Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits

Key Points

  • Transitions between epithelial and mesenchymal states underlie epithelial cell plasticity and contribute to tumour progression and intratumoural heterogeneity.

  • The epithelial–mesenchymal transition (EMT) is triggered by a diverse set of stimuli including growth factor signalling, tumour–stromal cell interactions and hypoxia. There is a significant crosstalk among EMT-inducing signals and transcription factors that can lead to stable reprogramming of epithelial cells to mesenchymal states.

  • EMT has been shown to result in cancer cells with stem cell-like characteristics that have a propensity to invade surrounding tissue and display resistance to certain therapeutic interventions.

  • The mesenchymal–epithelial transition (MET) may have a role in the reversion of disseminated mesenchymal tumour cells to a more epithelial state in distant metastases.

  • microRNAs have been identified as a new class of EMT regulators, in part owing to their regulation of EMT-inducing transcription factors.

Abstract

Transitions between epithelial and mesenchymal states have crucial roles in embryonic development. Emerging data suggest a role for these processes in regulating cellular plasticity in normal adult tissues and in tumours, where they can generate multiple, distinct cellular subpopulations contributing to intratumoural heterogeneity. Some of these subpopulations may exhibit more differentiated features, whereas others have characteristics of stem cells. Owing to the importance of these tumour-associated phenotypes in metastasis and cancer-related mortality, targeting the products of such cellular plasticity is an attractive but challenging approach that is likely to lead to improved clinical management of cancer patients.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: A simplified overview of signalling networks regulating epithelial–mesenchymal transitions (EMTs).
Figure 2: Transitions between epithelial and mesenchymal states during carcinoma progression.

Similar content being viewed by others

References

  1. Baum, B., Settleman, J. & Quinlan, M. P. Transitions between epithelial and mesenchymal states in development and disease. Semin. Cell Dev. Biol. 19, 294–308 (2008).

    CAS  PubMed  Google Scholar 

  2. Hugo, H. et al. Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J. Cell Physiol. 213, 374–383 (2007).

    CAS  PubMed  Google Scholar 

  3. Thiery, J. P. & Sleeman, J. P. Complex networks orchestrate epithelial–mesenchymal transitions. Nature Rev. Mol. Cell Biol. 7, 131–142 (2006).

    CAS  Google Scholar 

  4. Yang, J. & Weinberg, R. A. Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Dev. Cell 14, 818–829 (2008).

    CAS  PubMed  Google Scholar 

  5. Mani, S. A. et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008). This manuscript is the first demonstration that EMT leads to the generation of breast cancer cells with stem cell-like characteristics.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Morel, A. P. et al. Generation of breast cancer stem cells through epithelial–mesenchymal transition. PLoS ONE 3, e2888 (2008).

    PubMed  PubMed Central  Google Scholar 

  7. Sabbah, M. et al. Molecular signature and therapeutic perspective of the epithelial-to-mesenchymal transitions in epithelial cancers. Drug Resist. Updat. 11, 123–151 (2008).

    CAS  PubMed  Google Scholar 

  8. Peinado, H., Olmeda, D. & Cano, A. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nature Rev. Cancer 7, 415–428 (2007).

    CAS  Google Scholar 

  9. Dumont, N. et al. Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers. Proc. Natl Acad. Sci. USA 105, 14867–14872 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Massague, J. TGFβ in cancer. Cell 134, 215–230 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. James, D., Levine, A. J., Besser, D. & Hemmati-Brivanlou, A. TGFβ/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development 132, 1273–1282 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Ozdamar, B. et al. Regulation of the polarity protein Par6 by TGFβ receptors controls epithelial cell plasticity. Science 307, 1603–1609 (2005).

    CAS  PubMed  Google Scholar 

  13. Vincan, E. & Barker, N. The upstream components of the Wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progression. Clin. Exp. Metastasis 25, 657–663 (2008).

    CAS  PubMed  Google Scholar 

  14. Vogelstein, B. & Kinzler, K. W. Cancer genes and the pathways they control. Nature Med. 10, 789–799 (2004).

    CAS  PubMed  Google Scholar 

  15. Lombaerts, M. et al. E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. Br. J. Cancer 94, 661–671 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Onder, T. T. et al. Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Res. 68, 3645–3654 (2008).

