Resistance to Cell Death and Its Modulation in Cancer Stem Cells.
Resistance to Cell Death and Its Modulation in Cancer Stem Cells.
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DOI：
10.1615/critrevoncog.2016016976
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发表时间：
2016
影响因子：
--
通讯作者：
Safa AR
中科院分区：
文献类型：
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作者：
Safa AR
越来越多的证据表明，人类癌症起源于各种起源于癌症干细胞（CSC）或癌症起始细胞的组织。CSC中的外源性和内源性凋亡途径失调，这些细胞在肿瘤发生、进展、细胞死亡抵抗、化疗和放疗抵抗以及肿瘤复发中起着关键作用。了解CSC特异性信号蛋白和途径对于确定特定的治疗靶点是必要的，这些靶点可能导致选择性靶向CSC的更有效疗法的开发。几种信号通路-包括磷脂酰肌醇3-激酶（PI 3 K）/Akt/哺乳动物雷帕霉素靶蛋白（mTOR）、母体胚胎亮氨酸拉链激酶（MELK）、NOTCH 1和Wnt/β-连环蛋白-以及CSC标志物CD 133、CD 24、CD 44、Oct 4、Sox 2、Nanog和ALDH 1A 1的表达维持CSC特性。研究这些途径可能有助于了解CSC生物学，并导致潜在的治疗干预措施的发展，使CSC对化疗和放疗引发的细胞死亡更敏感。此外，最近分化的癌细胞去分化为CSC样细胞的证明已经在CSC假说中产生了显着的复杂性。因此，用于癌症治疗的任何成功的治疗剂或药物组合必须不仅消除CSC，而且消除分化的癌细胞和整个肿瘤细胞。这篇综述文章扩展了CSC的假设和范式方面的主要信号通路和效应器，调节CSC凋亡抗性。此外，选择性CSC凋亡调节剂和它们的治疗潜力，使肿瘤更敏感的治疗进行了讨论。使用新的疗法，包括调节干细胞，增殖和CSC迁移的信号通路中特定蛋白质的小分子抑制剂，免疫疗法和非编码microRNA可能提供更好的治疗CSC的方法。
Accumulating evidence has demonstrated that human cancers arise from various tissues of origin that initiate from cancer stem cells (CSCs) or cancer-initiating cells. The extrinsic and intrinsic apoptotic pathways are dysregulated in CSCs, and these cells play crucial roles in tumor initiation, progression, cell death resistance, chemo- and radiotherapy resistance, and tumor recurrence. Understanding CSC-specific signaling proteins and pathways is necessary to identify specific therapeutic targets that may lead to the development of more efficient therapies selectively targeting CSCs. Several signaling pathways—including the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR), maternal embryonic leucine zipper kinase (MELK), NOTCH1, and Wnt/β-catenin—and expression of the CSC markers CD133, CD24, CD44, Oct4, Sox2, Nanog, and ALDH1A1 maintain CSC properties. Studying such pathways may help to understand CSC biology and lead to the development of potential therapeutic interventions to render CSCs more sensitive to cell death triggered by chemotherapy and radiation therapy. Moreover, recent demonstrations of dedifferentiation of differentiated cancer cells into CSC-like cells have created significant complexity in the CSCs hypothesis. Therefore, any successful therapeutic agent or combination of drugs for cancer therapy must eliminate not only CSCs but differentiated cancer cells and the entire bulk of tumor cells. This review article expands on the CSC hypothesis and paradigm with respect to major signaling pathways and effectors that regulate CSC apoptosis resistance. Moreover, selective CSC apoptotic modulators and their therapeutic potential for making tumors more responsive to therapy are discussed. The use of novel therapies, including small-molecule inhibitors of specific proteins in signaling pathways that regulate stemness, proliferation and migration of CSCs, immunotherapy, and noncoding microRNAs may provide better means of treating CSCs.