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Cancer and Metastasis Reviews

, Volume 31, Issue 3–4, pp 469–478 | Cite as

Mesenchymal–epithelial transition (MET) as a mechanism for metastatic colonisation in breast cancer

  • N. P. A. Devika Gunasinghe
  • Alan Wells
  • Erik W. Thompson
  • Honor J. Hugo
Article

Abstract

As yet, there is no cure for metastatic breast cancer. Historically, considerable research effort has been concentrated on understanding the processes of metastasis, how a primary tumour locally invades and systemically disseminates using the phenotypic switching mechanism of epithelial to mesenchymal transition (EMT); however, much less is understood about how metastases are then formed. Breast cancer metastases often look (and may even function) as ‘normal’ breast tissue, a bizarre observation against the backdrop of the organ structure of the lung, liver, bone or brain. Mesenchymal to epithelial transition (MET), the opposite of EMT, has been proposed as a mechanism for establishment of the metastatic neoplasm, leading to questions such as: Can MET be clearly demonstrated in vivo? What factors cause this phenotypic switch within the cancer cell? Are these signals/factors derived from the metastatic site (soil) or expressed by the cancer cells themselves (seed)? How do the cancer cells then grow into a detectable secondary tumour and further disseminate? And finally—Can we design and develop therapies that may combat this dissemination switch? This review aims to address these important questions by evaluating long-standing paradigms and novel emerging concepts in the field of epithelial mesencyhmal plasticity.

Keywords

EMT MET Mesenchymal Epithelial Transition Breast cancer Metastasis Proliferation 

Notes

Acknowledgments

The authors wish to thank members of the Thompson and Wells laboratories for ideas and discussions which shaped the work and conception of this review and gratefully acknowledge the following sources of financial support: the National Breast Cancer Foundation, particularly the National Collaborative Research Program (EMPathy Breast Cancer Network) (Australia), Cancer Council Victoria, The Australian Government's Endeavour Awards Scholarship Program, the Victorian Government's Operational Infrastructure Support Program, the DoD CDMRP on Breast Cancer and the VA Merit Award Program, USA.

