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  • Opinion
  • Published:

To differentiate or not — routes towards metastasis

Abstract

Why are many metastases differentiated? Invading and disseminating carcinoma cells can undergo an epithelial–mesenchymal transition (EMT), which is associated with a gain of stem cell-like behaviour. Therefore, EMT has been linked to the cancer stem cell concept. However, it is a matter of debate how subsequent mesenchymal–epithelial transition (MET) fits into the metastatic process and whether a MET is essential. In this Opinion article, I propose two principle types of metastatic progression: phenotypic plasticity involving transient EMT–MET processes and intrinsic genetic alterations keeping cells in an EMT and stemness state. This simplified classification integrates clinically relevant aspects of dormancy, metastatic tropism and therapy resistance, and implies perspectives on treatment strategies against metastasis.

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Figure 1: Examples of typical differentiated metastases.
Figure 2: The classification of metastasis in plasticity type I and genetic type II.
Figure 3: Two reciprocal feedback loops exert phenotypic plasticity.
Figure 4: Therapeutic strategies against metastasis.

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References

  1. Gupta, G. P. & Massague, J. Cancer metastasis: building a framework. Cell 127, 679–695 (2006).

    Article  CAS  PubMed  Google Scholar 

  2. Thiery, J. P., Acloque, H., Huang, R. Y. & Nieto, M. A. Epithelial-mesenchymal transitions in development and disease. Cell 139, 871–890 (2009).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Brabletz, T., Jung, A., Spaderna, S., Hlubek, F. & Kirchner, T. Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nature Rev. Cancer 5, 744–749 (2005).

    Article  CAS  Google Scholar 

  5. Mani, S. A. et al. The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell 133, 704–715 (2008).

    Article  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).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Visvader, J. E. & Lindeman, G. J. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nature Rev. Cancer 8, 755–768 (2008).

    Article  CAS  Google Scholar 

  8. Spremulli, E. N. & Dexter, D. L. Human tumor cell heterogeneity and metastasis. J. Clin. Oncol. 1, 496–509 (1983).

    Article  CAS  PubMed  Google Scholar 

  9. Chafai, N. et al. What factors influence survival in patients with unresected synchronous liver metastases after resection of colorectal cancer? Color. Dis. 7, 176–181 (2005).

    Article  CAS  Google Scholar 

  10. Stillwell, A., Ho, Y.-H. & Veitch, C. Systematic review of prognostic factors related to overall survival in patients with stage IV colorectal cancer and unresectable metastases. World J. Surg. 35, 684–692 (2011).

    Article  PubMed  Google Scholar 

  11. Chaffer, C. L. & Weinberg, R. A. A perspective on cancer cell metastasis. Science 331, 1559–1564 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Burk, U. et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 9, 582–589 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Christoffersen, N. R., Silahtaroglu, A., Orom, U. A., Kauppinen, S. & Lund, A. H. miR-200b mediates post-transcriptional repression of ZFHX1B. RNA 13, 1172–1178 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. 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).

    Article  CAS  PubMed  Google Scholar 

  15. Hurteau, G. J., Carlson, J. A., Spivack, S. D. & Brock, G. J. Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Res. 67, 7972–7976 (2007).

    Article  CAS  PubMed  Google Scholar 

  16. Korpal, M., Lee, E. S., Hu, G. & Kang, Y. The miR-200 family inhibits epithelial-mesenchymal transition and cancer cell migration by direct targeting of E-cadherin transcriptional repressors ZEB1 and ZEB2. J. Biol. Chem. 283, 14910–14914 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Shimono, Y. et al. Downregulation of miRNA-200c links breast cancer stem cells with normal stem cells. Cell 138, 592–603 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wellner, U. et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nature Cell Biol. 11, 1487–1495 (2009).

    Article  CAS  PubMed  Google Scholar 

  20. Iliopoulos, D. et al. Loss of miR-200 inhibition of Suz12 leads to polycomb-mediated repression required for the formation and maintenance of cancer stem cells. Mol. Cell 39, 761–772 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

  22. Vandewalle, C., Van Roy, F. & Berx, G. The role of the ZEB family of transcription factors in development and disease. Cell. Mol. Life Sci. 66, 773–787 (2009).

    Article  CAS  PubMed  Google Scholar 

  23. Brabletz, S. & Brabletz, T. The ZEB/miR-200 feedback loop--a motor of cellular plasticity in development and cancer? EMBO Rep. 11, 670–677 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bendoraite, A. et al. Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial-to-epithelial transition. Gynecol. Oncol. 116, 117–125 (2010).

