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EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness

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Abstract

Cancer is a complex multistep process involving genetic and epigenetic changes that eventually result in the activation of oncogenic pathways and/or inactivation of tumor suppressor signals. During cancer progression, cancer cells acquire a number of hallmarks that promote tumor growth and invasion. A crucial mechanism by which carcinoma cells enhance their invasive capacity is the dissolution of intercellular adhesions and the acquisition of a more motile mesenchymal phenotype as part of an epithelial-to-mesenchymal transition (EMT). Although many transcription factors can trigger it, the full molecular reprogramming occurring during an EMT is mainly orchestrated by three major groups of transcription factors: the ZEB, Snail and Twist families. Upregulated expression of these EMT-activating transcription factors (EMT-ATFs) promotes tumor invasiveness in cell lines and xenograft mice models and has been associated with poor clinical prognosis in human cancers. Evidence accumulated in the last few years indicates that EMT-ATFs also regulate an expanding set of cancer cell capabilities beyond tumor invasion. Thus, EMT-ATFs have been shown to cooperate in oncogenic transformation, regulate cancer cell stemness, override safeguard programs against cancer like apoptosis and senescence, determine resistance to chemotherapy and promote tumor angiogenesis. This article reviews the expanding portfolio of functions played by EMT-ATFs in cancer progression.

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Abbreviations

bHLH:

Basic helix loop helix

CSC:

Cancer stem cells

EMT:

Epithelial-to-mesenchymal transition

EMT-ATF:

EMT-activating transcription factors

HNSCC:

Head and neck squamous cell carcinoma

MET:

Mesenchymal-to-epithelial transition

NSCLC:

Non-small cell lung carcinoma

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Acknowledgments

We apologize to those researchers whose relevant work was cited only indirectly through reviews because of space limitations. Experimental work was conducted by E.S.T., Y.L., O.d.B., L.S. and L.F.. M.C. and A.C. identified tissue samples and/or advised in the interpretation of immunostaining. A.P. wrote the article and all authors contributed to its critical revision. Comments on the manuscript by E.C. Vaquero are also greatly appreciated. Tissue samples for Fig. 4 were obtained from IDIBAPS’ Tumor Bank. Work in A.P.’s laboratory was funded by grants from Olga Torres Foundation, AVON Cosmetics SAU, Spanish Association Against Cancer (AECC), Spanish Ministry of Economy and Competitiveness (formerly of Science and Innovation, BFU2007-60302, BFU2010-15163), La Caixa Foundation, and the European Commission. E.S.T.’s salary is funded by CIBERehd. O.d.B. and L.S. are recipients of PhD scholarships from the Spanish Ministry of Education, Culture and Sports (FPU Program). L.S.’s salary was previously funded by AECC.

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Authors and Affiliations

  1. Group of Transcriptional Regulation of Gene Expression, Department of Oncology and Hematology, IDIBAPS, 08036, Barcelona, Spain

    Ester Sánchez-Tilló, Oriol de Barrios, Laura Siles, Lucia Fanlo & Antonio Postigo

  2. CIBERehd (Gastrointestinal and Pancreatic Oncology), IDIBAPS, 08036, Barcelona, Spain

    Ester Sánchez-Tilló, Antoni Castells & Antonio Postigo

  3. James Graham Brown Cancer Center, Louisville Health Science Center, Louisville, KY, 40202, USA

    Yongqing Liu, Douglas C. Dean & Antonio Postigo

  4. Department of Ophthalmology and Birth Defects Center, Louisville Health Science Center, Louisville, KY, 40202, USA

    Yongqing Liu & Douglas C. Dean

  5. Master Program in Biomedical Research, University Pompeu Fabra, 08003, Barcelona, Spain

    Lucia Fanlo

  6. Department of Pathology, Hospital Clinic and IDIBAPS’ Tumor Bank, 08036, Barcelona, Spain

    Miriam Cuatrecasas

  7. Department of Oral Health and Rehabilitation, Center for Genetics and Molecular Medicine, University of Louisville, Louisville, KY, 40202, USA

    Douglas S. Darling

  8. Institute of Digestive and Metabolic Diseases, Hospital Clinic, 08036, Barcelona, Spain

    Antoni Castells

  9. ICREA, 08010, Barcelona, Spain

    Antonio Postigo

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  1. Ester Sánchez-Tilló
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  2. Yongqing Liu
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  3. Oriol de Barrios
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  4. Laura Siles
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  9. Antoni Castells
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  10. Antonio Postigo
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Corresponding author

Correspondence to Antonio Postigo.

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E. Sánchez-Tilló, Y. Liu, O. de Barrios and L. Siles contributed equally.

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Sánchez-Tilló, E., Liu, Y., de Barrios, O. et al. EMT-activating transcription factors in cancer: beyond EMT and tumor invasiveness. Cell. Mol. Life Sci. 69, 3429–3456 (2012). https://doi.org/10.1007/s00018-012-1122-2

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  • DOI: https://doi.org/10.1007/s00018-012-1122-2

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