文章：

靶向癌症中的自噬

Targeting autophagy in cancer

原文发布日期：2017-07-28

DOI: 10.1038/nrc.2017.53

类型: Review Article

开放获取: 否

要点：

1. Macroautophagy (known as autophagy) is a highly regulated multi-step process that is involved in the bulk degradation of cellular proteins and organelles to provide macromolecular precursors that are recycled or that are used to fuel metabolic pathways.
2. Autophagy can be targeted for both stimulation and inhibition. Stimulation can be achieved through cellular stress (nutrient deprivation) and mTOR inhibition, and inhibition can be achieved through multiple targets both upstream (ULK1, Beclin 1 and VPS34 inhibitors) and downstream of the site of lysosomal fusion with the autophagosome.
3. Early clinical trials have demonstrated the feasibility and potential benefit of clinically inhibiting autophagy in multiple cancer types, including glioblastoma, pancreatic cancer, melanoma, sarcoma and multiple myeloma.
4. Ongoing studies are developing novel clinical biomarkers that can be used to monitor autophagy in patients, including electron microscopy evaluation of autophagosome number in peripheral blood mononuclear cells and tumour samples, LC3II and ATG13 puncta by immunohistochemistry, and novel imaging techniques that use positron emission tomography and metabolomics profiles.
5. The role of autophagy in regulating tumour immune responses is unclear, with arguments both for and against autophagy inhibition. Further research is needed to define the safety and utility of autophagy inhibition while also maximizing tumour immune responses for improved clinical outcomes.
6. Markers of autophagy dependence have the potential to identify patients who will best respond to autophagy inhibition therapy. Such markers include altered RAS signalling, BRAF mutations, signal transducer and activator of transcription 3 (STAT3) activation, autophagy-dependent secretion of interleukins and p53 status.
7. Autophagy can be an effective cancer escape mechanism and has been implicated in the development of resistance in multiple cancer types, including BRAF-mutated central nervous system (CNS) tumours and melanoma, non-small-cell lung cancer (NSCLC), bladder cancer and thyroid cancer. Combination therapy with autophagy inhibition in these cancers has the potential to reduce and reverse resistance to therapy.

要点翻译：

1. 巨自噬（即自噬）是一种高度调控的多步骤过程，参与细胞蛋白质和细胞器的大规模降解，以提供可被循环利用或用于维持代谢通路的大分子前体。
2. 自噬可作为刺激或抑制的靶点。刺激可通过细胞应激（营养剥夺）和mTOR抑制实现；抑制则可通过作用于溶酶体与自噬体融合位点的上游（ULK1、Beclin 1和VPS34抑制剂）及下游多个靶点实现。
3. 早期临床试验已证明在胶质母细胞瘤、胰腺癌、黑色素瘤、肉瘤和多发性骨髓瘤等多种癌症中临床抑制自噬的可行性及潜在获益。
4. 现有研究正在开发可用于监测患者自噬的新型临床生物标志物，包括通过电镜评估外周血单核细胞和肿瘤样本中的自噬体数量、免疫组化检测LC3II和ATG13斑点、以及采用正电子发射断层扫描与代谢组学图谱的新型成像技术。
5. 自噬在调节肿瘤免疫应答中的作用尚不明确，支持与反对抑制自噬的观点并存。需要进一步研究以明确自噬抑制的安全性及效用，同时最大化肿瘤免疫应答以改善临床结局。
6. 自噬依赖性标志物有望识别对自噬抑制疗法反应最佳的患者。这类标志物包括RAS信号改变、BRAF突变、STAT3激活、白细胞介素的自噬依赖性分泌及p53状态。
7. 自噬可作为有效的癌症逃逸机制，并与多种癌症治疗耐药性的产生相关，包括BRAF突变的中枢神经系统肿瘤、黑色素瘤、非小细胞肺癌、膀胱癌和甲状腺癌。在这些癌症中联合应用自噬抑制疗法，可能减少并逆转治疗耐药性。

英文摘要：

Autophagy is a mechanism by which cellular material is delivered to lysosomes for degradation, leading to the basal turnover of cell components and providing energy and macromolecular precursors. Autophagy has opposing, context-dependent roles in cancer, and interventions to both stimulate and inhibit autophagy have been proposed as cancer therapies. This has led to the therapeutic targeting of autophagy in cancer to be sometimes viewed as controversial. In this Review, we suggest a way forwards for the effective targeting of autophagy by understanding the context-dependent roles of autophagy and by capitalizing on modern approaches to clinical trial design.

摘要翻译： 

自噬是一种将细胞物质运送至溶酶体进行降解的机制，导致细胞组分的基础更新，并提供能量和大分子前体。自噬在癌症中具有相反且依赖情境的作用，因此刺激和抑制自噬的干预措施均被提出作为癌症治疗手段。这使得自噬在癌症中的治疗性靶向有时被视为具有争议。在本综述中，我们建议通过理解自噬的情境依赖性作用，并利用现代临床试验设计方法，来推进自噬的有效靶向治疗。

原文链接：

Targeting autophagy in cancer