The epithelial-mesenchymal transition: new insights in signaling, development, and disease

Abstract

The conversion of an epithelial cell to a mesenchymal cell is critical to metazoan embryogenesis and a defining structural feature of organ development. Current interest in this process, which is described as an epithelial-mesenchymal transition (EMT), stems from its developmental importance and its involvement in several adult pathologies. Interest and research in EMT are currently at a high level, as seen by the attendance at the recent EMT meeting in Vancouver, Canada (October 1-3, 2005). The meeting, which was hosted by The EMT International Association, was the second international EMT meeting, the first being held in Port Douglas, Queensland, Australia in October 2003. The EMT International Association was formed in 2002 to provide an international body for those interested in EMT and the reverse process, mesenchymal-epithelial transition, and, most importantly, to bring together those working on EMT in development, cancer, fibrosis, and pathology. These themes continued during the recent meeting in Vancouver. Discussion at the Vancouver meeting spanned several areas of research, including signaling pathway activation of EMT and the transcription factors and gene targets involved. Also covered in detail was the basic cell biology of EMT and its role in cancer and fibrosis, as well as the identification of new markers to facilitate the observation of EMT in vivo. This is particularly important because the potential contribution of EMT during neoplasia is the subject of vigorous scientific debate (Tarin, D., E.W. Thompson, and D.F. Newgreen. 2005. Cancer Res. 65:5996-6000; Thompson, E.W., D.F. Newgreen, and D. Tarin. 2005. Cancer Res. 65:5991-5995).

Figure 1.

Signaling events during EMT. The major signaling events that were reported in the meeting are summarized. Cleavage of E-cadherin (yellow) by MMP-3 resulted in activation of Snail1 through ROS. Snail1 localization to the nucleus is controlled by phosphorylation of a nuclear export motif and a proteosomal degradation motif, which are each phosphorylatable by GSK-3β. An ILK-responsive element in the Snail1 promoter binds PARP-1. Snail1 expression is inhibited by the MTA3–NuRD chromosomal rearrangement complex, acting downstream of the activated estrogen receptor. Repression of E-cadherin by Snail1, Twist, or other repressors leads indirectly to expression of vimentin and other mesenchymal gene products, partly because of β-catenin/Tcf–Lef1 activation. FOX-C2, as well as SIP1, can also directly activate mesenchymal gene expression. Translocation of β-catenin to the nucleus requires BCL9-2, which itself can induce EMT. Abundance of β-catenin is regulated by phosphorylation-dependent proteosomal degradation, unless GSK-3β is silenced through Wnt signaling. TGF-β is known to activate this canonical Wnt pathway, but TGF-β also directly activates the Tcf–Lef1 transcription complex through tyrosine phosphorylation of SMAD-2. The c-Met receptor tyrosine kinase, through the Crk adaptor, also stimulates EMT.

Figure 2.

The metastable cell phenotype. Several studies have identified a hybrid cell showing both epithelial and mesenchymal traits. These cells are summarized here, in conjunction with their epithelial and mesenchymal counterparts. The term metastable was introduced at the meeting by Pierre Savagner, who showed evidence of epithelial and mesenchymal Rac localization within the same cells. Similar scenarios of hybrid cells were shown by Chaffer (metastasis-derived T24 human bladder carcinoma cells) and Thompson (EGF-treated PMC42 human breast cancer cells). Coexpression of mixed lineage traits within the same cell may be consistent with the stem cell–like profiles reported by Brabletz in colon carcinoma cells at the invasive front.