Molecular signaling of the epithelial to mesenchymal transition in generating and maintaining cancer stem cells

Abstract

The epithelial to mesenchymal transition (EMT) is a highly conserved cellular program that allows polarized, well-differentiated epithelial cells to convert to unpolarized, motile mesenchymal cells. EMT is critical for appropriate embryogenesis and plays a crucial role in tumorigenesis and cancer progression. Recent studies revealed that there is a direct link between the EMT program and the gain of epithelial stem cell properties. EMT is sufficient to induce a population with stem cell characteristics from well-differentiated epithelial cells and cancer cells. In this review, we briefly introduce the biology of EMT inducers and transcription factors in tumorigenesis and then focus on the role of these key players of the EMT in generating and maintaining cancer stem cells.

Fig. 1

Overview of molecular markers and cellular changes during the epithelial-mesenchymal transition (EMT). EMT is a well-coordinated event during embryonic development and a pathological feature in tumorigenesis. During the EMT process, epithelial cells undergo dramatic phenotypic changes, lose expression of E-cadherin and other components of epithelial cell junctions, adopt a mesenchymal cell phenotype, and acquire motility and invasive properties that allow them to migrate through the extracellular matrix

Fig. 2

Schematic diagram of the epithelial mesenchymal transition (EMT) generates cancer stem-like cells from epithelial cancer cells. EMT can be triggered by several extracellular inducing signals such as TGF-β, Wnt, and other tumor microenvironmental cues. Receptor-mediated signaling in response to these EMT signals activates intracellular effectors and then a set of EMT transcription factors including Twist 1, Twist 2, Snai1, Slug, ZEB1, ZEB2, Goosecoid, and FOXC2. The signaling cascades from extracellular EMT-inducing signals to EMT transcription factors result in reprogramming of epithelial nonstem cancer cells into mesenchymal cells. These mesenchymal cells take on typical properties and abilities of cancer stem cells (CSCs) to self-renew and differentiate into heterogeneous populations of cancer cells. CSCs not only have potent tumorigenic capacity to be involved in tumor initiation and growth but also play an essential role in tumor metastasis, therapeutic resistance, and recurrence