    Article  CAS  PubMed  Google Scholar 

  25. Mees, S. T. et al. EP300--a miRNA-regulated metastasis suppressor gene in ductal adenocarcinomas of the pancreas. Int. J. Cancer 126, 114–124 (2009).

    Article  CAS  Google Scholar 

  26. Nam, E. J. et al. MicroRNA expression profiles in serous ovarian carcinoma. Clin. Cancer Res. 14, 2690–2695 (2008).

    Article  CAS  PubMed  Google Scholar 

  27. Snowdon, J., Zhang, X., Childs, T., Tron, V. A. & Feilotter, H. The MicroRNA-200 family is upregulated in endometrial carcinoma. PLoS ONE 6, e22828 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Korpal, M. et al. Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nature Med. 17, 1101–1108 (2011).

    Article  CAS  PubMed  Google Scholar 

  29. Arumugam, T. et al. Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Res. 69, 5820–5828 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Haddad, Y., Choi, W. & McConkey, D. J. Delta-crystallin enhancer binding factor 1 controls the epithelial to mesenchymal transition phenotype and resistance to the epidermal growth factor receptor inhibitor erlotinib in human head and neck squamous cell carcinoma lines. Clin. Cancer Res. 15, 532–542 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Shah, A. N. et al. Development and characterization of gemcitabine-resistant pancreatic tumor cells. Ann. Surg. Oncol. 14, 3629–3637 (2007).

    Article  PubMed  Google Scholar 

  32. Wang, Z. et al. Acquisition of epithelial-mesenchymal transition phenotype of gemcitabine-resistant pancreatic cancer cells is linked with activation of the notch signaling pathway. Cancer Res. 69, 2400–2407 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Adam, L. et al. miR-200 Expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clinical Cancer Res. 15, 5060–5072 (2009).

    Article  CAS  Google Scholar 

  34. Cochrane, D. R., Spoelstra, N. S., Howe, E. N., Nordeen, S. K. & Richer, J. K. MicroRNA-200c mitigates invasiveness and restores sensitivity to microtubule-targeting chemotherapeutic agents. Mol. Cancer Ther. 8, 1055–1066 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Schickel, R., Park, S. M., Murmann, A. E. & Peter, M. E. miR-200c regulates induction of apoptosis through CD95 by targeting FAP-1. Mol. Cell 38, 908–915 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Tryndyak, V. P., Frederick, A. B. & Igor, P. P. E-cadherin transcriptional down-regulation by epigenetic and microRNA-200 family alterations is related to mesenchymal and drug-resistant phenotypes in human breast cancer cells. Int. J. Cancer 126, 2575–2583 (2010).

    CAS  PubMed  Google Scholar 

  37. Kim, N. H. et al. A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. J. Cell Biol. 195, 417–433 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Siemens, H. et al. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle 10, 4256–4271 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Davalos, V. Dynamic epigenetic regulation of the microRNA-200 family mediates epithelial and mesenchymal transitions in human tumorigenesis. Oncogene 29 Aug 2011 (doi: 10.1038/onc).

  40. Vogt, M. et al. Frequent concomitant inactivation of miR-34aand miR-34b/c by CpG methylation in colorectal, pancreatic, mammary, ovarian, urothelial, and renal cell carcinomas and soft tissue sarcomas. Virchows Arch. 458, 313–322 (2011).

    Article  PubMed  Google Scholar 

  41. Chang, C.-J. et al. p53 regulates epithelial-mesenchymal transition and stem cell properties through modulating miRNAs. Nature Cell Biol. 13, 317–323 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Hermeking, H. The miR-34 family in cancer and apoptosis. Cell Death Differ. 17, 193–199 (2010).

    Article  CAS  PubMed  Google Scholar 

  43. Kim, T. et al. p53 regulates epithelial to mesenchymal transition through microRNAs targeting ZEB1 and ZEB2. J. Exp. Med. 208, 875–883 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yamakuchi, M. & Lowenstein, C. J. MiR-34, SIRT1 and p53: the feedback loop. Cell Cycle 8, 712–715 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Vousden, K. H. & Prives, C. Blinded by the light: the growing complexity of p53. Cell 137, 413–431 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Jung, A. et al. The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear β-catenin, cyclin D1, and p16INK4A and is a region of low proliferation. Am. J. Pathol. 159, 1613–1617 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Wassermann, S. et al. p16INK4a is a beta-catenin target gene and indicates low survival in human colorectal tumors. Gastroenterology 136, 196–205 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Alix-Panabieres, C., Riethdorf, S. & Pantel, K. Circulating tumor cells and bone marrow micrometastasis. Clin. Cancer Res. 14, 5013–5021 (2008).

