Epithelial to mesenchymal transition in tumor cells as consequence of phenotypic instability

Abstract

During the last years many articles have reported epithelial-to-mesenchymal transitions (EMT) induced by a myriad of gene products either when added to the cell medium or when transfected. Molecularly the EMT is characterized by the up-regulation of transcriptional factors (EMT-TFs) repressing the epithelial gene E-cadherin, a protein essential for the maintenance of the epithelial phenotype. These EMT-TFs are subjected to a complex regulation involving binary self-stimulatory loops, allowing the possibility of the amplification of input signals. The capability of EMT-TFs to promote an EMT is controlled by E-cadherin that limits the transcription of mesenchymal genes. We discuss here the differences between normal and tumor epithelial cells; in the latter a partial inactivation of E-cadherin function enables extracellular signals to be amplified and induce an EMT. This tumor cell phenotypic instability is exacerbated in cell culture conditions. Therefore, it is likely that many of the gene products reported to control this transition act only in very specific cell tumor cell lines; thus, in cells with an unstable phenotype due to pre-existing alterations in E-cadherin safeguard mechanism.

Keywords: E-cadherin; EMT; Snail1; self-amplification; tumor instability.

Figure 1

EMT-TFs are controlled by self-inhibition and self-activation. The figure shows examples of mechanisms of self-inhibition (left) or activation (right) controlling the expression of Snail1, Twist1, and Zeb1. The number indicates the type of control. Besides the references indicated in the text, the mechanisms shown in this figure are documented in Howe et al. (2003), Barberà et al. (2004), Bachelder et al. (2005), Yook et al. (2006), Julien et al. (2007), Stemmer et al. (2008), Kudo-Saito et al. (2009), Wu et al. (2009), Sánchez-Tillo et al. (2011).

Figure 2

Tumor cells are more receptive to signals inducing EMT. According to our model, an epithelial cell with functional E-cadherin and stable adherens junctions is not sensitive to extracellular signals inducing Snail1 and EMT such as TGF-β (left). Although these cytokines activate Snail1 expression, due to the high stability of E-cadherin protein the down-regulation in E-cadherin mRNA is not translated in changes in the protein. Moreover, stable junctional complexes retain β-catenin and NF-κB restrained their traffic to the nucleus and transcriptional activity. In these conditions Snail1 expression is self-inhibited and the EMT process is not initiated. Tumor epithelial cells contain less static adherens junctions due to post-translational modifications of E-cadherin or associated proteins, such as β-catenin; consequently the stability of E-cadherin protein is lower. In these conditions Snail1 increases do cause a significant down-modulation in E-cadherin protein and facilitates the traffic of NF-κB ad β-catenin to the nucleus and the activation of their transcriptional activity. These two factors further stimulate Snail1 expression, either by directly stimulating Snail gene transcription (NF-κB) or increasing protein stability (NF-κB, β-catenin), therefore amplifying the initial signal. Moreover, they also up-regulate the transcription of other mesenchymal markers such as Zeb1 or fibronectin (FN1), triggering a self-stimulatory circuit described in Figure 1 and supporting the EMT.