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Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?

Key Points

  • Local tumour invasion represents the first step of the metastatic cascade of carcinomas, and requires profound changes in the cell adhesion and migration properties of tumour cells that are reminiscent of developmental epithelial–mesenchymal transition (EMT). EMT is thought to be a dynamic and transient process, and as such is a manifestation of epithelial cell plasticity during tumour progression.

  • The loss of functional E-cadherin is a hallmark of EMT and carcinoma cell invasiveness. Transcriptional repression mediated by factors from the Snail (SNAI1 and SNAI2), Zeb (ZEB1 and ZEB2) and basic helix-loop-helix (bHLH: E47 and TWIST) families is a basic mechanism for the dynamic silencing of CDH1 (the gene that encodes E-cadherin).

  • Post-transcriptional modifications are emerging as a meaningful additional level of regulation of various repressors. The protein stability, nuclear localization and functional activity of SNAI1 seem to be controlled by a delicate balance between phosphorylation, zinc transporter proteins and interaction with lysyl-oxidase-like proteins.

  • Besides CDH1, additional direct and indirect target genes of Snail, ZEB and bHLH factors are being described that encode proteins involved in EMT as well as in cell proliferation, cell survival or angiogenesis, indicating that these factors have additional functions beyond the repression of CDH1 and the induction of EMT.

  • Snail and bHLH factors have recently been implicated in cell-survival and acquired resistance to genotoxic agents by cancer cells, providing new insights into the biological properties conferred by these factors, with potential clinical implications.

  • The expression patterns of Snail, ZEB and bHLH factors in different human carcinomas, together with functional studies, indicate that the various factors have different roles during tumour progression, with a more prominent role for SNAI1 in the induction of EMT in primary tumours, whereas the other factors are involved in maintaining the migratory phenotype.

  • Complex signalling networks from the tumour microenvironment, including hypoxia and transforming growth factor β (TGFβ), can coordinate the expression and/or function of Snail, ZEB and bHLH factors, and promote their interplay in orchestrating CDH1 repression and malignant tumour migration.

Abstract

The molecular mechanisms that underlie tumour progression are still poorly understood, but recently our knowledge of particular aspects of some of these processes has increased. Specifically, the identification of Snail, ZEB and some basic helix-loop-helix (bHLH) factors as inducers of epithelial–mesenchymal transition (EMT) and potent repressors of E-cadherin expression has opened new avenues of research with potential clinical implications.

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Figure 1: EMT as a dynamic process and a manifestation of epithelial plasticity.
Figure 2: Signalling pathways and repressor mechanisms implicated in the regulation and function of Snail, bHLH and ZEB factors.
Figure 3: Post-transcriptional regulatory mechanisms of Snail, bHLH and ZEB factors.
Figure 4: Interplay of different factors in cancer.

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Acknowledgements

The authors wish to thank F. Portillo, G. Moreno-Bueno, E. Cubillo and all the members of AC's laboratory for their critical feedback and thoughtful suggestions. We apologize to those investigators whose experimental work has not been cited or cited indirectly owing to space limitations. Experimental work at AC's laboratory was supported by grants from the Ministerio de Educación y Ciencia (MEC) and the European Union. HP and DO are supported by postdoctoral contracts from the Fundación Científica de la Asociación Española Contra el Cáncer and MEC, respectively.

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Glossary

Tumour invasion

Inasive tumour cells are able to dissociate and emigrate from primary tumours into adjacent tissues.

Epithelial–mesenchymal transition

The cellular and molecular processes by which epithelial cells lose cell–cell interactions and apico-basal polarity at the same time as acquiring mesenchymal and migratory properties. EMT has a fundamental role in specific developmental stages under strict spatio-temporal regulation.

Intravasation

The process by which tumour cells penetrate the blood or lymphatic vessels, allowing their eventual dissemination to distant organs.

E-cadherin

The major calcium-dependent cell–cell adhesion molecule, functionally organized in cadherin–catenin complexes at adherens junctions and essential for the establishment of embryonic epithelium and the homeostasis of adult epithelial tissues. The functional loss of E-cadherin occurs in most carcinomas associated with a high tumour grade and invasiveness.

Epithelial cell plasticity

Progressive changes occurring in the gene-expression programmes that correspond with the diverse phenotypic manifestations that are seen as cells progress from an epithelial cell type to a complete mesenchymal phenotype and vice versa.

E-boxes

Recognition sequences for basic helix-loop-helix (bHLH) factors and other transcription factors like Snail and ZEB. They are formed by the consensus palindromic sequence CANNTG.

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Peinado, H., Olmeda, D. & Cano, A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype?. Nat Rev Cancer 7, 415–428 (2007). https://doi.org/10.1038/nrc2131

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