    Article  CAS  PubMed  Google Scholar 

  49. Uhr, J. W. & Pantel, K. Controversies in clinical cancer dormancy. Proc. Nat. Acad. Sci. 108, 12396–12400 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  51. Postigo, A. A. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J. 22, 2443–2452 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Vega, S. et al. Snail blocks the cell cycle and confers resistance to cell death. Genes Dev. 18, 1131–1143 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Park, J. H. et al. The zinc-finger transcription factor Snail downregulates proliferating cell nuclear antigen expression in colorectal carcinoma cells. Int. J. Oncol. 26, 1541–1547 (2005).

    CAS  PubMed  Google Scholar 

  54. Mejlvang, J. et al. Direct repression of cyclin D1 by SIP1 attenuates cell cycle progression in cells undergoing an epithelial mesenchymal transition. Mol. Biol. Cell 18, 4615–4624 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Aguirre-Ghiso, J. A. Models, mechanisms and clinical evidence for cancer dormancy. Nature Rev. Cancer 7, 834–846 (2007).

    Article  CAS  Google Scholar 

  56. Chambers, A. F., Groom, A. C. & MacDonald, I. C. Dissemination and growth of cancer cells in metastatic sites. Nature Rev. Cancer 2, 563–572 (2002).

    Article  CAS  Google Scholar 

  57. Weiss, L. Metastatic inefficiency. Adv. Cancer Res. 54, 159–211 (1990).

    Article  CAS  PubMed  Google Scholar 

  58. Mateescu, B. et al. miR-141 and miR-200a act on ovarian tumorigenesis by controlling oxidative stress response. Nature Med. 17, 1627–1635 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Gao, D. et al. Endothelial progenitor cells control the angiogenic switch in mouse lung metastasis. Science 319, 195–198 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. Holmgren, L., O'Reilly, M. S. & Folkman, J. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med. 1, 149–153 (1995).

    Article  CAS  PubMed  Google Scholar 

  61. Ledford, H. Cancer therory faces doubts. Nature 472, 273 (2011).

    Article  CAS  PubMed  Google Scholar 

  62. Tsuji, T., Ibaragi, S. & Hu, G. F. Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res. 69, 7135–7139 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Dieter, Sebastian M. et al. Distinct types of tumor-initiating cells form human colon cancer tumors and metastases. Cell Stem Cell 9, 357–365 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Larue, L. & Bellacosa, A. Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene 24, 7443–7454 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Kalluri, R. & Weinberg, R. A. The basics of epithelial-mesenchymal transition. J. Clin. Invest. 119, 1420–1428 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hase, K., Shatney, C., Johnson, D., Trollope, M. & Vierra, M. Prognostic value of tumor “budding” in patients with colorectal cancer. Dis. Colon Rectum 36, 627–635 (1993).

    Article  CAS  PubMed  Google Scholar 

  67. Hostettler, L., Zlobec, I., Terracciano, L. & Lugli, A. ABCG5-positivity in tumor buds is an indicator of poor prognosis in node-negative colorectal cancer patients. World J. Gastroenterol. 16, 732–739 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Spaderna, S. et al. A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology 131, 830–840 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Prall, F., Nizze, H. & Barten, M. Tumour budding as prognostic factor in stage I/II colorectal carcinoma. Histopathology 47, 17–24 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Tanaka, M., Hashiguchi, Y., Ueno, H., Hase, K. & Mochizuki, H. Tumor budding at the invasive margin can predict patients at high risk of recurrence after curative surgery for stage, I. I., T3 colon cancer. Dis. Colon Rectum 46, 1054–1059 (2003).

    Article  PubMed  Google Scholar 

  71. Ueno, H., Murphy, J., Jass, J. R., Mochizuki, H. & Talbot, I. C. Tumour 'budding' as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology 40, 127–132 (2002).

    Article  CAS  PubMed  Google Scholar 

  72. Kazama, S., Watanabe, T., Ajioka, Y., Kanazawa, T. & Nagawa, H. Tumour budding at the deepest invasive margin correlates with lymph node metastasis in submucosal colorectal cancer detected by anticytokeratin antibody CAM5.2. Br. J. Cancer 94, 293–298 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Zlobec, I. & Lugli, A. Epithelial mesenchymal transition and tumor budding in aggressive colorectal cancer: tumor budding as oncotarget. Oncotarget 1, 651–661 (2010).