    CAS  PubMed  Google Scholar 

  17. Zhang, W. et al. Epigenetic inactivation of the canonical Wnt antagonist SRY-box containing gene 17 in colorectal cancer. Cancer Res. 68, 2764–2772 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Suzuki, H. et al. Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer. Nature Genet. 36, 417–422 (2004).

    CAS  PubMed  Google Scholar 

  19. Caldwell, G. M. et al. The Wnt antagonist sFRP1 in colorectal tumorigenesis. Cancer Res. 64, 883–888 (2004).

    CAS  PubMed  Google Scholar 

  20. Aguilera, O. et al. Epigenetic inactivation of the Wnt antagonist DICKKOPF-1 (DKK-1) gene in human colorectal cancer. Oncogene 25, 4116–4121 (2006).

    CAS  PubMed  Google Scholar 

  21. Bailey, J. M., Singh, P. K. & Hollingsworth, M. A. Cancer metastasis facilitated by developmental pathways: Sonic hedgehog, Notch, and bone morphogenic proteins. J. Cell Biochem. 102, 829–839 (2007).

    CAS  PubMed  Google Scholar 

  22. Wang, Z. et al. Down-regulation of notch-1 inhibits invasion by inactivation of nuclear factor-kappaB, vascular endothelial growth factor, and matrix metalloproteinase-9 in pancreatic cancer cells. Cancer Res. 66, 2778–2784 (2006).

    CAS  PubMed  Google Scholar 

  23. Gort, E. H., Groot, A. J., van der Wall, E., van Diest, P. J. & Vooijs, M. A. Hypoxic regulation of metastasis via hypoxia-inducible factors. Curr. Mol. Med. 8, 60–67 (2008).

    CAS  PubMed  Google Scholar 

  24. Cannito, S. et al. Redox mechanisms switch on hypoxia-dependent epithelial–mesenchymal transition in cancer cells. Carcinogenesis 29, 2267–2278 (2008).

    CAS  PubMed  Google Scholar 

  25. Sahlgren, C., Gustafsson, M. V., Jin, S., Poellinger, L. & Lendahl, U. Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc. Natl Acad. Sci. USA 105, 6392–6397 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Radisky, D. C. et al. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436, 123–127 (2005). This study is the first to establish a link between EMT and reactive oxygen species generation and subsequent genomic instability.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Brabletz, T. et al. Variable β-catenin expression in colorectal cancers indicates tumor progression driven by the tumor environment. Proc. Natl Acad. Sci. USA 98, 10356–10361 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Franci, C. et al. Expression of Snail protein in tumor–stroma interface. Oncogene 25, 5134–5144 (2006). This is the first report describing EMT in physiological in vivo conditions in tumours.

    CAS  PubMed  Google Scholar 

  29. Sheehan, K. M. et al. Signal pathway profiling of epithelial and stromal compartments of colonic carcinoma reveals epithelial–mesenchymal transition. Oncogene 27, 323–331 (2008).

    CAS  PubMed  Google Scholar 

  30. Yates, C. C., Shepard, C. R., Stolz, D. B. & Wells, A. Co-culturing human prostate carcinoma cells with hepatocytes leads to increased expression of E-cadherin. Br. J. Cancer 96, 1246–1252 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Frisch, S. M. The epithelial cell default-phenotype hypothesis and its implications for cancer. Bioessays 19, 705–709 (1997).

    CAS  PubMed  Google Scholar 

  32. Chaffer, C. L., Thompson, E. W. & Williams, E. D. Mesenchymal to epithelial transition in development and disease. Cells Tissues Organs 185, 7–19 (2007).

    PubMed  Google Scholar 

  33. Bloushtain-Qimron, N. et al. Cell type-specific DNA methylation patterns in the human breast. Proc. Natl Acad. Sci. USA 105, 14076–14081 (2008). The first comprehensive characterization of cell type-specific DNA methylation patterns of normal breast progenitor cells and identification of epigenetically regulated transcription factors, including FOXC1, as regulators of stem cell properties.