References

  1. 1.
    Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E., & Forman, D. (2011). Global cancer statistics. CA: A Cancer Journal for Clinicians, 61, 69–90.CrossRefGoogle Scholar
  2. 2.
    Desantis, C., Siegel, R., Bandi, P., & Jemal, A. (2011). Breast cancer statistics, 2011. CA: A Cancer Journal for Clinicians, 61, 408–418.CrossRefGoogle Scholar
  3. 3.
    Jones, S. E. (2008). Metastatic breast cancer: the treatment challenge. Clinical Breast Cancer, 8, 224–233.PubMedCrossRefGoogle Scholar
  4. 4.
    Lopez-Tarruella, S., & Martin, M. (2009). Recent advances in systemic therapy: advances in adjuvant systemic chemotherapy of early breast cancer. Breast Cancer Research, 11, 204.PubMedCrossRefGoogle Scholar
  5. 5.
    Fisher, B., Jeong, J. H., Bryant, J., et al. (2004). Treatment of lymph-node-negative, oestrogen-receptor-positive breast cancer: long-term findings from National Surgical Adjuvant Breast and Bowel Project randomised clinical trials. Lancet, 364, 858–868.PubMedCrossRefGoogle Scholar
  6. 6.
    Early Breast Cancer Trialists' Collaborative Group. (1998). Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet, 352, 930–942.CrossRefGoogle Scholar
  7. 7.
    Hanahan, D., & Weinberg, R. A. (2000). The hallmarks of cancer. Cell, 100, 57–70.PubMedCrossRefGoogle Scholar
  8. 8.
    Woodhouse, E. C., Chuaqui, R. F., & Liotta, L. A. (1997). General mechanisms of metastasis. Cancer, 80, 1529–1537.PubMedCrossRefGoogle Scholar
  9. 9.
    Chambers, A. F., Groom, A. C., & MacDonald, I. C. (2002). Dissemination and growth of cancer cells in metastatic sites. Nature Reviews. Cancer, 2, 563–572.PubMedCrossRefGoogle Scholar
  10. 10.
    Weidner, N., Folkman, J., Pozza, F., et al. (1992). Tumor angiogenesis: a new significant and independent prognostic indicator in early-stage breast carcinoma. Journal of the National Cancer Institute, 84, 1875–1887.PubMedCrossRefGoogle Scholar
  11. 11.
    Folkman, J., & Shing, Y. (1992). Angiogenesis. Journal of Biological Chemistry, 267, 10931–10934.PubMedGoogle Scholar
  12. 12.
    Folkman, J. (1992). The role of angiogenesis in tumor growth. Seminars in Cancer Biology, 3, 65–71.PubMedGoogle Scholar
  13. 13.
    Kiaris, H., Chatzistamou, I., Kalofoutis, C., Koutselini, H., Piperi, C., & Kalofoutis, A. (2004). Tumour-stroma interactions in carcinogenesis: basic aspects and perspectives. Molecular and Cellular Biochemistry, 261, 117–122.PubMedCrossRefGoogle Scholar
  14. 14.
    Pupa, S. M., Menard, S., Forti, S., & Tagliabue, E. (2002). New insights into the role of extracellular matrix during tumor onset and progression. Journal of Cellular Physiology, 192, 259–267.PubMedCrossRefGoogle Scholar
  15. 15.
    Wells, A., Chao, Y. L., Grahovac, J., Wu, Q., & Lauffenburger, D. A. (2011). Epithelial and mesenchymal phenotypic switchings modulate cell motility in metastasis. Frontiers in Bioscience, 16, 815–837.PubMedCrossRefGoogle Scholar
  16. 16.
    Kienast, Y., von Baumgarten, L., Fuhrmann, M., et al. (2010). Real-time imaging reveals the single steps of brain metastasis formation. Nature Medicine, 16, 116–122.PubMedCrossRefGoogle Scholar
  17. 17.
    Luzzi, K. J., MacDonald, I. C., Schmidt, E. E., et al. (1998). Multistep nature of metastatic inefficiency: dormancy of solitary cells after successful extravasation and limited survival of early micrometastases. American Journal of Pathology, 153, 865–873.PubMedCrossRefGoogle Scholar
  18. 18.
    Howlett, A. R., & Bissell, M. J. (1993). The influence of tissue microenvironment (stroma and extracellular matrix) on the development and function of mammary epithelium. Epithelial Cell Biology, 2, 79–89.PubMedGoogle Scholar
  19. 19.
    Jechlinger, M., Grunert, S., & Beug, H. (2002). Mechanisms in epithelial plasticity and metastasis: insights from 3D cultures and expression profiling. Journal of Mammary Gland Biology and Neoplasia, 7, 415–432.PubMedCrossRefGoogle Scholar
  20. 20.