    PubMed  PubMed Central  Google Scholar 

  74. Nakamura, T., Mitomi, H., Kikuchi, S., Ohtani, Y. & Sato, K. Evaluation of the usefulness of tumor budding on the prediction of metastasis to the lung and liver after curative excision of colorectal cancer. Hepatogastroenterology 52, 1432–1435 (2005).

    PubMed  Google Scholar 

  75. Shipitsin, M. et al. Molecular definition of breast tumor heterogeneity. Cancer Cell 11, 259–273 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Aktas, B. et al. Stem cell and epithelial-mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Res. 11, R46 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  77. Pantel, K., Brakenhoff, R. H. & Brandt, B. Detection, clinical relevance and specific biological properties of disseminating tumour cells. Nature Rev. Cancer 8, 329–340 (2008).

    Article  CAS  Google Scholar 

  78. Balic, M. et al. Most early disseminated cancer cells detected in bone marrow of breast cancer patients have a putative breast cancer stem cell phenotype. Clin. Cancer Res. 12, 5615–5621 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Muller, V. et al. Circulating tumor cells in breast cancer: correlation to bone marrow micrometastases, heterogeneous response to systemic therapy and low proliferative activity. Clin. Cancer Res. 11, 3678–3685 (2005).

    Article  PubMed  Google Scholar 

  80. Nagrath, S. et al. Isolation of rare circulating tumour cells in cancer patients by microchip technology. Nature 450, 1235–1239 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Wiedswang, G. et al. Isolated tumor cells in bone marrow three years after diagnosis in disease-free breast cancer patients predict unfavorable clinical outcome. Clin. Cancer Res. 10, 5342–5348 (2004).

    Article  PubMed  Google Scholar 

  82. Malanchi, I. et al. Interactions between cancer stem cells and their niche govern metastatic colonization. Nature 481, 85–89 (2011).

    Article  PubMed  CAS  Google Scholar 

  83. 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).

    Article  CAS  PubMed  Google Scholar 

  84. Chaffer, C. L. et al. Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Research 66, 11271–11278 (2006).

    Article  CAS  PubMed  Google Scholar 

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

    Article  Google Scholar 

  86. Dykxhoorn, D. M. et al. miR-200 enhances mouse breast cancer cell colonization to form distant metastases. PLoS ONE 4, e7181 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Giampieri, S. et al. Localized and reversible TGFβ signalling switches breast cancer cells from cohesive to single cell motility. Nature Cell Biol. 11, 1287–1296 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Oltean, S., Febbo, P. G. & Garcia-Blanco, M. A. Dunning rat prostate adenocarcinomas and alternative splicing reporters: powerful tools to study epithelial plasticity in prostate tumors in vivo. Clin. Exp. Metastasis 25, 611–619 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Oltean, S. et al. Alternative inclusion of fibroblast growth factor receptor 2 exon IIIc in Dunning prostate tumors reveals unexpected epithelial mesenchymal plasticity. Proc. Natl Acad. Sci. USA 103, 14116–14121 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Rhim, Andrew D. et al. EMT and dissemination precede pancreatic tumor formation. Cell 148, 349–361 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Psaila, B. & Lyden, D. The metastatic niche: adapting the foreign soil. Nature Rev. Cancer 9, 285–293 (2009).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  93. Solanas, G. et al. E-cadherin controls β-catenin and NF-ΰB transcriptional activity in mesenchymal gene expression. J. Cell Sci. 121, 2224–2234 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chao, Y. L., Shepard, C. R. & Wells, A. Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Mol. Cancer 9, 179 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Zeisberg, M., Shah, A. A. & Kalluri, R. Bone morphogenic protein-7 induces mesenchymal to epithelial transition in adult renal fibroblasts and facilitates regeneration of injured kidney. J. Biol. Chem. 280, 8094–8100 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Buijs, J. T. et al. Bone morphogenetic protein 7 in the development and treatment of bone metastases from breast cancer. Cancer Res. 67, 8742–8751 (2007).

    Article  CAS  PubMed  Google Scholar 

  98. Buijs, J. T. et al. BMP7, a putative regulator of epithelial homeostasis in the human prostate, is a potent inhibitor of prostate cancer bone metastasis in vivo. Am. J. Pathol. 171, 1047–1057 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yee, D. S. et al. The Wnt inhibitory factor 1 restoration in prostate cancer cells was associated with reduced tumor growth, decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition. Mol. Cancer 9, 162 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Vincan, E. et al. Frizzled-7 dictates three-dimensional organization of colorectal cancer cell carcinoids. Oncogene 26, 2340–2352 (2007).

