The origins of the mesenchymal cells participating in tissue repair and pathological processes, notably tissue fibrosis, tumor invasiveness, and metastasis, are poorly understood. However, emerging evidence suggests that epithelial-mesenchymal transitions (EMTs) represent one important source of these cells. As we discuss here, processes similar to the EMTs associated with embryo implantation, embryogenesis, and organ development are appropriated and subverted by chronically inflamed tissues and neoplasias. The identification of the signaling pathways that lead to activation of EMT programs during these disease processes is providing new insights into the plasticity of cellular phenotypes and possible therapeutic interventions.

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The basics of epithelial-mesenchymal transition

The Epithelial-Mesenchymal Transition Generates Cells with Properties of Stem Cells

Without epithelial–mesenchymal transitions, in which polarized epithelial cells are converted into motile cells, multicellular organisms would be incapable of getting past the blastula stage of embryonic development. However, this important developmental programme has a more sinister role in tumour progression. Epithelial–mesenchymal transition provides a new basis for understanding the progression of carcinoma towards dedifferentiated and more malignant states.

Epithelial–mesenchymal transitions in tumour progression

The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

Molecular mechanisms of epithelial–mesenchymal transition

https://onlinelibrary.wiley.com/doi/pdf/10.1002/jor.1100090504

Mesenchymal stem cells

Epithelium is the tissue phenotype of early embryos and primitive adults of the chordate phylum. A second tissue type, however, is produced by epithelial-mesenchymal transformation (EMT) in higher cho

An Overview of Epithelio-Mesenchymal Transformation

This review centers on the role of the mesenchymal cell in development. The creation of this cell is a remarkable process, one where a tightly knit, impervious epithelium suddenly extends filopodia from its basal surface and gives rise to migrating cells. The ensuing process of epithelial-mesenchymal transformation (EMT) creates the mechanism that makes it possible for the mesenchymal cell to become mobile, so as to leave the epithelium and move through the extracellular matrix. EMT is now recognized as a very important mechanism for the remodeling of embryonic tissues, with the power to turn an epithelial somite into sclerotome mesenchyme, and the neural crest into mesenchyme that migrates to many targets. Thus, the time has come for serious study of the underlying mechanisms and the signaling pathways that are used to form the mesenchymal cell in the embryo. In this review, I discuss EMT centers in the embryo that are ready for such serious study and review our current understanding of the mechanisms used for EMT in vitro, as well as those that have been implicated in EMT in vivo. The purpose of this review is not to describe every study published in this rapidly expanding field but rather to stimulate the interest of the reader in the study of the role of the mesenchymal cell in the embryo, where it plays profound roles in development. In the adult, mesenchymal cells may give rise to metastatic tumor cells and other pathological conditions that we will touch on at the end of the review.

The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it

This study of epithelial-mesenchymal transformation and epithelial cell polarity in vitro reveals that environmental conditions can have a profound effect on the epithelial phenotype, cell shape, and polarity as expressed by the presence of apical and basal surfaces. A number of different adult and embryonic epithelia were suspended within native collagen gels. Under these conditions, cells elongate, detach from the explants, and migrate as individual cells within the three-dimensional lattice, a previously unknown property of well-differentiated epithelia. Epithelial cells from adult and embryonic anterior lens were studied in detail. Elongated cells derived from the apical surface develop pseudopodia and filopodia characteristic of migratory cells and acquire a morphology and ultrastructure virtually indistinguishable from that of mesenchymal cells in vivo. It is concluded from these experiments that the three-dimensional collagen gel can promote dissociation, migration, and acquisition of secretory organelles by differentiated epithelial cells, and can abolish the apical-basal cell polarity characteristic of the original epithelium.

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Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells.

Members of the Snail family of transcription factors have been shown to induce epithelial-mesenchymal transition (EMT), a fundamental mechanism of embryogenesis and progressive disease. Here, we show that Snail and Slug promote formation of beta-catenin-T-cell factor (TCF)-4 transcription complexes that bind to the promoter of the TGF-beta3 gene to increase its transcription. Subsequent transforming growth factor (TGF)-beta3 signaling increases LEF-1 gene expression causing formation of beta-catenin-lymphoid enhancer factor (LEF)-1 complexes that initiate EMT. TGF-beta1 or TGF-beta2 stimulates this signaling mechanism by up-regulating synthesis of Snail and Slug. TGF-beta1- and TGF-beta2-induced EMT were found to be TGF-beta3 dependent, establishing essential roles for multiple TGF-beta isoforms. Finally, we determined that beta-catenin-LEF-1 complexes can promote EMT without upstream signaling pathways. These findings provide evidence for a unified signaling mechanism driven by convergence of multiple TGF-beta and TCF signaling molecules that confers loss of cell-cell adhesion and acquisition of the mesenchymal phenotype.

/pdf/snail-and-slug-promote-epithelial-mesenchymal-transition-adjdyrjvyh.pdf

Elizabeth D. Hay

Papers

An Overview of Epithelio-Mesenchymal Transformation

The mesenchymal cell, its role in the embryo, and the remarkable signaling mechanisms that create it

Epithelia suspended in collagen gels can lose polarity and express characteristics of migrating mesenchymal cells.

Snail and Slug Promote Epithelial-Mesenchymal Transition through β-Catenin–T-Cell Factor-4-dependent Expression of Transforming Growth Factor-β3

Cell contact during early morphogenesis in the chick embryo.