    de Herreros, A. G., Peiro, S., Nassour, M., & Savagner, P. (2010). Snail family regulation and epithelial mesenchymal transitions in breast cancer progression. Journal of Mammary Gland Biology and Neoplasia, 15, 135–147.PubMedCrossRefGoogle Scholar
  21. 21.
    Creighton, C. J., Chang, J. C., & Rosen, J. M. (2010). Epithelial-mesenchymal transition (EMT) in tumor-initiating cells and its clinical implications in breast cancer. Journal of Mammary Gland Biology and Neoplasia, 15, 253–260.PubMedCrossRefGoogle Scholar
  22. 22.
    Wang, Y., & Zhou, B. P. (2011). Epithelial-mesenchymal transition in breast cancer progression and metastasis. Chinese Journal of Cancer, 30, 603–611.PubMedCrossRefGoogle Scholar
  23. 23.
    Chao, Y. L., Shepard, C. R., & Wells, A. (2010). Breast carcinoma cells re-express E-cadherin during mesenchymal to epithelial reverting transition. Molecular Cancer, 9, 179.PubMedCrossRefGoogle Scholar
  24. 24.
    Chaffer, C. L., Brennan, J. P., Slavin, J. L., Blick, T., Thompson, E. W., & Williams, E. D. (2006). Mesenchymal-to-epithelial transition facilitates bladder cancer metastasis: role of fibroblast growth factor receptor-2. Cancer Research, 66, 11271–11278.PubMedCrossRefGoogle Scholar
  25. 25.
    Chaffer, C. L., Thompson, E. W., & Williams, E. D. (2007). Mesenchymal to epithelial transition in development and disease. Cells, Tissues, Organs, 185, 7–19.PubMedCrossRefGoogle Scholar
  26. 26.
    Hugo, H., Ackland, M. L., Blick, T., et al. (2007). Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. Journal of Cellular Physiology, 213, 374–383.PubMedCrossRefGoogle Scholar
  27. 27.
    Bernards, R., & Weinberg, R. A. (2002). A progression puzzle. Nature, 418, 823.PubMedCrossRefGoogle Scholar
  28. 28.
    Weinberg, R. A. (2008). Leaving home early: reexamination of the canonical models of tumor progression. Cancer Cell, 14, 283–284.PubMedCrossRefGoogle Scholar
  29. 29.
    Al-Hajj, M., Wicha, M. S., Benito-Hernandez, A., Morrison, S. J., & Clarke, M. F. (2003). Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the United States of America, 100, 3983–3988.PubMedCrossRefGoogle Scholar
  30. 30.
    Blick, T., Hugo, H., Widodo, E., et al. (2010). Epithelial mesenchymal transition traits in human breast cancer cell lines parallel the CD44(hi/)CD24 (lo/-) stem cell phenotype in human breast cancer. Journal of Mammary Gland Biology and Neoplasia, 15, 235–252.PubMedCrossRefGoogle Scholar
  31. 31.
    Mani, S. A., Guo, W., Liao, M. J., et al. (2008). The epithelial-mesenchymal transition generates cells with properties of stem cells. Cell, 133, 704–715.PubMedCrossRefGoogle Scholar
  32. 32.
    Kowalski, P. J., Rubin, M. A., & Kleer, C. G. (2003). E-cadherin expression in primary carcinomas of the breast and its distant metastases. Breast Cancer Research, 5, R217–R222.PubMedCrossRefGoogle Scholar
  33. 33.
    Stessels, F., Van den Eynden, G., Van der Auwera, I., et al. (2004). Breast adenocarcinoma liver metastases, in contrast to colorectal cancer liver metastases, display a non-angiogenic growth pattern that preserves the stroma and lacks hypoxia. British Journal of Cancer, 90, 1429–1436.PubMedCrossRefGoogle Scholar
  34. 34.
    Chao, Y., Wu, Q., Acquafondata, M., Dhir, R., & Wells, A. (2012). Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenvironment, 5, 19–28.PubMedCrossRefGoogle Scholar
  35. 35.
    Korpal, M., Ell, B. J., Buffa, F. M., et al. (2011). Direct targeting of Sec23a by miR-200s influences cancer cell secretome and promotes metastatic colonization. Nature Medicine, 17, 1101–1108.PubMedCrossRefGoogle Scholar
  36. 36.
    Hurteau, G. J., Carlson, J. A., Spivack, S. D., & Brock, G. J. (2007). Overexpression of the microRNA hsa-miR-200c leads to reduced expression of transcription factor 8 and increased expression of E-cadherin. Cancer Research, 67, 7972–7976.PubMedCrossRefGoogle Scholar
  37. 37.
    Bendoraite, A., Knouf, E. C., Garg, K. S., et al. (2010). Regulation of miR-200 family microRNAs and ZEB transcription factors in ovarian cancer: evidence supporting a mesothelial-to-epithelial transition. Gynecologic Oncology, 116, 117–125.PubMedCrossRefGoogle Scholar
