Li Wen Jess, Wang Yunfei, Liu Ruifang, Kasinski Andrea L, Shen Haifa, Slack Frank J, Tang Dean G
Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.
Experimental Therapeutics Graduate Program, Roswell Park Comprehensive Cancer Center, Buffalo, NY, United States.
Front Cell Dev Biol. 2021 Mar 8;9:640587. doi: 10.3389/fcell.2021.640587. eCollection 2021.
Overwhelming evidence indicates that virtually all treatment-naive tumors contain a subpopulation of cancer cells that possess some stem cell traits and properties and are operationally defined as cancer cell stem cells (CSCs). CSCs manifest inherent heterogeneity in that they may exist in an epithelial and proliferative state or a mesenchymal non-proliferative and invasive state. Spontaneous tumor progression, therapeutic treatments, and (epi)genetic mutations may also induce plasticity in non-CSCs and reprogram them into stem-like cancer cells. Intrinsic cancer cell heterogeneity and induced cancer cell plasticity, constantly and dynamically, generate a pool of CSC subpopulations with varying levels of epigenomic stability and stemness. Despite the dynamic and transient nature of CSCs, they play fundamental roles in mediating therapy resistance and tumor relapse. It is now clear that the stemness of CSCs is coordinately regulated by genetic factors and epigenetic mechanisms. Here, in this perspective, we first provide a brief updated overview of CSCs. We then focus on microRNA-34a (miR-34a), a tumor-suppressive microRNA (miRNA) devoid in many CSCs and advanced tumors. Being a member of the miR-34 family, miR-34a was identified as a p53 target in 2007. It is a bona fide tumor suppressor, and its expression is dysregulated and downregulated in various human cancers. By targeting stemness factors such as NOTCH, MYC, BCL-2, and CD44, miR-34a epigenetically and negatively regulates the functional properties of CSCs. We shall briefly discuss potential reasons behind the failure of the first-in-class clinical trial of MRX34, a liposomal miR-34a mimic. Finally, we offer several clinical settings where miR-34a can potentially be deployed to therapeutically target CSCs and advanced, therapy-resistant, and p53-mutant tumors in order to overcome therapy resistance and curb tumor relapse.
大量证据表明，几乎所有未经治疗的肿瘤都包含一群具有某些干细胞特征和特性的癌细胞亚群，这些细胞在操作上被定义为癌细胞干细胞（CSCs）。CSCs表现出内在的异质性，因为它们可能以上皮和增殖状态或间充质非增殖和侵袭状态存在。自发的肿瘤进展、治疗以及（表观）基因突变也可能诱导非CSCs的可塑性，并将它们重编程为干细胞样癌细胞。内在的癌细胞异质性和诱导的癌细胞可塑性不断动态地产生具有不同表观基因组稳定性和干性水平的CSC亚群池。尽管CSCs具有动态和短暂的性质，但它们在介导治疗抗性和肿瘤复发中起着基本作用。现在很清楚，CSCs的干性由遗传因素和表观遗传机制协同调节。在此观点中，我们首先简要更新了CSCs的概述。然后，我们重点关注微小RNA-34a（miR-34a），这是一种在许多CSCs和晚期肿瘤中缺失的肿瘤抑制性微小RNA（miRNA）。作为miR-34家族的成员，miR-34a在2007年被鉴定为p53靶点。它是一种真正的肿瘤抑制因子，其表达在各种人类癌症中失调并下调。通过靶向NOTCH、MYC、BCL-2和CD44等干性因子，miR-34a在表观遗传上负调节CSCs的功能特性。我们将简要讨论MRX34（一种脂质体miR-34a模拟物）的首例临床试验失败背后的潜在原因。最后，我们提供了几种临床情况，在这些情况下，miR-34a可能被用于治疗性靶向CSCs以及晚期、治疗抗性和p53突变肿瘤，以克服治疗抗性并抑制肿瘤复发。
