Epithelial–mesenchymal transitions in development and pathologies

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Abstract

The epithelial–mesenchymal transition (EMT) is a fundamental process governing morphogenesis in multicellular organisms. This process is also reactivated in a variety of diseases including fibrosis and in the progression of carcinoma. The molecular mechanisms of EMT were primarily studied in epithelial cell lines, leading to the discovery of transduction pathways involved in the loss of epithelial cell polarity and the acquisition of a variety of mesenchymal phenotypic traits. Similar mechanisms have also been uncovered in vivo in different species, showing that EMT is controlled by remarkably well-conserved mechanisms. Current studies further emphasise the critical importance of EMT and provide a better molecular and functional definition of mesenchymal cells and how they emerged >500 million years ago as a key event in evolution.

Section snippets

Introduction: how to define epithelial–mesenchymal transitions

Originally an epithelial–mesenchymal transition (EMT) was defined by the formation of mesenchymal cells from epithelia in different embryonic territories, although the delamination process was more precisely described in vitro in epithelial tissue explants grown in 3D collagen gels. Embryonic mesenchymal cells are formed following the loss of epithelial cell polarity, which occurs as a result of the disappearance of differentiated junctions, the reorganisation of the cytoskeleton and the

Molecular mechanisms of EMT

The original discovery by Michael Stoker and Michael Perryman in 1985 [2] that a fibroblast culture supernatant contains a scatter activity for epithelial Madin-Darby canine kidney (MDCK) cells have prompted major studies in the field of EMT. By the early 1990s, the scatter factor was found to be the hepatocyte growth factor, the ligand of the c-met receptor. Several other growth factors recognising tyrosine kinase surface receptors are now known to induce EMT in epithelial cell lines.

Tyrosine kinase surface-receptor-associated pathways

The canonical Ras pathway has been shown to be of crucial importance in EMT by both in vitro and in vivo studies. However, several distinct pathways downstream of Ras may be required to obtain a complete EMT. The activation of MEK and Rac was found to induce EMT in a bladder carcinoma line even though PI3K was not required for scattering [3]. In other studies using EpH4 mammary epithelial cells in vitro and in nude mice, EMT was found to be dependent on activation of the mitogen-activated

TGFβ signalling pathways

TGFβ is a potent inducer of EMT in co-operation with the Ras pathway. Murine mammary epithelial cells can undergo a complete EMT only if the Ras pathway is constitutively activated. A TGFβ autocrine loop becomes progressively operational in these cells when grafted in nude mice [4]. A significant increase in TGFβ and in mutated H-Ras was found during the progression to the spindle carcinoma stage in a comparative analysis of different clones derived from a chemically induced squamous carcinoma

Small GTPases

High expression of RhoA can control the disruption of adherens junctions in normal and malignant epithelial cells. This mechanism implicates ROCK (rho-associated kinase) activation, which can also be induced by normal levels of RhoC. However, normal levels of RhoA favor the diaphanous pathway, which enhances the formation of cadherin–catenin complexes and their connection to actin filaments [15].

Rho GTPases can also activate several transcription factors such as serum response factor (SRF) and

Transcriptional regulation

The demonstration that several zinc-finger transcriptional repressors can control E-cadherin expression in epithelial cells has provided a new avenue of research in the field of EMT. Snail or Slug, a closely related member of the Snail superfamily, control gastrulation and neural-crest EMT in different species. In mouse gastrulation, Snail is clearly placed in the FGFR1 (fibroblast growth factor receptor 1) pathway downstream of MAP kinase, which is similar to what is observed in vitro in

EMT in development and diseases

The extensive analysis of EMT in development should provide much better insights into the molecular mechanisms governing EMT. The recent exploration of the gene network controlling the ontogeny of the primitive mesenchyme cell lineage has shown that the β-catenin/LEF (lymphoid enhancer factor) signalling pathway induces ALX1, a paired class homeodomain protein. ALX1 in turn controls the co-ordinated expression of effector genes involved in ingression of the primary mesenchyme and of those

Progression of carcinoma

Epithelial cell plasticity and dedifferentiation is a landmark of carcinoma progression during the invasive and metastatic phases. An EMT process is difficult to discern in progressing carcinoma, however, although there is renewed hope with the development of new in vivo imaging techniques [35]. There is however plenty of indirect evidence that EMT occurs at certain sites in primary tumours [1]. One of the best-documented cases of the formation of individualised cells from a carcinoma

Conclusions and future prospects

EMT and MET involve distinct signalling pathways whose co-operation results in complex networks that are dependent upon cell type (see Figure 1). The regulation of E-cadherin by membrane internalisation or by gene suppression also illustrates the need to know more about the temporal relationships within these networks. Numerous initiatives to improve our understanding of these networks have been launched in different laboratories that aim to describe the interactome and gene-expression profiles

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • of special interest

  • ••

    of outstanding interest

Acknowledgements

I would like to thank Matthew Morgan for helpful discussions and critical reading of the manuscript.

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