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Shipitsin, M. et al. Molecular definition of breast tumor heterogeneity. Cancer Cell 11, 259–273 (2007). This study is the first comprehensive molecular characterization of CD44+CD24 breast cancer cells and identification of the TGFβ signalling pathway as a candidate regulator of their stem cell-like phenotype.

    CAS  PubMed  Google Scholar 

  35. Dunbier, A. & Guilford, P. Hereditary diffuse gastric cancer. Adv. Cancer Res. 83, 55–65 (2001).

    CAS  PubMed  Google Scholar 

  36. Schrader, K. A. et al. Hereditary diffuse gastric cancer: association with lobular breast cancer. Fam. Cancer 7, 73–82 (2008).

    PubMed  Google Scholar 

  37. Berx, G. et al. E-cadherin is inactivated in a majority of invasive human lobular breast cancers by truncation mutations throughout its extracellular domain. Oncogene 13, 1919–1925 (1996).

    CAS  PubMed  Google Scholar 

  38. Ateeq, B., Unterberger, A., Szyf, M. & Rabbani, S. A. Pharmacological inhibition of DNA methylation induces proinvasive and prometastatic genes in vitro and in vivo. Neoplasia 10, 266–278 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Guo, Y. et al. Regulation of DNA methylation in human breast cancer. Effect on the urokinase-type plasminogen activator gene production and tumor invasion. J. Biol. Chem. 277, 41571–41579 (2002).

    CAS  PubMed  Google Scholar 

  40. Moreno-Bueno, G., Portillo, F. & Cano, A. Transcriptional regulation of cell polarity in EMT and cancer. Oncogene 27, 6958–6969 (2008).

    CAS  PubMed  Google Scholar 

  41. Ansieau, S. et al. Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell 14, 79–89 (2008). An important study demonstrating a dual role for EMT-inducing transcription factors in tumorigenesis and senescence.

    CAS  PubMed  Google Scholar 

  42. Perez-Losada, J. et al. Zinc-finger transcription factor Slug contributes to the function of the stem cell factor c-kit signaling pathway. Blood 100, 1274–1286 (2002).

    CAS  PubMed  Google Scholar 

  43. Sanchez-Martin, M. et al. SLUG (SNAI2) deletions in patients with Waardenburg disease. Hum. Mol. Genet. 11, 3231–3236 (2002).

    CAS  PubMed  Google Scholar 

  44. Gregory, P. A. et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nature Cell Biol. 10, 593–601 (2008).

    CAS  PubMed  Google Scholar 

  45. Gregory, P. A., Bracken, C. P., Bert, A. G. & Goodall, G. J. MicroRNAs as regulators of epithelial–mesenchymal transition. Cell Cycle 7, 3112–3118 (2008).

    CAS  PubMed  Google Scholar 

  46. Park, S. M., Gaur, A. B., Lengyel, E. & Peter, M. E. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 22, 894–907 (2008). An important study describing the regulation of EMT-inducing transcription factors by miRNAs.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Beltran, M. et al. A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial–mesenchymal transition. Genes Dev. 22, 756–769 (2008). An interesting study identifying a novel mechanism for the regulation of EMT through the expression of a natural antisense RNA suppressing ZEB2 expression.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Cano, A. & Nieto, M. A. Non-coding RNAs take centre stage in epithelial-to-mesenchymal transition. Trends Cell Biol. 18, 357–359 (2008).

    CAS  PubMed  Google Scholar 

  49. Ma, L., Teruya-Feldstein, J. & Weinberg, R. A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature 449, 682–688 (2007). The first study demonstrating a role for miRNAs in breast cancer metastasis.

    CAS  PubMed  Google Scholar 

  50. Tavazoie, S. F. et al. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451, 147–152 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Liu, R. et al. The prognostic role of a gene signature from tumorigenic breast-cancer cells. N. Engl. J. Med. 356, 217–226 (2007).

    CAS  PubMed  Google Scholar 

  52. Sheridan, C. et al. CD44+, CD24 breast cancer cells exhibit enhanced invasive properties: an early step necessary for metastasis. Breast Cancer Res. 8, R59 (2006).

