Section of Medical Oncology, Department of Medicine, Azienda Ospedaliera Universitaria Integrata (AOUI), Verona, Italy.
Target Oncol. 2012 Sep;7(3):183-8. doi: 10.1007/s11523-012-0226-9. Epub 2012 Aug 14.
The serine/threonine kinase mammalian target of rapamycin (mTOR) plays a central role in regulating critical cellular processes such as growth, proliferation, and protein synthesis. The study of cancer predisposing syndromes within which neuroendocrine tumors (NETs) may arise has furnished clues on the involvement of mTOR pathway in sporadic diseases so far. Recent comprehensive analyses have definitely shown activation of mTOR pathway in both experimental and human sporadic NETs. Upstream regulators of mTOR (PTEN and TSC2) have been found mutated in sporadic pNETs. Activation of mTOR pathways in NETs is already demonstrated by expression profiles analysis that revealed downregulation of TSC2 gene and alterations of TSC2 and PTEN protein expression in the vast majority of well-differentiated tumors. Moreover, a global microRNA expression analysis revealed the overexpression, in highly aggressive tumors, of a microRNA (miR-21) that targets PTEN reducing its expression and therefore leading to mTOR activation as well. Overall, these clues have furnished the rationale for the use of mTOR inhibitors the treatment of pNETs. With the recent approval of Everolimus (mTOR-targeted drug) for the treatment of advanced pNETs, this paradigm has been effectively translated into the clinical setting. In this review, we discuss mTOR pathway involvement in NETs, the clinical evidence supporting the use of mTOR inhibitors in cancer treatment, and the current clinical issues that remain to be elucidated to improve patient management.
丝氨酸/苏氨酸激酶哺乳动物雷帕霉素靶蛋白（mTOR）在调节细胞生长、增殖和蛋白质合成等关键过程中发挥核心作用。在可能发生神经内分泌肿瘤（NET）的癌症易感综合征的研究中，迄今已提供了 mTOR 途径参与散发性疾病的线索。最近的全面分析肯定表明 mTOR 途径在实验性和人类散发性 NET 中均被激活。mTOR 的上游调节剂（PTEN 和 TSC2）已在散发性 pNET 中发现突变。NET 中 mTOR 途径的激活已通过表达谱分析得到证实，该分析显示 TSC2 基因下调以及 TSC2 和 PTEN 蛋白表达在绝大多数分化良好的肿瘤中改变。此外，全局 microRNA 表达分析显示，高度侵袭性肿瘤中存在一种 microRNA（miR-21）的过表达，该 microRNA 靶向 PTEN，降低其表达，从而导致 mTOR 激活。总之，这些线索为使用 mTOR 抑制剂治疗 pNET 提供了依据。随着 Everolimus（mTOR 靶向药物）最近被批准用于治疗晚期 pNET，这一范例已有效地转化为临床实践。在这篇综述中，我们讨论了 mTOR 途径在 NET 中的参与、支持在癌症治疗中使用 mTOR 抑制剂的临床证据以及仍需阐明以改善患者管理的当前临床问题。
