Pan Jie, Bao Qi, Enders Georg
Department of Endocrinology and Metabolism, School of Medicine, Second Affiliated Hospital of Zhejiang University, Hangzhou, China.
Institution of Gastroenterology, Zhejiang University, Hangzhou, China.
Front Oncol. 2020 Apr 21;10:546. doi: 10.3389/fonc.2020.00546. eCollection 2020.
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 and . 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 and , the phosphorylation of 4EBP1 was only partially inhibited and unaffected . 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.
尽管抑制mTOR是神经内分泌肿瘤一种有前景的治疗方法，但在细胞特异性和耐药性方面仍存在一些问题。利用新建立的胃神经内分泌肿瘤小鼠模型（CEA424 - SV40 T抗原转基因小鼠），对RAD001（依维莫司）的抗肿瘤效率进行了测试。通过cDNA微阵列分析肿瘤样本的RNA表达以及信号通路，以获取更多关于局部存活或选择细胞的详细信息。RAD001治疗显著减缓了肿瘤生长并延长了动物的生存期。这种抑制作用对肿瘤细胞具有偏好性，因为胃肠激素和神经内分泌肿瘤特异性标志物的减少比上皮标志物更明显。虽然p70S6K的磷酸化在[具体情况1]和[具体情况2]中几乎完全被阻断，但4EBP1的磷酸化仅在[具体情况3]中受到部分抑制，在[具体情况4]中未受影响。RAD001治疗诱导了与代谢相关通路如PI(3)K - Akt - mTOR和MEK/ERK信号的反馈激活。还观察到衰老的诱导以及负责代谢的基因的差异表达，这突出了代谢分子特征对肿瘤细胞逃避治疗的作用。总之，我们的数据揭示了RAD001在新的胃神经内分泌肿瘤小鼠模型系统中的高效抗肿瘤能力，并为接受治疗患者中肿瘤细胞未完全清除的临床情况提供了新的见解。