    Article  CAS  PubMed  Google Scholar 

  101. Gao, D. et al. Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Res. 72, 1384–1394 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Klein, C. A. Parallel progression of primary tumours and metastases. Nature Rev. Cancer 9, 302–312 (2009).

    Article  CAS  Google Scholar 

  103. Hennessy, B. T. et al. Characterization of a naturally occurring breast cancer subset enriched in epithelial-to-mesenchymal transition and stem cell characteristics. Cancer Res. 69, 4116–4124 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Herschkowitz, J. et al. Identification of conserved gene expression features between murine mammary carcinoma models and human breast tumors. Genome Biology 8, R76 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Prat, A. & Perou, C. M. Deconstructing the molecular portraits of breast cancer. Mol. Oncol. 5, 5–23 (2011).

    Article  CAS  PubMed  Google Scholar 

  106. Elsawaf, Z. & Sinn, H. P. Triple-negative breast cancer: clinical and histological correlations. Breast Care 6, 273–278 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Creighton, C. J., Chang, J. C. & Rosen, J. M. Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. J. Mamm. Gland Biol. Neopl. 15, 253–260 (2010).

    Article  Google Scholar 

  108. Creighton, C. J. et al. Residual breast cancers after conventional therapy display mesenchymal as well as tumor-initiating features. Proc. Natl Acad. Sci. 106, 13820–13825 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Lien, H. C. et al. Molecular signatures of metaplastic carcinoma of the breast by large-scale transcriptional profiling: identification of genes potentially related to epithelial-mesenchymal transition. Oncogene 26, 7859–7871 (2007).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  111. Gupta, Piyush B. et al. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Cell 146, 633–644 (2011).

    Article  CAS  PubMed  Google Scholar 

  112. Collisson, E. A. et al. Subtypes of pancreatic ductal adenocarcinoma and their differing responses to therapy. Nature Med. 17, 500–503 (2011).

    Article  CAS  PubMed  Google Scholar 

  113. Castilla, M. Á. et al. Micro-RNA signature of the epithelial–mesenchymal transition in endometrial carcinosarcoma. J. Pathol. 223, 72–80 (2011).

    Article  CAS  PubMed  Google Scholar 

  114. Friedman, S., Lu, M., Schultz, A., Thomas, D. & Lin, R.-Y. CD133+Anaplastic thyroid cancer cells initiate tumors in immunodeficient mice and are regulated by thyrotropin. PLoS ONE 4, e5395 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Braun, J., Hoang-Vu, C., Dralle, H. & Huttelmaier, S. Downregulation of microRNAs directs the EMT and invasive potential of anaplastic thyroid carcinomas. Oncogene 29, 4237–4244 (2010).

    Article  CAS  PubMed  Google Scholar 

  116. Becker, K. F. et al. E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res. 54, 3845–3852 (1994).

    CAS  PubMed  Google Scholar 

  117. Humar, B. & Guilford, P. Hereditary diffuse gastric cancer: A manifestation of lost cell polarity. Cancer Science 100, 1151–1157 (2009).

    Article  CAS  PubMed  Google Scholar 

  118. Kim, M. A. et al. Prognostic importance of epithelial–mesenchymal transition-related protein expression in gastric carcinoma. Histopathology 54, 442–451 (2009).

    Article  PubMed  Google Scholar 

  119. Diehn, M., Cho, R. W. & Clarke, M. F. Therapeutic implications of the cancer stem cell hypothesis. Semin. Rad. Oncol. 19, 78–86 (2009).

    Article  Google Scholar 

  120. Singh, A. & Settleman, J. EMT, cancer stem cells and drug resistance: an emerging axis of evil in the war on cancer. Oncogene 29, 4741–4751 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Gerlinger, M. et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. NEJM 366, 883–892 (2012).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  123. Monteiro, J. & Fodde, R. Cancer stemness and metastasis: Therapeutic consequences and perspectives. Eur. J. Cancer 46, 1198–1203 (2010).

    Article  CAS  PubMed  Google Scholar 

  124. 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).

    Article  CAS  PubMed  Google Scholar 

  125. Liu, Y., El-Naggar, S., Darling, D. S., Higashi, Y. & Dean, D. C. Zeb1 links epithelial-mesenchymal transition and cellular senescence. Development 135, 579–588 (2008).