  38. 38.
    Brabletz, S., & Brabletz, T. (2010). The ZEB/miR-200 feedback loop—a motor of cellular plasticity in development and cancer? EMBO Reports, 11, 670–677.PubMedCrossRefGoogle Scholar
  39. 39.
    Gregory, P. A., Bracken, C. P., Smith, E., et al. (2011). An autocrine TGF-beta/ZEB/miR-200 signaling network regulates establishment and maintenance of epithelial-mesenchymal transition. Molecular Biology of the Cell, 22, 1686–1698.PubMedCrossRefGoogle Scholar
  40. 40.
    Burk, U., Schubert, J., Wellner, U., et al. (2008). A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Reports, 9, 582–589.PubMedCrossRefGoogle Scholar
  41. 41.
    Bullock, M. D., Sayan, A. E., Packham, G. K., & Mirnezami, A. H. (2012). MicroRNAs: critical regulators of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transition (MET) in cancer progression. Biology of the Cell, 104, 3–12.PubMedCrossRefGoogle Scholar
  42. 42.
    Celia-Terrassa, T., Meca-Cortes, O., Mateo, F., et al. (2012). Epithelial-mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. The Journal of Clinical Investigation, 122, 1849–1868.PubMedCrossRefGoogle Scholar
  43. 43.
    Sporn, M. B. (1996). The war on cancer. Lancet, 347, 1377–1381.PubMedCrossRefGoogle Scholar
  44. 44.
    Mettlin, C. (1999). Global breast cancer mortality statistics. CA: A Cancer Journal for Clinicians, 49, 138–144.CrossRefGoogle Scholar
  45. 45.
    No authors listed (2000). Breast cancer statistics. Journal of the National Cancer Institute, 92, 445.Google Scholar
  46. 46.
    Kamo, K., & Sobue, T. (2004). Cancer statistics digest. Mortality trend of prostate, breast, uterus, ovary, bladder and “kidney and other urinary tract” cancer in Japan by birth cohort. Japanese Journal of Clinical Oncology, 34, 561–563.PubMedCrossRefGoogle Scholar
  47. 47.
    Birchmeier, W., & Behrens, J. (1994). Cadherin expression in carcinomas: role in the formation of cell junctions and the prevention of invasiveness. Biochimica et Biophysica Acta, 1198, 11–26.PubMedGoogle Scholar
  48. 48.
    Berx, G., Staes, K., van Hengel, J., et al. (1995). Cloning and characterization of the human invasion suppressor gene E-cadherin (CDH1). Genomics, 26, 281–289.PubMedCrossRefGoogle Scholar
  49. 49.
    Pecina-Slaus, N. (2003). Tumor suppressor gene E-cadherin and its role in normal and malignant cells. Cancer Cell International, 3, 17.PubMedCrossRefGoogle Scholar
  50. 50.
    Perl, A. K., Wilgenbus, P., Dahl, U., Semb, H., & Christofori, G. (1998). A causal role for E-cadherin in the transition from adenoma to carcinoma. Nature, 392, 190–193.PubMedCrossRefGoogle Scholar
  51. 51.
    Wells, A., Yates, C., & Shepard, C. R. (2008). E-cadherin as an indicator of mesenchymal to epithelial reverting transitions during the metastatic seeding of disseminated carcinomas. Clinical & Experimental Metastasis, 25, 621–628.CrossRefGoogle Scholar
  52. 52.
    Saha, B., Chaiwun, B., Imam, S. S., et al. (2007). Overexpression of E-cadherin protein in metastatic breast cancer cells in bone. Anticancer Research, 27, 3903–3908.PubMedGoogle Scholar
  53. 53.
    Bastid, J. (2012). EMT in carcinoma progression and dissemination: facts, unanswered questions, and clinical considerations. Cancer and Metastasis Reviews, 31, 277–283.PubMedCrossRefGoogle Scholar
  54. 54.
    Wendt, M. K., Taylor, M. A., Schiemann, B. J., & Schiemann, W. P. (2011). Down-regulation of epithelial cadherin is required to initiate metastatic outgrowth of breast cancer. Molecular Biology of the Cell, 22, 2423–2435.PubMedCrossRefGoogle Scholar
  55. 55.
    Cailleau, R., Olive, M., & Cruciger, Q. V. (1978). Long-term human breast carcinoma cell lines of metastatic origin: preliminary characterization. In Vitro, 14, 911–915.PubMedCrossRefGoogle Scholar
  56. 56.
