Institute of Molecular Genetics (IGM); National Research Council (CNR), 27100 Pavia, Italy.
SYSBIO.IT, Centre of Systems Biology, University of Milano-Bicocca, 20126 Milano, Italy.
Cells. 2019 Dec 21;9(1):34. doi: 10.3390/cells9010034.
During tumor progression, hypoxia, nutrient deprivation or changes in the extracellular environment (i.e., induced by anti-cancer drugs) elicit adaptive responses in cancer cells. Cellular plasticity increases the chance that tumor cells may survive in a challenging microenvironment, acquire new mechanisms of resistance to conventional drugs, and spread to distant sites. Re-activation of stem pathways appears as a significant cause of cellular plasticity because it promotes the acquisition of stem-like properties through a profound phenotypic reprogramming of cancer cells. In addition, it is a major contributor to tumor heterogeneity, depending on the coexistence of phenotypically distinct subpopulations in the same tumor bulk. Several cellular mechanisms may drive this fundamental change, in particular, high-throughput sequencing technologies revealed a key role for alternative splicing (AS). Effectively, AS is one of the most important pre-mRNA processes that increases the diversity of transcriptome and proteome in a tissue- and development-dependent manner. Moreover, defective AS has been associated with several human diseases. However, its role in cancer cell plasticity and tumor heterogeneity remains unclear. Therefore, unravelling the intricate relationship between AS and the maintenance of a stem-like phenotype may explain molecular mechanisms underlying cancer cell plasticity and improve cancer diagnosis and treatment.
在肿瘤进展过程中，缺氧、营养缺乏或细胞外环境的变化（例如，由抗癌药物引起的）会引发癌细胞的适应性反应。细胞可塑性增加了肿瘤细胞在具有挑战性的微环境中存活、获得对传统药物新的耐药机制以及扩散到远处部位的机会。干细胞途径的重新激活似乎是细胞可塑性的一个重要原因，因为它通过对癌细胞进行深刻的表型重编程来促进获得类似干细胞的特性。此外，它是肿瘤异质性的主要贡献者，这取决于同一肿瘤块中存在表型不同的亚群。几种细胞机制可能驱动这种根本变化，特别是高通量测序技术揭示了选择性剪接 (AS) 的关键作用。实际上，AS 是最重要的前体 RNA 加工之一，它以组织和发育依赖的方式增加转录组和蛋白质组的多样性。此外，有缺陷的 AS 与几种人类疾病有关。然而，它在癌细胞可塑性和肿瘤异质性中的作用尚不清楚。因此，揭示 AS 与维持类似干细胞的表型之间的复杂关系可能有助于解释癌细胞可塑性的分子机制，并改善癌症的诊断和治疗。