    Article  CAS  PubMed  Google Scholar 

  126. Wang, J. et al. The transcription repressor, ZEB1, cooperates with CtBP2 and HDAC1 to suppress IL-2 gene activation in T cells. Int. Immunol. 21, 227–235 (2009).

    Article  CAS  PubMed  Google Scholar 

  127. Wang, Y. et al. LSD1 is a subunit of the NuRD complex and targets the metastasis programs in breast cancer. Cell 138, 660–672 (2009).

    Article  CAS  PubMed  Google Scholar 

  128. Tellez, C. S. et al. EMT and stem cell like properties associated with miR-205 and miR-200 epigenetic silencing are early manifestations during carcinogen-induced transformation of human lung epithelial dells. Cancer Res. 71, 3087–3097 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Takahashi-Yanaga, F. & Kahn, M. Targeting Wnt signaling: can we safely eradicate cancer stem cells? Clin. Cancer Res. 16, 3153–3162 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Feldmann, G. et al. An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Mol. Cancer Ther. 7, 2725–2735 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Dubrovska, A. et al. The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proc. Natl Acad. Sci. USA 106, 268–273 (2009).

    Article  CAS  PubMed  Google Scholar 

  132. Mueller, M.-T. et al. Combined targeted treatment to eliminate tumorigenic cancer stem cells in human pancreatic cancer. Gastroenterology 137, 1102–1113 (2009).

    Article  CAS  PubMed  Google Scholar 

  133. Farnie, G. & Clarke, R. B. Mammary stem cells and breast cancer--role of Notch signalling. Stem Cell Rev. 3, 169–175 (2007).

    Article  CAS  PubMed  Google Scholar 

  134. Plentz, R. et al. Inhibition of gamma-secretase activity inhibits tumor progression in a mouse model of pancreatic ductal adenocarcinoma. Gastroenterology 136, 1741–1749 e6 (2009).

    Article  CAS  PubMed  Google Scholar 

  135. Hirsch, H. A., Iliopoulos, D., Tsichlis, P. N. & Struhl, K. Metformin selectively targets cancer stem cells, and acts together with chemotherapy to block tumor growth and prolong remission. Cancer Res. 69, 7507–7511 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Iliopoulos, D., Hirsch, H. A. & Struhl, K. Metformin decreases the dose of chemotherapy for prolonging tumor remission in mouse xenografts involving multiple cancer cell types. Cancer Res. 71, 3196–3201 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Finn, R. S. et al. Dasatinib, an orally active small molecule inhibitor of both the src and abl kinases, selectively inhibits growth of basal-type/'triple-negative' breast cancer cell lines growing in vitro. Breast Cancer Res. Treat 105, 319–326 (2007).

    Article  CAS  PubMed  Google Scholar 

  138. Gupta, P. B. et al. Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell 138, 645–659 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Chaffer, C. L. et al. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Proc. Natl Acad. of Sci. 108, 7950–7955 (2011).

    Article  CAS  Google Scholar 

  140. Iliopoulos, D., Hirsch, H. A., Wang, G. & Struhl, K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc. Natl Acad. Sci. 108, 1397–1402 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Sharma, S. V. et al. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Cell 141, 69–80 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Fidler, I. J. The pathogenesis of cancer metastasis: the 'seed and soil' hypothesis revisited. Nature Rev. Cancer 3, 453–458 (2003).

    Article  CAS  Google Scholar 

  143. Nguyen, D. X., Bos, P. D. & Massague, J. Metastasis: from dissemination to organ-specific colonization. Nature Rev. Cancer 9, 274–284 (2009).

    Article  CAS  Google Scholar 

  144. Meng, S. et al. Circulating tumor cells in patients with breast cancer dormancy. Clin. Cancer Res. 10, 8152–8162 (2004).

    Article  PubMed  Google Scholar 

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Acknowledgements

The author apologizes to those authors whose work could not be cited directly owing to space constraints. For stimulating discussions and critical reading of the manuscript the author is very grateful to S. Brabletz and M. Swierk. T.B. is supported by the DFG (no. BR 1399/6-1 and the SFB 850, B2), the Deutsche Krebshilfe (grant no. 109430), the Speman Graduate School of Biology and Medicine (SGBM) and the BIOSS Centre for Biological Signalling Studies.

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Brabletz, T. To differentiate or not — routes towards metastasis. Nat Rev Cancer 12, 425–436 (2012). https://doi.org/10.1038/nrc3265

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