Cancer stem cells and epithelial-mesenchymal transition: concepts and molecular links

Abstract

The epithelial-mesenchymal transition (EMT) confers mesenchymal properties on epithelial cells and has been closely associated with the acquisition of aggressive traits by carcinoma cells. EMT programs are orchestrated by a set of pleiotropically acting transcription factors (TFs). The actions of these EMT-TFs enable the early steps of metastasis: local invasion and subsequent dissemination of carcinoma cells to distant sites. However, in most malignancies, the subsequent outgrowth of micrometastatic deposits into macroscopic metastases has the greatest impact on clinical progression. Such metastatic "colonization" reflects the ability of disseminated tumor cells to adapt to a foreign tissue microenvironment. The outgrowth of a metastasis is also thought to be associated with self-renewal, the defining cellular trait of cancer stem cells (CSCs), also termed tumor-initiating cells. Importantly, molecular links between EMT-TFs and self-renewal have emerged, suggesting that EMT programs play critical roles both early and late in the metastatic cascade. The genetic and epigenetic mechanisms that regulate the activation of EMT-TFs and the traits they induce are areas under intensive investigation. Such studies may provide new opportunities for therapeutic intervention and help to overcome tumor heterogeneity and therapeutic resistance.

Fig. 1.

The metastatic cascade. EMT programs are involved in early steps of the metastatic cascade, where they enable the invasion into the stroma (depicted in orange, underdlying the basement membrane in blue) and translocation of carcinoma cells (depicted in blue, changing to red when undergoing an EMT) to distant parenchyma (green). EMT programs are dynamically regulated and, during the last step of the metastatic cascade, colonization, carcinoma cells are thought to switch back to an epithelial state (blue cells) through the reverse process, mesenchymal–epithelial transition (MET).

Fig. 2.

Molecular links between proteins implicated in self-renewal of normal and cancer stem cells (polycomb proteins Bmi-1, histone modifying protein Suz12 and Wnt/beta-catenin signaling) and EMT-TFs (Zeb1, Twist, Snail). Blue arrows indicate repressive/inhibitory actions, red arrows an upregulation. In the absence of active Wnt/beta-catenin signaling, GSK-3-beta phosphorylates both Snail and beta-catenin, thereby targeting them for ubiquitination and destruction in the proteasome. Both Snail and Zeb1 repress the CDH1 gene whose product, E-Cadherin (indicated through dashed blue line) binds and inactivates beta-catenin, thereby preventing it to associated with TCF/LEF-TFs (dashed blue line) and activate Wnt target genes in the nucleus.