Revisiting epithelial-mesenchymal transition in cancer metastasis: the connection between epithelial plasticity and stemness

Abstract

Epithelial-mesenchymal transition (EMT) is an important process in embryonic development, fibrosis, and cancer metastasis. During cancer progression, the activation of EMT permits cancer cells to acquire migratory, invasive, and stem-like properties. A growing body of evidence supports the critical link between EMT and cancer stemness. However, contradictory results have indicated that the inhibition of EMT also promotes cancer stemness, and that mesenchymal-epithelial transition, the reverse process of EMT, is associated with the tumor-initiating ability required for metastatic colonization. The concept of 'intermediate-state EMT' provides a possible explanation for this conflicting evidence. In addition, recent studies have indicated that the appearance of 'hybrid' epithelial-mesenchymal cells is favorable for the establishment of metastasis. In summary, dynamic changes or plasticity between the epithelial and the mesenchymal states rather than a fixed phenotype is more likely to occur in tumors in the clinical setting. Further studies aimed at validating and consolidating the concept of intermediate-state EMT and hybrid tumors are needed for the establishment of a comprehensive profile of cancer metastasis.

Keywords: epithelial-mesenchymal transition; metastasis; plasticity; stemness.

Figure 1

The dynamic change between the epithelial and the mesenchymal phenotype in cancer cells during metastasis. In response to EMT‐triggering events, such as the activation of signaling pathways (e.g., TGF‐β, hypoxia, Notch, WNT) or the expression of EMT‐TFs (e.g., Snail1/2, Twist1, ZEB1/2, Prrx1) and miRNAs (e.g., miR‐103/107, miR‐181a, miR‐9), cancer cells transition from an epithelial phenotype to a mesenchymal phenotype, with the suppression of epithelial markers and expression of mesenchymal markers. Activation of an EMT program results in the acquisition of migration and invasion abilities for facilitating cancer dissemination. Furthermore, EMT‐TFs promote cancer cells to acquire the stem‐like features. After the mesenchymal‐type cancer cells reaching the metastatic sites, the cancer cells reverse back to the epithelial type through MET, which is critical for cancer colonization. The effectors of MET include the activation of certain transcriptional factors (e.g., Id1, OVOL1/2), miRNAs (e.g., miR‐200), and receptor (VDR).

Figure 2

A model for depicting cellular plasticity for cancer metastasis. In primary tumors, most cancer cells have an epithelial type. In metastatic cancer, hybrid epithelial/mesenchymal (E/M) cells or partial EMT is favorable for cancer dissemination. When the hybrid E/M cells reach the metastatic site, they will revert back to epithelial cells to form metastatic colonies, possibly via rapid kinetics. Therefore, the epithelial/mesenchymal features and stem‐like properties are no longer a fixed state. A dynamic or a flexible feature of E/M phenotype is a better description for the plasticity of cancer cells.