    Brinkley, B. R., Beall, P. T., Wible, L. J., Mace, M. L., Turner, D. S., & Cailleau, R. M. (1980). Variations in cell form and cytoskeleton in human breast carcinoma cells in vitro. Cancer Research, 40, 3118–3129.PubMedGoogle Scholar
  57. 57.
    Thompson, E. W., Paik, S., Brunner, N., et al. (1992). Association of increased basement membrane invasiveness with absence of estrogen receptor and expression of vimentin in human breast cancer cell lines. Journal of Cellular Physiology, 150, 534–544.PubMedCrossRefGoogle Scholar
  58. 58.
    Sheikh, M. S., Shao, Z. M., Hussain, A., & Fontana, J. A. (1993). The p53-binding protein MDM2 gene is differentially expressed in human breast carcinoma. Cancer Research, 53, 3226–3228.PubMedGoogle Scholar
  59. 59.
    Maemura, M., Akiyama, S. K., Woods, V. L., Jr., & Dickson, R. B. (1995). Expression and ligand binding of alpha 2 beta 1 integrin on breast carcinoma cells. Clinical & Experimental Metastasis, 13, 223–235.CrossRefGoogle Scholar
  60. 60.
    Hiraguri, S., Godfrey, T., Nakamura, H., et al. (1998). Mechanisms of inactivation of E-cadherin in breast cancer cell lines. Cancer Research, 58, 1972–1977.PubMedGoogle Scholar
  61. 61.
    Pishvaian, M. J., Feltes, C. M., Thompson, P., Bussemakers, M. J., Schalken, J. A., & Byers, S. W. (1999). Cadherin-11 is expressed in invasive breast cancer cell lines. Cancer Research, 59, 947–952.PubMedGoogle Scholar
  62. 62.
    Jo, M., Lester, R. D., Montel, V., Eastman, B., Takimoto, S., & Gonias, S. L. (2009). Reversibility of epithelial-mesenchymal transition (EMT) induced in breast cancer cells by activation of urokinase receptor-dependent cell signaling. Journal of Biological Chemistry, 284, 22825–22833.PubMedCrossRefGoogle Scholar
  63. 63.
    Lester, R. D., Jo, M., Montel, V., Takimoto, S., & Gonias, S. L. (2007). uPAR induces epithelial-mesenchymal transition in hypoxic breast cancer cells. The Journal of Cell Biology, 178, 425–436.PubMedCrossRefGoogle Scholar
  64. 64.
    Lo, H. W., Hsu, S. C., Xia, W., et al. (2007). Epidermal growth factor receptor cooperates with signal transducer and activator of transcription 3 to induce epithelial-mesenchymal transition in cancer cells via up-regulation of TWIST gene expression. Cancer Research, 67, 9066–9076.PubMedCrossRefGoogle Scholar
  65. 65.
    Bonnomet, A., Syne, L., Brysse, A., et al. (2011). A dynamic in vivo model of epithelial-to-mesenchymal transitions in circulating tumor cells and metastases of breast cancer. Oncogene. (In press)Google Scholar
  66. 66.
    Lee, J. M., Dedhar, S., Kalluri, R., & Thompson, E. W. (2006). The epithelial-mesenchymal transition: new insights in signaling, development, and disease. The Journal of Cell Biology, 172, 973–981.PubMedCrossRefGoogle Scholar
  67. 67.
    Klymkowsky, M. W., & Savagner, P. (2009). Epithelial-mesenchymal transition: a cancer researcher's conceptual friend and foe. American Journal of Pathology, 174, 1588–1593.PubMedCrossRefGoogle Scholar
  68. 68.
    Martinez, V., & Azzopardi, J. G. (1979). Invasive lobular carcinoma of the breast: incidence and variants. Histopathology, 3, 467–488.PubMedCrossRefGoogle Scholar
  69. 69.
    DiCostanzo, D., Rosen, P. P., Gareen, I., Franklin, S., & Lesser, M. (1990). Prognosis in infiltrating lobular carcinoma. An analysis of “classical” and variant tumors. The American Journal of Surgical Pathology, 14, 12–23.PubMedCrossRefGoogle Scholar
  70. 70.
    Da Silva, L., Parry, S., Reid, L., et al. (2008). Aberrant expression of E-cadherin in lobular carcinomas of the breast. The American Journal of Surgical Pathology, 32, 773–783.PubMedCrossRefGoogle Scholar
  71. 71.
    Oltean, S., Sorg, B. S., Albrecht, T., et al. (2006). Alternative inclusion of fibroblast growth factor receptor 2 exon IIIc in Dunning prostate tumors reveals unexpected epithelial mesenchymal plasticity. Proceedings of the National Academy of Sciences of the United States of America, 103, 14116–14121.PubMedCrossRefGoogle Scholar
  72. 72.
