理解自噬在癌症干细胞维护与治疗抵抗中的作用
Understanding the autophagic functions in cancer stem cell maintenance and therapy resistance
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影响因子:5.5
分区:医学3区 / 生化与分子生物学3区 医学：研究与实验3区
发表日期:2024 Oct 08
作者:
Niharika, Minal Garg
DOI:
10.1017/erm.2024.23
摘要
复杂的肿瘤生态系统由肿瘤细胞及其相关的肿瘤微环境（TME）共同影响肿瘤行为，并最终影响治疗失败、疾病进展、复发及患者的整体生存。肿瘤细胞与TME之间的相互作用通过诱导如缺氧环境和营养波动等代谢变化，进一步增加了肿瘤的复杂性。这些变化激活癌细胞的干细胞样程序，促使肿瘤异质性增加，增强肿瘤的韧性。最新研究表明，自噬在促进成纤维细胞产生、维持干性、肿瘤细胞在长期休眠期间的存活、转移性疾病的生长及治疗抵抗中扮演多重角色。当前研究集中在自噬/线粒体自噬作为应对营养缺乏、缺氧及TME环境压力的强大生存策略，防止不可逆的衰老，维持休眠的干细胞样状态，诱导上皮-间充质转化，并增强肿瘤细胞的迁移和侵袭能力。本文讨论了自噬依赖性诱导癌症干细胞（CSC）表型的各种理论与机制。鉴于自噬功能在CSC的侵袭性和治疗抵抗中的作用，分析了通过抑制自噬来抑制细胞可塑性的多种机制和研究，作为一种强有力的治疗策略以杀死肿瘤细胞。
Abstract
Complex tumour ecosystem comprising tumour cells and its associated tumour microenvironment (TME) constantly influence the tumoural behaviour and ultimately impact therapy failure, disease progression, recurrence and poor overall survival of patients. Crosstalk between tumour cells and TME amplifies the complexity by creating metabolic changes such as hypoxic environment and nutrient fluctuations. These changes in TME initiate stem cell-like programmes in cancer cells, contribute to tumoural heterogeneity and increase tumour robustness. Recent studies demonstrate the multifaceted role of autophagy in promoting fibroblast production, stemness, cancer cell survival during longer periods of dormancy, eventual growth of metastatic disease and disease resistance. Recent ongoing studies examine autophagy/mitophagy as a powerful survival strategy in response to environmental stress including nutrient deprivation, hypoxia and environmental stress in TME. It prevents irreversible senescence, promotes dormant stem-like state, induces epithelial-mesenchymal transition and increases migratory and invasive potential of tumour cells. The present review discusses various theories and mechanisms behind the autophagy-dependent induction of cancer stem cell (CSC) phenotype. Given the role of autophagic functions in CSC aggressiveness and therapeutic resistance, various mechanisms and studies based on suppressing cellular plasticity by blocking autophagy as a powerful therapeutic strategy to kill tumour cells are discussed.