EMT, CSCs, and drug resistance: the mechanistic link and clinical implications

According to the cancer stem cell (CSC) paradigm, a minor subpopulation of cancer cells with stem-cell properties predominantly underlies tumour progression, therapy resistance, and disease recurrence. Notably, epithelial-to-mesenchymal transition (EMT) is implicated in these processes, and CSCs typically show markers of EMT-programme activation. Herein, the authors outline our current understanding of the links between the EMT programme, the CSC phenotype, metastasis, and drug resistance, and discuss the potential for therapeutic targeting of these facets of tumour biology. The success of anticancer therapy is usually limited by the development of drug resistance. Such acquired resistance is driven, in part, by intratumoural heterogeneity — that is, the phenotypic diversity of cancer cells co-inhabiting a single tumour mass. The introduction of the cancer stem cell (CSC) concept, which posits the presence of minor subpopulations of CSCs that are uniquely capable of seeding new tumours, has provided a framework for understanding one dimension of intratumoural heterogeneity. This concept, taken together with the identification of the epithelial-to-mesenchymal transition (EMT) programme as a critical regulator of the CSC phenotype, offers an opportunity to investigate the nature of intratumoural heterogeneity and a possible mechanistic basis for anticancer drug resistance. In fact, accumulating evidence indicates that conventional therapies often fail to eradicate carcinoma cells that have entered the CSC state via activation of the EMT programme, thereby permitting CSC-mediated clinical relapse. In this Review, we summarize our current understanding of the link between the EMT programme and the CSC state, and also discuss how this knowledge can contribute to improvements in clinical practice.