    Oltean, S., Febbo, P. G., & Garcia-Blanco, M. A. (2008). Dunning rat prostate adenocarcinomas and alternative splicing reporters: powerful tools to study epithelial plasticity in prostate tumors in vivo. Clinical & Experimental Metastasis, 25, 611–619.CrossRefGoogle Scholar
  73. 73.
    Tsuji, T., Ibaragi, S., Shima, K., et al. (2008). Epithelial-mesenchymal transition induced by growth suppressor p12CDK2-AP1 promotes tumor cell local invasion but suppresses distant colony growth. Cancer Research, 68, 10377–10386.PubMedCrossRefGoogle Scholar
  74. 74.
    Martorana, A. M., Zheng, G., Crowe, T. C., O’Grady, R. L., & Lyons, J. G. (1998). Epithelial cells up-regulate matrix metalloproteinases in cells within the same mammary carcinoma that have undergone an epithelial-mesenchymal transition. Cancer Research, 58, 4970–4979.PubMedGoogle Scholar
  75. 75.
    Kleer, C. G., van Golen, K. L., Braun, T., & Merajver, S. D. (2001). Persistent E-cadherin expression in inflammatory breast cancer. Modern Pathology, 14, 458–464.PubMedCrossRefGoogle Scholar
  76. 76.
    Lang, S. H., Sharrard, R. M., Stark, M., Villette, J. M., & Maitland, N. J. (2001). Prostate epithelial cell lines form spheroids with evidence of glandular differentiation in three-dimensional Matrigel cultures. British Journal of Cancer, 85, 590–599.PubMedCrossRefGoogle Scholar
  77. 77.
    Kurahara, H., Takao, S., Maemura, K., et al. (2012). Epithelial-mesenchymal transition and mesenchymal-epithelial transition via regulation of ZEB-1 and ZEB-2 expression in pancreatic cancer. Journal of Surgical Oncology, 105, 655–61.PubMedCrossRefGoogle Scholar
  78. 78.
    Chao, Y., Wu, Q., Shepard, C., & Wells, A. (2012). Hepatocyte induced re-expression of E-cadherin in breast and prostate cancer cells increases chemoresistance. Clinical & Experimental Metastasis, 29, 39–50.CrossRefGoogle Scholar
  79. 79.
    Yates, C. C., Shepard, C. R., Stolz, D. B., & Wells, A. (2007). Co-culturing human prostate carcinoma cells with hepatocytes leads to increased expression of E-cadherin. British Journal of Cancer, 96, 1246–1252.PubMedCrossRefGoogle Scholar
  80. 80.
    Lopes, N., Carvalho, J., Duraes, C., et al. (2012). 1Alpha,25-dihydroxyvitamin D3 induces de novo E-cadherin expression in triple-negative breast cancer cells by CDH1-promoter demethylation. Anticancer Research, 32, 249–257.PubMedGoogle Scholar
  81. 81.
    Yilmaz, M., & Christofori, G. (2009). EMT, the cytoskeleton, and cancer cell invasion. Cancer and Metastasis Reviews, 28, 15–33.PubMedCrossRefGoogle Scholar
  82. 82.
    Valastyan, S., & Weinberg, R. A. (2011). Tumor metastasis: molecular insights and evolving paradigms. Cell, 147, 275–292.PubMedCrossRefGoogle Scholar
  83. 83.
    Yang, J., & Weinberg, R. A. (2008). Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Developmental Cell, 14, 818–829.PubMedCrossRefGoogle Scholar
  84. 84.
    Jung, A., Schrauder, M., Oswald, U., et al. (2001). The invasion front of human colorectal adenocarcinomas shows co-localization of nuclear beta-catenin, cyclin D1, and p16INK4A and is a region of low proliferation. American Journal of Pathology, 159, 1613–1617.PubMedCrossRefGoogle Scholar
  85. 85.
    Vega, S., Morales, A. V., Ocana, O. H., Valdes, F., Fabregat, I., & Nieto, M. A. (2004). Snail blocks the cell cycle and confers resistance to cell death. Genes & Development, 18, 1131–1143.CrossRefGoogle Scholar
  86. 86.
    Mejlvang, J., Kriajevska, M., Vandewalle, C., et al. (2007). Direct repression of cyclin D1 by SIP1 attenuates cell cycle progression in cells undergoing an epithelial mesenchymal transition. Molecular Biology of the Cell, 18, 4615–4624.PubMedCrossRefGoogle Scholar
  87. 87.
    Rubio, C. A. (2006). Cell proliferation at the leading invasive front of colonic carcinomas. Preliminary observations. Anticancer Research, 26, 2275–2278.PubMedGoogle Scholar
  88. 88.
    Rubio, C. A. (2007). Further studies on the arrest of cell proliferation in tumor cells at the invading front of colonic adenocarcinoma. Journal of Gastroenterology and Hepatology, 22, 1877–1881.PubMedCrossRefGoogle Scholar