    PubMed  PubMed Central  Google Scholar 

  53. Graff, J. R., Gabrielson, E., Fujii, H., Baylin, S. B. & Herman, J. G. Methylation patterns of the E-cadherin 5′ CpG island are unstable and reflect the dynamic, heterogeneous loss of E-cadherin expression during metastatic progression. J. Biol. Chem. 275, 2727–2732 (2000).

    CAS  PubMed  Google Scholar 

  54. Nass, S. J. et al. Aberrant methylation of the estrogen receptor and E-cadherin 5′ CpG islands increases with malignant progression in human breast cancer. Cancer Res. 60, 4346–4348 (2000).

    CAS  PubMed  Google Scholar 

  55. Riethdorf, S. & Pantel, K. Disseminated tumor cells in bone marrow and circulating tumor cells in blood of breast cancer patients: current state of detection and characterization. Pathobiology 75, 140–148 (2008).

    PubMed  Google Scholar 

  56. Riethdorf, S., Wikman, H. & Pantel, K. Biological relevance of disseminated tumor cells in cancer patients. Int. J. Cancer 123, 1991–2006 (2008).

    CAS  PubMed  Google Scholar 

  57. Slade, M. J. et al. Comparison of bone marrow, disseminated tumour cells and blood-circulating tumour cells in breast cancer patients after primary treatment. Br. J. Cancer 100, 160–166 (2008).

    PubMed  PubMed Central  Google Scholar 

  58. Sarrio, D. et al. Epithelial–mesenchymal transition in breast cancer relates to the basal-like phenotype. Cancer Res. 68, 989–997 (2008).

    CAS  PubMed  Google Scholar 

  59. Mani, S. A. et al. Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proc. Natl Acad. Sci. USA 104, 10069–10074 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  60. Perou, C. M. et al. Molecular portraits of human breast tumours. Nature 406, 747–752 (2000).

    CAS  PubMed  Google Scholar 

  61. Sorlie, T. et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc. Natl Acad. Sci. USA 98, 10869–10874 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Honeth, G. et al. The CD44+/CD24 phenotype is enriched in basal-like breast tumors. Breast Cancer Res. 10, R53 (2008).

    PubMed  PubMed Central  Google Scholar 

  63. Yu, F. et al. let-7 regulates self renewal and tumorigenicity of breast cancer cells. Cell 131, 1109–1123 (2007).

    CAS  PubMed  Google Scholar 

  64. Li, X. et al. Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. J. Natl Cancer Inst. 100, 672–679 (2008).

    CAS  PubMed  Google Scholar 

  65. Barr, S. et al. Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions. Clin. Exp. Metastasis 25, 685–693 (2008).

    PubMed  PubMed Central  Google Scholar 

  66. Robson, E. J., Khaled, W. T., Abell, K. & Watson, C. J. Epithelial-to-mesenchymal transition confers resistance to apoptosis in three murine mammary epithelial cell lines. Differentiation 74, 254–264 (2006).

    CAS  PubMed  Google Scholar 

  67. Muerkoster, S. S. et al. Role of myofibroblasts in innate chemoresistance of pancreatic carcinoma — epigenetic downregulation of caspases. Int. J. Cancer 123, 1751–1760 (2008).

    PubMed  Google Scholar 

  68. Bertout, J. A., Patel, S. A. & Simon, M. C. The impact of O2 availability on human cancer. Nature Rev. Cancer 8, 967–975 (2008).

    CAS  Google Scholar 

  69. Husemann, Y. et al. Systemic spread is an early step in breast cancer. Cancer Cell 13, 58–68 (2008).

    PubMed  Google Scholar 

  70. Norton, L. & Massague, J. Is cancer a disease of self-seeding? Nature Med. 12, 875–878 (2006).

    CAS  PubMed  Google Scholar 

  71. Jones, P. A. & Takai, D. The role of DNA methylation in mammalian epigenetics. Science 293, 1068–1070 (2001).

    CAS  PubMed  Google Scholar 

  72. Feinberg, A. P. & Tycko, B. The history of cancer epigenetics. Nature Rev. Cancer 4, 143–153 (2004).

    CAS  Google Scholar 

  73. Herman, J. G. & Baylin, S. B. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med. 349, 2042–2054 (2003).

    CAS  PubMed  Google Scholar 

  74. Futscher, B. W. et al. Role for DNA methylation in the control of cell type specific maspin expression. Nature Genet. 31, 175–179 (2002).

