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

Abstract

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.

HIPK2 inhibits cell metastasis and improves chemosensitivity in esophageal squamous cell carcinoma

“…Upregulation of HIPK2 inhibited the migration and invasion of ESCC cells. HIPK2 decreased the level of mesenchymal marker N-cadherin mRNA, which is one of the most important markers of EMT (27). By contrast, HIPK2 increased the expression of epithelial marker E-cadherin.…”

Friend leukemia virus integration 1 is a predictor of poor prognosis of breast cancer and promotes metastasis and cancer stem cell properties of breast cancer cells

“…Studies have demonstrated that tumor cells can eventually enter the invasion‐metastasis cascade, a prerequisite is the acquisition of mesenchymal properties—epithelial‐mesenchymal transition (EMT) 4, 23. Combined with the tissue analysis results and the previous finding that FLI‐1 activated the Rho GTPase pathway,15 a pathway closely related to the EMT process,24 elucidated the potential association between FLI‐1 and the EMT program. To verify the hypothesis, we compared the difference in the expression of EMT‐related proteins in the MDA‐MB231 and MCF‐7 cell lines.…”

“…As a prerequisite of metastasis, tumor cells lose the epithelial phenotype and acquire mesenchymal properties. The activation of Rho GTPase, that is, RhoA, Rac1, and Cdc42, is often involved in the migratory and metastatic biological behaviors of tumor cells 24. FLI‐1 can activate RhoA and Rac1, which correlates with breast cancer metastasis 15.…”

Concise Review: Aggressive Colorectal Cancer: Role of Epithelial Cell Adhesion Molecule in Cancer Stem Cells and Epithelial-to-Mesenchymal Transition

“…CSCs 33, 34, 60 and EMT 35, 37, 42, 43 both fuel cancer progression and mediate drug resistance. The transmembranous glycoprotein EpCAM exerts distinct and partially paradoxical functions in CSCs and EMT: while CSCs from epithelial‐derived tumors express high levels of EpCAM, EMT cells have downregulated the expression of this key epithelial denominator.…”

“…Accumulating evidence suggests a strong and possibly causal link between EMT and the acquisition of stem cell properties in both normal and malignant epithelial cells 42, 43. In addition, EpCAM, along with other markers such as E‐cadherin and cytokeratins, defines a key denominator of the epithelial cell state.…”