  89. 89.
    Spaderna, S., Schmalhofer, O., Hlubek, F., et al. (2006). A transient, EMT-linked loss of basement membranes indicates metastasis and poor survival in colorectal cancer. Gastroenterology, 131, 830–840.PubMedCrossRefGoogle Scholar
  90. 90.
    Gao, D., Joshi, N., Choi, H., et al. (2012). Myeloid progenitor cells in the premetastatic lung promote metastases by inducing mesenchymal to epithelial transition. Cancer Research, 72, 1384–94.PubMedCrossRefGoogle Scholar
  91. 91.
    Thiery, J. P., Acloque, H., Huang, R. Y., & Nieto, M. A. (2009). Epithelial-mesenchymal transitions in development and disease. Cell, 139, 871–890.PubMedCrossRefGoogle Scholar
  92. 92.
    Thomson, S., Buck, E., Petti, F., et al. (2005). Epithelial to mesenchymal transition is a determinant of sensitivity of non-small-cell lung carcinoma cell lines and xenografts to epidermal growth factor receptor inhibition. Cancer Research, 65, 9455–9462.PubMedCrossRefGoogle Scholar
  93. 93.
    Thomson, S., Petti, F., Sujka-Kwok, I., Epstein, D., & Haley, J. D. (2008). Kinase switching in mesenchymal-like non-small cell lung cancer lines contributes to EGFR inhibitor resistance through pathway redundancy. Clinical & Experimental Metastasis, 25, 843–854.CrossRefGoogle Scholar
  94. 94.
    Yauch, R. L., Januario, T., Eberhard, D. A., et al. (2005). Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clinical Cancer Research, 11, 8686–8698.PubMedCrossRefGoogle Scholar
  95. 95.
    Creighton, C. J., Reid, J. G., & Gunaratne, P. H. (2009). Expression profiling of microRNAs by deep sequencing. Briefings in Bioinformatics, 10, 490–497.PubMedCrossRefGoogle Scholar
  96. 96.
    Cooke, V. G., LeBleu, V. S., Keskin, D., et al. (2012). Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by MET signaling pathway. Cancer Cell, 21, 66–81.PubMedCrossRefGoogle Scholar
  97. 97.
    Valdes, F., Alvarez, A. M., Locascio, A., et al. (2002). The epithelial mesenchymal transition confers resistance to the apoptotic effects of transforming growth factor beta in fetal rat hepatocytes. Molecular Cancer Research, 1, 68–78.PubMedGoogle Scholar
  98. 98.
    Ansieau, S., Bastid, J., Doreau, A., et al. (2008). Induction of EMT by twist proteins as a collateral effect of tumor-promoting inactivation of premature senescence. Cancer Cell, 14, 79–89.PubMedCrossRefGoogle Scholar
  99. 99.
    Gal, A., Sjoblom, T., Fedorova, L., Imreh, S., Beug, H., & Moustakas, A. (2008). Sustained TGF beta exposure suppresses Smad and non-Smad signalling in mammary epithelial cells, leading to EMT and inhibition of growth arrest and apoptosis. Oncogene, 27, 1218–1230.PubMedCrossRefGoogle Scholar
  100. 100.
    Sayan, A. E., Griffiths, T. R., Pal, R., et al. (2009). SIP1 protein protects cells from DNA damage-induced apoptosis and has independent prognostic value in bladder cancer. Proceedings of the National Academy of Sciences of the United States of America, 106, 14884–14889.PubMedCrossRefGoogle Scholar
  101. 101.
    Straub, B. K., Rickelt, S., Zimbelmann, R., et al. (2011). E-N-cadherin heterodimers define novel adherens junctions connecting endoderm-derived cells. The Journal of Cell Biology, 195, 873–887.PubMedCrossRefGoogle Scholar
  102. 102.
    Thiery, J. P. (2002). Epithelial to mesenchymal transitions in tumour progression. Nature Cancer, 2, 442–454.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • N. P. A. Devika Gunasinghe
    • 1
    • 2
  • Alan Wells
    • 3
  • Erik W. Thompson
    • 1
    • 4
  • Honor J. Hugo
    • 4
  1. 1.Department of Surgery, St. Vincent’s HospitalUniversity of MelbourneMelbourneAustralia
  2. 2.Department of Anatomy, Faculty of MedicineUniversity of PeradeniyaPeradeniyaSri Lanka
  3. 3.Department of PathologyUniversity of Pittsburgh and Pittsburgh VA Medical CenterPittsburghUSA
  4. 4.VBCRC Invasion and Metastasis UnitSt. Vincent’s InstituteMelbourneAustralia

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