1 was only partially inhibited in vitro and unaffected in vivo. RAD001 treatment induced feedback activation of metabolism related pathways like PI(3)K–Akt–mTOR and MEK/ERK signalings. An induction of senescence as well as differential expression of genes responsible for metabolism was also observed, which highlighted the contribution of metabolic molecular signatures to the escape of the tumor cells from the treatment. Together, our data revealed efficient anti-tumor ability of RAD001 in a new gastric neuroendocrine tumor mouse model system and offered new insights into the clinical aspects of the incomplete elimination of tumor cells in patients treated.
Highlights
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) comprise a highly heterogeneous group of tumors with strikingly various clinical behaviors [1]
Genes specific for neuroendocrine family were significantly up-regulated in the tumors spontaneously developed in the antral region of the stomach as well as in cell line 424GC, which is derived from the primary tumor [19]
These observations were further confirmed by the phase III studies for pancreatic neuroendocrine tumors (p-NETs) with a significantly increased progress free survival in Everolimus treated patients [25,26,27,28], which leads to the approval of this drug by the Food and Drug Administration (FDA) and European Medicines Agency (EMA)
Summary
Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) comprise a highly heterogeneous group of tumors with strikingly various clinical behaviors [1]. Several cell lines were established from the primary tumor [20] which we further characterized and found to have a similar cDNA profile like the tumor samples and express chromogranin A, B, as well as secretin and glucagon [19] (Figure 1). They clearly resemble the tumor originating and located in the antrum of the stomach in CEA-T antigen heterozygous mice and offer good in vitro capabilities to screen drugs
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