29 TGF-β Signaling in Epithelial–Mesenchymal Transition and Invasion and Metastasis

Abstract

WHAT IS EPITHELIAL–MESENCHYMAL TRANSITION?
Epithelial–mesenchymal transition, transformation, or transdifferentiation (EMT) refers to the delamination of mesenchymal cells from epithelia. This is a fundamental developmental process that is recapitulated numerous times during embryogenesis and is revisited in various adult pathologies, particularly fibrosis and cancer. The acquisition of the mesenchymal phenotype increases cellular plasticity by decreasing cell–cell and enhancing cell–substrate contacts to increase cellular movement that is essential for morphogenesis or, in the case of cancer, invasion and metastasis. In each biological scenario, the basic cellular and molecular mechanisms defining and regulating EMT are very similar, with differences in the molecular mechanisms. EMT was first observed when Greenburg and Hay (1982) observed the transition toward a mesenchymal phenotype when they disrupted epithelial cell–cell contacts by suspending cells in collagen gels. In the late 1980s, Thiery et al. (1988) recognized the importance of this process to cancer invasion and metastasis.

Examples of embryonic EMT include trophoblast development (Vicovac and Aplin 1996), formation of the meso-endoderm lineage at gastrulation (Sirard et al. 1998), neural crest migration (Cheung et al. 2005), and organogenesis of the heart (Potts and Runyan 1989) and secondary palate (Proetzel et al. 1995). Defective EMT at any of these sites can lead to embryonic lethality or congenital malformation (Proetzel et al. 1995; Sanford et al. 1997; Sirard et al. 1998; Waldrip et al. 1998). In the adult, many fibrotic conditions, some previously thought to be caused by infiltration and/or proliferation of preexisting fibroblasts, have now been...