Imodoye Sikiru O, Adedokun Kamoru A, Muhammed Abdurrasheed Ola, Bello Ibrahim O, Muhibi Musa A, Oduola Taofeeq, Oyenike Musiliu A
Department of Medical Laboratory Science, College of Medicine, University of Lagos, Lagos, Nigeria.
Department of Oral Pathology, Dental University Hospital, King Saud University Medical City, Riyadh, Saudi Arabia.
Front Oncol. 2021 Nov 18;11:762817. doi: 10.3389/fonc.2021.762817. eCollection 2021.
Epithelial-mesenchymal transition (EMT) is a physiological program during which polarised, immobile epithelial cells lose connection with their neighbours and are converted to migratory mesenchymal phenotype. Mechanistically, EMT occurs a series of genetic and cellular events leading to the repression of epithelial-associated markers and upregulation of mesenchymal-associated markers. EMT is very crucial for many biological processes such as embryogenesis and ontogenesis during human development, and again it plays a significant role in wound healing during a programmed replacement of the damaged tissues. However, this process is often hijacked in pathological conditions such as tumour metastasis, which constitutes the most significant drawback in the fight against cancer, accounting for about 90% of cancer-associated mortality globally. Worse still, metastatic tumours are not only challenging to treat with the available conventional radiotherapy and surgical interventions but also resistant to several cytotoxic agents during treatment, owing to their anatomically diffuse localisation in the body system. As the quest to find an effective method of addressing metastasis in cancer intervention heightens, understanding the molecular interplay involving the signalling pathways, downstream effectors, and their interactions with the EMT would be an important requisite while the challenges of metastasis continue to punctuate. Unfortunately, the molecular underpinnings that govern this process remain to be completely illuminated. However, it is becoming increasingly clear that EMT, which initiates every episode of metastasis, significantly requires some master regulators called EMT transcription factors (EMT-TFs). Thus, this review critically examines the roles of TFs as drivers of molecular rewiring that lead to tumour initiation, progression, EMT, metastasis, and colonisation. In addition, it discusses the interaction of various signalling molecules and effector proteins with these factors. It also provides insight into promising therapeutic targets that may inhibit the metastatic process to overcome the limitation of "undruggable" cancer targets in therapeutic design and upturn the current spate of drug resistance. More so, it extends the discussion from the basic understanding of the EMT binary switch model, and ultimately unveiling the E/M cellular plasticity along a phenotypic spectrum multiple trans-differentiations. It wraps up on how this knowledge update shapes the diagnostic and clinical approaches that may demand a potential shift in investigative paradigm using novel technologies such as single-cell analyses to improve overall patient survival.
上皮-间质转化（EMT）是一个生理过程，在此过程中，极化的、静止的上皮细胞与相邻细胞失去连接，并转变为具有迁移能力的间质表型。从机制上讲，EMT发生一系列遗传和细胞事件，导致上皮相关标志物的抑制和间质相关标志物的上调。EMT对许多生物学过程至关重要，如人类发育过程中的胚胎发生和个体发生，并且在受损组织的程序性替代过程中的伤口愈合中也发挥着重要作用。然而，在肿瘤转移等病理条件下，这个过程常常被劫持，这是对抗癌症过程中最显著的缺点，全球约90%的癌症相关死亡都与此有关。更糟糕的是，转移性肿瘤不仅难以用现有的传统放疗和手术干预进行治疗，而且在治疗过程中对几种细胞毒性药物具有抗性，这是由于它们在身体系统中解剖学上的弥漫性定位。随着在癌症干预中寻找有效解决转移问题方法的需求日益增加，在转移挑战持续存在的情况下，了解涉及信号通路、下游效应器及其与EMT相互作用的分子相互作用将是一个重要的必要条件。不幸的是，控制这个过程的分子基础仍有待完全阐明。然而，越来越明显的是，引发每一次转移事件的EMT，显著需要一些称为EMT转录因子（EMT-TFs）的主调节因子。因此，本综述批判性地研究了转录因子作为分子重排驱动因素的作用，这些分子重排导致肿瘤起始、进展、EMT、转移和定植。此外，它还讨论了各种信号分子和效应蛋白与这些因子的相互作用。它还深入探讨了有前景的治疗靶点，这些靶点可能抑制转移过程，以克服治疗设计中“不可成药”癌症靶点的局限性，并扭转当前的耐药局面。更重要的是，它从对EMT二元开关模型的基本理解展开讨论，最终揭示沿表型谱的E/M细胞可塑性以及多种转分化。它总结了这种知识更新如何塑造诊断和临床方法，这可能需要使用单细胞分析等新技术改变研究范式，以提高患者的总体生存率。
