Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Molecular Pharmacology, University of Groningen, The Netherlands.
Biochem Pharmacol. 2019 Feb;160:121-133. doi: 10.1016/j.bcp.2018.12.010. Epub 2018 Dec 14.
Lung cancer remains the leading cause of cancer-related deaths despite recent breakthroughs in immunotherapy. The widely embraced cancer stem cell (CSC) theory has also been applied for lung cancer, postulating that an often small proportion of tumor cells with stem cell properties are responsible for tumor growth, therapeutic resistance and metastasis. The identification of these CSCs and underlying molecular maintenance mechanisms is considered to be absolutely necessary for developing therapies for their riddance, hence achieving remission. In this review, we will critically address the CSC concept in lung cancer and its advancement thus far. We will describe both normal lung stem cells and their malignant counterparts in order to identify common aspects with respect to their emergence and regulation. Subsequently, the importance of CSCs and their molecular features in lung cancers will be discussed in a preclinical and clinical context. We will highlight some examples on how lung CSCs attain stemness through different molecular modifications and cellular assistance from the tumor microenvironment. The exploitation of these mechanistic features for the development of pharmacological therapy will also be discussed. In summary, the validity of the CSC concept has been evidenced by various studies. Ongoing research to identify molecular mechanisms driving lung CSC have revealed potential new cell intrinsic as well as tumor microenvironment-derived therapeutic targets. Although successfully demonstrated in preclinical models, the clinical benefit of lung CSC targeted therapies has thus far not been demonstrated. Therefore, further research to validate the therapeutic value of CSC concept is required.
尽管免疫疗法最近取得了突破，但肺癌仍然是癌症相关死亡的主要原因。广泛接受的癌症干细胞 (CSC) 理论也被应用于肺癌，推测肿瘤细胞中经常只有一小部分具有干细胞特性的细胞负责肿瘤生长、治疗抵抗和转移。这些 CSCs 的鉴定及其潜在的分子维持机制被认为对于开发消除它们的治疗方法绝对必要，从而实现缓解。在这篇综述中，我们将批判性地探讨肺癌中的 CSC 概念及其迄今为止的进展。我们将描述正常的肺干细胞及其恶性对应物，以确定它们出现和调节的共同方面。随后，将在临床前和临床背景下讨论 CSCs 及其在肺癌中的分子特征的重要性。我们将重点介绍一些例子，说明肺 CSCs 如何通过不同的分子修饰和肿瘤微环境中的细胞辅助获得干性。还将讨论利用这些机制特征开发药理学治疗的情况。总之，CSC 概念的有效性已被各种研究证明。正在进行的研究以确定驱动肺 CSC 的分子机制已经揭示了潜在的新的细胞内在和肿瘤微环境衍生的治疗靶点。尽管在临床前模型中得到了成功证明，但迄今为止，肺 CSC 靶向治疗的临床获益尚未得到证明。因此，需要进一步研究来验证 CSC 概念的治疗价值。
