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Epithelial–mesenchymal transitions in tumour progression

Key Points

  • Epithelial–mesenchymal transition (EMT) is a highly conserved and fundamental process that governs morphogenesis in multicellular organisms.

  • There is good evidence that EMT gives rise to the dissemination of single carcinoma cells from the sites of the primary tumours. More generally, EMT might be involved in the dedifferentiation programme that leads to malignant carcinoma.

  • Recent research conducted in embryonic model systems and in normal and transformed cell lines has identified several signal-transduction pathways for EMT, including the activation of several receptor tyrosine kinases and transforming growth factor-β receptors.

  • Transcriptional repressors of the E-cadherin gene are activated downstream in these pathways, leading to the loss of the epithelial phenotype.

  • Other effectors of the EMT can modulate other adhesion systems and trigger the remodelling of the actin cytoskeleton, leading to the mesenchymal phenotype and the scattering of carcinoma cells.

  • Potential drug targets of EMT in carcinoma are now in development: inhibitors of receptor tyrosine kinases are in Phase III clinical trials. These drugs might have a considerable impact on the long-term survival of people diagnosed with cancer.

Abstract

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.

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Figure 1: Matthias Duval's 1879 drawing of a transverse section of a 2-day-old chick embryo at the head level.
Figure 2: Sites of EMT and MET in the emergence and progression of carcinoma.
Figure 3: Signalling mechanisms in EMT of the NBT-II cell line and in mouse gastrulation.
Figure 4: Dual functions of TGF-β in the emergence and progression of carcinomas.

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Acknowledgements

The author is indebted to J.-M. Coindre, X. Sastre and A. Vincent-Salomon for their help with the anatomopathology of tumours. Many colleagues (not all cited in this review) should be thanked for their significant contribution to this field.

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FURTHER INFORMATION

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MET

Glossary

EPITHELIUM

Assembly of polarized cells with defined apical and basolateral domains.

METAZOANS

Multicellular organisms that acquire their morphology during successive embryonic developmental stages.

PRIMITIVE STREAK

The site of invagination of the mesoderm and definitive endoderm cells during gastrulation. It appears as an elongating pit in the epithelial layer of the blastula embryo in reptiles, birds and mammals.

ADHERENS JUNCTION

A specialized junction that connects epithelial cells. It is characterized by the presence of E-cadherin clusters that are linked to actin microfilaments.

DESMOSOME

A specialized junction between two epithelial cells, characterized by an electron-dense line in the intercellular space and dense plaques lining the adhesive sites. Desmosomal cadherin, the main adhesive component, is indirectly linked to cytokeratin intermediate filaments.

PARIETAL ENDODERM

An epithelial layer that covers the trophectoderm that is formed by cells connected to the visceral endoderm. The parietal endoderm lines the blastocoel cavity of a blastula-stage mammalian embryo.

E2 BOX

Consensus DNA sequence for class I basic domain helix–loop–helix transcription factors of the E2A and E2B family. It is also recognized by the four-zinc-finger-containing transcription factor Snail.

ZINC FINGER

Protein module in which conserved cysteine or histidine residues coordinate a zinc atom. Some zinc-finger regions bind specific DNA sequences; others are involved in protein–protein interactions.

VENTRAL FURROW

An invagination that appears in the ventral side of a Drosophila gastrula. Internalized epithelial cells convert into migratory mesenchymal cells before differentiating in mesoderm derivatives such as muscles.

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Thiery, J. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer 2, 442–454 (2002). https://doi.org/10.1038/nrc822

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