Targeting Notch to target cancer stem cells.
Targeting Notch to target cancer stem cells.
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DOI：
10.1158/1078-0432.ccr-09-2823
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发表时间：
2010-06-15
期刊：
影响因子：
--
通讯作者：
Miele L
中科院分区：
文献类型：
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作者：
Pannuti A;Foreman K;Rizzo P;Osipo C;Golde T;Osborne B;Miele L
肿瘤的细胞异质性一直是相当大的兴趣，因为“癌症干细胞假说”，最初制定的血液恶性肿瘤，扩展到实体瘤的中心。癌症干细胞（CSCs）或肿瘤起始细胞（TICs）（以下简称CSCs）的起源及其鉴定方法是一个备受争议的话题。然而，具有干细胞样特征的肿瘤细胞亚群的存在具有重要的治疗意义。干细胞样表型包括无限的自我复制，多能性，重要的是，对化疗药物的抗性。因此，这是合理的，CSC，无论其起源，可能逃脱标准治疗，并导致疾病复发和/或转移后，显然完全缓解。因此，用新的治疗剂选择性靶向CSC的想法获得了相当大的兴趣。Notch通路是CSC中研究最深入的假定治疗靶点之一，并且正在开发几种研究性Notch抑制剂。然而，成功靶向CSC中的Notch信号传导将需要彻底理解Notch调控以及Notch与其他治疗相关途径之间的背景依赖性相互作用。了解这些相互作用将提高我们设计合理的组合方案的能力，这些方案更有可能被证明是安全和有效的。此外，为了确定哪些患者最有可能受益于Notch靶向治疗剂的治疗，必须鉴定和验证用于测量特定肿瘤CSC中通路活性的可靠生物标志物。本文总结了Notch靶向肿瘤治疗领域的最新进展，重点是CSC。
The cellular heterogeneity of neoplasms has been at the center of considerable interest since the “cancer stem cell hypothesis”, originally formulated for hematologic malignancies, was extended to solid tumors. The origins of cancer “stem” cells (CSCs) or tumor-initiating cells (TICs) (henceforth referred to as CSCs) and the methods to identify them are hotly debated topics. Nevertheless, the existence of sub-populations of tumor cells with stem-like characteristics has significant therapeutic implications. The stem-like phenotype includes indefinite self-replication, pluripotency and, importantly, resistance to chemotherapeutics. Thus, it is plausible that CSC, regardless of their origin, may escape standard therapies and cause disease recurrences and/or metastasis after apparently complete remissions. Consequently, the idea of selectively targeting CSCs with novel therapeutics is gaining considerable interest. The Notch pathway is one of the most intensively studied putative therapeutic targets in CSC, and several investigational Notch inhibitors are being developed. However, successful targeting of Notch signaling in CSC will require a thorough understanding of Notch regulation and the context-dependent interactions between Notch and other therapeutically relevant pathways. Understanding these interactions will increase our ability to design rational combination regimens that are more likely to prove safe and effective. Additionally, to determine which patients are most likely to benefit from treatment with Notch-targeting therapeutics, reliable biomarkers to measure pathway activity in CSC from specific tumors will have to be identified and validated. This article summarizes the most recent developments in the field of Notch-targeted cancer therapeutics, with emphasis on CSC.