    CAS  PubMed  Google Scholar 

  75. Feinberg, A. P., Ohlsson, R. & Henikoff, S. The epigenetic progenitor origin of human cancer. Nature Rev. Genet. 7, 21–33 (2006).

    CAS  PubMed  Google Scholar 

  76. Baylin, S. B. & Ohm, J. E. Epigenetic gene silencing in cancer-mechanims for early oncogenic pathway addiction? Nature Rev. Cancer 6, 107–116 (2006).

    CAS  Google Scholar 

  77. Holm, T. M. et al. Global loss of imprinting leads to widespread tumorigenesis in adult mice. Cancer Cell 8, 275–285 (2005).

    CAS  PubMed  Google Scholar 

  78. Plass, C. Cancer epigenomics. Hum. Mol. Genet. 11, 2479–2488 (2002).

    CAS  PubMed  Google Scholar 

  79. Kouzarides, T. Chromatin modifications and their function. Cell 128, 693–705 (2007).

    CAS  PubMed  Google Scholar 

  80. Stefani, G. & Slack, F. J. Small non-coding RNAs in animal development. Nature Rev. Mol. Cell Biol. 9, 219–230 (2008).

    CAS  Google Scholar 

  81. Filipowicz, W., Bhattacharyya, S. N. & Sonenberg, N. Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nature Rev. Genet. 9, 102–114 (2008).

    CAS  PubMed  Google Scholar 

  82. Garzon, R., Fabbri, M., Cimmino, A., Calin, G. A. & Croce, C. M. MicroRNA expression and function in cancer. Trends Mol. Med. 12, 580–587 (2006).

    CAS  PubMed  Google Scholar 

  83. Come, C. et al. Snail and slug play distinct roles during breast carcinoma progression. Clin. Cancer Res. 12, 5395–5402 (2006).

    CAS  PubMed  Google Scholar 

  84. Aigner, K. et al. The transcription factor ZEB1 (deltaEF1) represses Plakophilin 3 during human cancer progression. FEBS Lett. 581, 1617–1624 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Zhou, B. P. et al. Dual regulation of Snail by GSK-3β-mediated phosphorylation in control of epithelial–mesenchymal transition. Nature Cell Biol. 6, 931–940 (2004).

    CAS  PubMed  Google Scholar 

  86. Martin, T. A., Goyal, A., Watkins, G. & Jiang, W. G. Expression of the transcription factors snail, slug, and twist and their clinical significance in human breast cancer. Ann. Surg. Oncol. 12, 488–496 (2005).

    PubMed  Google Scholar 

  87. Elloul, S. et al. Snail, Slug, and Smad-interacting protein 1 as novel parameters of disease aggressiveness in metastatic ovarian and breast carcinoma. Cancer 103, 1631–1643 (2005).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank members of our laboratories for their critical reading of this manuscript and useful discussions. Research related to EMT in our laboratories is supported by National Institute of Health P50 CA89393 and PO1 CA80111 (K.P. and R.A.W.), U54 CA 126515 (R.A.W.), DoD Breast Cancer Research Program W81XWH-07-1-0294 (K.P.) and BC073843 (R.A.W.), American Cancer Society RSG-05-154-01-MGO (K.P.), Breast Cancer Research Foundation (K.P. and R.A.W.), Ludwig Fund for Cancer Research (R.A.W.), and the Advanced Medical Research Foundation (R.A.W.). R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Cancer Research Professor.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kornelia Polyak.

Ethics declarations

Competing interests

Kornelia Polyak receives research funding and is a consultant to Novartis

Related links

Related links

DATABASES

National Cancer Institute Drug Dictionary

5-aza-cytidine

lapatinib

FURTHER INFORMATION

Kornelia Polyak's homepage

Rights and permissions

Reprints and permissions

About this article

Cite this article

Polyak, K., Weinberg, R. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer 9, 265–273 (2009). https://doi.org/10.1038/nrc2620

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrc2620

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing