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The rejuvenated scenario of epithelial–mesenchymal transition (EMT) and cancer metastasis

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Abstract

The molecular mechanisms underlying cancer progression and metastasis are still poorly understood. In recent years, the epithelial-to-mesenchymal transition (EMT), a traditional phenomenon revealed in embryonic development, has been gradually accepted as a potential mechanism underlying cancer progression and metastasis. Many cell signaling pathways involved in development have been shown to contribute to EMT. An increasing number of genetic and epigenetic elements have been discovered, and their cross-talk relationship in EMT remains to be explored. In addition, accumulating experimental evidence suggests that EMT plays a critical role in different aspects of cancer progression, such as metastasis, stem cell traits, and chemoresistance. However, there are some disagreements and debate about these studies, which raise critical questions worthy of further investigation. Solving these questions will lead to a more complete understanding of cancer metastasis. Due to the close relationship of EMT to cancer metastasis and chemoresistance, targeting EMT or reversing EMT is likely to lead to novel therapeutic approaches for the treatment of human cancers.

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References

  1. Acloque, H., Thiery, J. P., & Nieto, M. A. (2008). The physiology and pathology of the EMT. EMBO Reports, 9(4), 322–326. doi:10.1038/embor.2008.30.

    PubMed  CAS  Google Scholar 

  2. Baum, B., Settleman, J., & Quinlan, M. P. (2008). Transitions between epithelial and mesenchymal states in development and disease. Seminars in Cell & Developmental Biology, 19(3), 294–308. doi:10.1016/j.semcdb.2008.02.001.

    CAS  Google Scholar 

  3. Thiery, J. P. (2002). Epithelial–mesenchymal transitions in tumour progression. Nature Reviews. Cancer, 2(6), 442–454. doi:10.1038/nrc822nrc822.

    PubMed  CAS  Google Scholar 

  4. Thiery, J. P., & Sleeman, J. P. (2006). Complex networks orchestrate epithelial–mesenchymal transitions. Nature Reviews Molecular Cell Biology, 7(2), 131–142. doi:10.1038/nrm1835.

    PubMed  CAS  Google Scholar 

  5. Yang, J., & Weinberg, R. A. (2008). Epithelial–mesenchymal transition: at the crossroads of development and tumor metastasis. Developmental Cell, 14(6), 818–829. doi:10.1016/j.devcel.2008.05.009.

    PubMed  CAS  Google Scholar 

  6. Davies, J. A. (1996). Mesenchyme to epithelium transition during development of the mammalian kidney tubule. Acta Anat (Basel), 156(3), 187–201.

    CAS  Google Scholar 

  7. Voulgari, A., & Pintzas, A. (2009). Epithelial–mesenchymal transition in cancer metastasis: Mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochimica et Biophysica Acta, 1796(2), 75–90. doi:10.1016/j.bbcan.2009.03.002.

    PubMed  CAS  Google Scholar 

  8. Barr, S., Thomson, S., Buck, E., Russo, S., Petti, F., Sujka-Kwok, I., et al. (2008). Bypassing cellular EGF receptor dependence through epithelial-to-mesenchymal-like transitions. Clinical & Experimental Metastasis, 25(6), 685–693. doi:10.1007/s10585-007-9121-7.

    Google Scholar 

  9. Huber, M. A., Kraut, N., & Beug, H. (2005). Molecular requirements for epithelial–mesenchymal transition during tumor progression. Current Opinion in Cell Biology, 17(5), 548–558. doi:10.1016/j.ceb.2005.08.001.

    PubMed  CAS  Google Scholar 

  10. Moustakas, A., & Heldin, C. H. (2007). Signaling networks guiding epithelial–mesenchymal transitions during embryogenesis and cancer progression. Cancer Science, 98(10), 1512–1520. doi:10.1111/j.1349-7006.2007.00550.x.

    PubMed  CAS  Google Scholar 

  11. Lo, H. W., Hsu, S. C., Xia, W., Cao, X., Shih, J. Y., Wei, Y., 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(19), 9066–9076. doi:10.1158/0008-5472.CAN-07-0575.

    PubMed  CAS  Google Scholar 

  12. Birchmeier, C., Birchmeier, W., Gherardi, E., & Vande Woude, G. F. (2003). Met, metastasis, motility and more. Nature Reviews Molecular Cell Biology, 4(12), 915–925. doi:10.1038/nrm1261nrm1261.

    PubMed  CAS  Google Scholar 

  13. Boyer, B., & Thiery, J. P. (1993). Cyclic AMP distinguishes between two functions of acidic FGF in a rat bladder carcinoma cell line. The Journal of Cell Biology, 120(3), 767–776.

    PubMed  CAS  Google Scholar 

  14. Savagner, P., Yamada, K. M., & Thiery, J. P. (1997). The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial–mesenchymal transition. The Journal of Cell Biology, 137(6), 1403–1419.

    PubMed  CAS  Google Scholar 

  15. Bellusci, S., Moens, G., Thiery, J. P., & Jouanneau, J. (1994). A scatter factor-like factor is produced by a metastatic variant of a rat bladder carcinoma cell line. Journal of Cell Science, 107(Pt 5), 1277–1287.

    PubMed  CAS  Google Scholar 

  16. Grotegut, S., von Schweinitz, D., Christofori, G., & Lehembre, F. (2006). Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO Journal, 25(15), 3534–3545. doi:10.1038/sj.emboj.7601213.

    PubMed  CAS  Google Scholar 

  17. Min, C., Eddy, S. F., Sherr, D. H., & Sonenshein, G. E. (2008). NF-kappaB and epithelial to mesenchymal transition of cancer. Journal of Cellular Biochemistry, 104(3), 733–744. doi:10.1002/jcb.21695.

    PubMed  CAS  Google Scholar 

  18. Taylor, M. A., Parvani, J. G., & Schiemann, W. P. (2010). The pathophysiology of epithelial–mesenchymal transition induced by transforming growth factor-beta in normal and malignant mammary epithelial cells. Journal of Mammary Gland Biology and Neoplasia, 15(2), 169–190. doi:10.1007/s10911-010-9181-1.

    PubMed  Google Scholar 

  19. Vincan, E., & Barker, N. (2008). The upstream components of the Wnt signalling pathway in the dynamic EMT and MET associated with colorectal cancer progression. Clinical & Experimental Metastasis, 25(6), 657–663. doi:10.1007/s10585-008-9156-4.

    CAS  Google Scholar 

  20. Wang, Z., Li, Y., Kong, D., & Sarkar, F. H. (2010). The role of Notch signaling pathway in epithelial–mesenchymal transition (EMT) during development and tumor aggressiveness. Current Drug Targets, 11(6), 745–751.

    PubMed  CAS  Google Scholar 

  21. Wendt, M. K., Allington, T. M., & Schiemann, W. P. (2009). Mechanisms of the epithelial–mesenchymal transition by TGF-beta. Future Oncology, 5(8), 1145–1168. doi:10.2217/fon.09.90.

    PubMed  CAS  Google Scholar 

  22. Tian, M., & Schiemann, W. P. (2009). The TGF-beta paradox in human cancer: an update. Future Oncology, 5(2), 259–271. doi:10.2217/14796694.5.2.259.

    PubMed  CAS  Google Scholar 

  23. Tian, F., DaCosta Byfield, S., Parks, W. T., Yoo, S., Felici, A., Tang, B., et al. (2003). Reduction in Smad2/3 signaling enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Research, 63(23), 8284–8292.

    PubMed  CAS  Google Scholar 

  24. Tian, F., Byfield, S. D., Parks, W. T., Stuelten, C. H., Nemani, D., Zhang, Y. E., et al. (2004). Smad-binding defective mutant of transforming growth factor beta type I receptor enhances tumorigenesis but suppresses metastasis of breast cancer cell lines. Cancer Research, 64(13), 4523–4530. doi:10.1158/0008-5472.CAN-04-003064/13/4523.

    PubMed  CAS  Google Scholar 

  25. Deckers, M., van Dinther, M., Buijs, J., Que, I., Lowik, C., van der Pluijm, G., et al. (2006). The tumor suppressor Smad4 is required for transforming growth factor beta-induced epithelial to mesenchymal transition and bone metastasis of breast cancer cells. Cancer Research, 66(4), 2202–2209. doi:10.1158/0008-5472.CAN-05-3560.

    PubMed  CAS  Google Scholar 

  26. Kang, Y., He, W., Tulley, S., Gupta, G. P., Serganova, I., Chen, C. R., et al. (2005). Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway. Proceedings of the National Academy of Sciences of the United States of America, 102(39), 13909–13914. doi:10.1073/pnas.0506517102.

    PubMed  CAS  Google Scholar 

  27. Hayashi, H., Abdollah, S., Qiu, Y., Cai, J., Xu, Y. Y., Grinnell, B. W., et al. (1997). The MAD-related protein Smad7 associates with the TGFbeta receptor and functions as an antagonist of TGFbeta signaling. Cell, 89(7), 1165–1173.

    PubMed  CAS  Google Scholar 

  28. Souchelnytskyi, S., Nakayama, T., Nakao, A., Moren, A., Heldin, C. H., Christian, J. L., et al. (1998). Physical and functional interaction of murine and Xenopus Smad7 with bone morphogenetic protein receptors and transforming growth factor-beta receptors. Journal of Biological Chemistry, 273(39), 25364–25370.

    PubMed  CAS  Google Scholar 

  29. Azuma, H., Ehata, S., Miyazaki, H., Watabe, T., Maruyama, O., Imamura, T., et al. (2005). Effect of Smad7 expression on metastasis of mouse mammary carcinoma JygMC(A) cells. Journal of the National Cancer Institute, 97(23), 1734–1746. doi:10.1093/jnci/dji399.

    PubMed  CAS  Google Scholar 

  30. Leivonen, S. K., Ala-Aho, R., Koli, K., Grenman, R., Peltonen, J., & Kahari, V. M. (2006). Activation of Smad signaling enhances collagenase-3 (MMP-13) expression and invasion of head and neck squamous carcinoma cells. Oncogene, 25(18), 2588–2600. doi:10.1038/sj.Onc.1209291.

    PubMed  CAS  Google Scholar 

  31. Leivonen, S. K., & Kahari, V. M. (2007). Transforming growth factor-beta signaling in cancer invasion and metastasis. International Journal of Cancer, 121(10), 2119–2124. doi:10.1002/ijc.23113.

    CAS  Google Scholar 

  32. Javelaud, D., Mohammad, K. S., McKenna, C. R., Fournier, P., Luciani, F., Niewolna, M., et al. (2007). Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis. Cancer Research, 67(5), 2317–2324. doi:10.1158/0008-5472.CAN-06-3950.

    PubMed  CAS  Google Scholar 

  33. Janda, E., Lehmann, K., Killisch, I., Jechlinger, M., Herzig, M., Downward, J., et al. (2002). Ras and TGF[beta] cooperatively regulate epithelial cell plasticity and metastasis: dissection of Ras signaling pathways. The Journal of Cell Biology, 156(2), 299–313. doi:10.1083/jcb.200109037jcb.200109037.

    PubMed  CAS  Google Scholar 

  34. Xie, L., Law, B. K., Chytil, A. M., Brown, K. A., Aakre, M. E., & Moses, H. L. (2004). Activation of the Erk pathway is required for TGF-beta1-induced EMT in vitro. Neoplasia, 6(5), 603–610. doi:10.1593/neo.04241.

    PubMed  CAS  Google Scholar 

  35. Neil, J. R., Johnson, K. M., Nemenoff, R. A., & Schiemann, W. P. (2008). Cox-2 inactivates Smad signaling and enhances EMT stimulated by TGF-beta through a PGE2-dependent mechanisms. Carcinogenesis, 29(11), 2227–2235. doi:10.1093/carcin/bgn202.

    PubMed  CAS  Google Scholar 

  36. Bhowmick, N. A., Zent, R., Ghiassi, M., McDonnell, M., & Moses, H. L. (2001). Integrin beta 1 signaling is necessary for transforming growth factor-beta activation of p38MAPK and epithelial plasticity. Journal of Biological Chemistry, 276(50), 46707–46713. doi:10.1074/jbc.M106176200M106176200.

    PubMed  CAS  Google Scholar 

  37. Galliher, A. J., & Schiemann, W. P. (2006). Beta3 integrin and Src facilitate transforming growth factor-beta mediated induction of epithelial–mesenchymal transition in mammary epithelial cells. Breast Cancer Research, 8(4), R42. doi:10.1186/bcr1524.

    PubMed  Google Scholar 

  38. Galliher-Beckley, A. J., & Schiemann, W. P. (2008). Grb2 binding to Tyr284 in TbetaR-II is essential for mammary tumor growth and metastasis stimulated by TGF-beta. Carcinogenesis, 29(2), 244–251. doi:10.1093/carcin/bgm245.

    PubMed  CAS  Google Scholar 

  39. Miele, L. (2006). Notch signaling. Clinical Cancer Research, 12(4), 1074–1079. doi:10.1158/1078-0432.CCR-05-2570.

    PubMed  CAS  Google Scholar 

  40. Miele, L., & Osborne, B. (1999). Arbiter of differentiation and death: Notch signaling meets apoptosis. Journal of Cellular Physiology, 181(3), 393–409. doi:10.1002/(SICI)1097-4652(199912)181:3<393::AID-JCP3>3.0.CO;2-6 [pii]10.1002/(SICI)1097-4652(199912)181:3<393::AID-JCP3>3.0.CO;2-6.

    PubMed  CAS  Google Scholar 

  41. Niessen, K., Fu, Y., Chang, L., Hoodless, P. A., McFadden, D., & Karsan, A. (2008). Slug is a direct Notch target required for initiation of cardiac cushion cellularization. The Journal of Cell Biology, 182(2), 315–325. doi:10.1083/jcb.200710067.

    PubMed  CAS  Google Scholar 

  42. Zavadil, J., Cermak, L., Soto-Nieves, N., & Bottinger, E. P. (2004). Integration of TGF-beta/Smad and Jagged1/Notch signalling in epithelial-to-mesenchymal transition. EMBO Journal, 23(5), 1155–1165. doi:10.1038/sj.emboj.76000697600069.

    PubMed  CAS  Google Scholar 

  43. Niimi, H., Pardali, K., Vanlandewijck, M., Heldin, C. H., & Moustakas, A. (2007). Notch signaling is necessary for epithelial growth arrest by TGF-beta. The Journal of Cell Biology, 176(5), 695–707. doi:10.1083/jcb.200612129.

    PubMed  CAS  Google Scholar 

  44. Jechlinger, M., Sommer, A., Moriggl, R., Seither, P., Kraut, N., Capodiecci, P., et al. (2006). Autocrine PDGFR signaling promotes mammary cancer metastasis. The Journal of Clinical Investigation, 116(6), 1561–1570. doi:10.1172/JCI24652.

    PubMed  CAS  Google Scholar 

  45. Fischer, A. N., Fuchs, E., Mikula, M., Huber, H., Beug, H., & Mikulits, W. (2007). PDGF essentially links TGF-beta signaling to nuclear beta-catenin accumulation in hepatocellular carcinoma progression. Oncogene, 26(23), 3395–3405. doi:10.1038/sj.onc.1210121.

    PubMed  CAS  Google Scholar 

  46. Gotzmann, J., Fischer, A. N., Zojer, M., Mikula, M., Proell, V., Huber, H., et al. (2006). A crucial function of PDGF in TGF-beta-mediated cancer progression of hepatocytes. Oncogene, 25(22), 3170–3185. doi:10.1038/sj.onc.1209083.

    PubMed  CAS  Google Scholar 

  47. Zhao, J. H., Luo, Y., Jiang, Y. G., He, D. L., & Wu, C. T. (2011). Knockdown of beta-catenin through shRNA cause a reversal of EMT and metastatic phenotypes induced by HIF-1alpha. Cancer Investigation, 29(6), 377–382. doi:10.3109/07357907.2010.512595.

    PubMed  CAS  Google Scholar 

  48. Cheng, Z. X., Sun, B., Wang, S. J., Gao, Y., Zhang, Y. M., Zhou, H. X., et al. (2011). Nuclear factor-kappaB-dependent epithelial to mesenchymal transition induced by HIF-1alpha activation in pancreatic cancer cells under hypoxic conditions. PLoS One, 6(8), e23752. doi:10.1371/journal.pone.0023752PONE-D-11-07211.

    PubMed  CAS  Google Scholar 

  49. Batlle, E., Sancho, E., Franci, C., Dominguez, D., Monfar, M., Baulida, J., et al. (2000). The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nature Cell Biology, 2(2), 84–89. doi:10.1038/35000034.

    PubMed  CAS  Google Scholar 

  50. Cano, A., Perez-Moreno, M. A., Rodrigo, I., Locascio, A., Blanco, M. J., del Barrio, M. G., et al. (2000). The transcription factor snail controls epithelial–mesenchymal transitions by repressing E-cadherin expression. Nature Cell Biology, 2(2), 76–83. doi:10.1038/35000025.

    PubMed  CAS  Google Scholar 

  51. Hajra, K. M., Chen, D. Y., & Fearon, E. R. (2002). The SLUG zinc-finger protein represses E-cadherin in breast cancer. Cancer Research, 62(6), 1613–1618.

    PubMed  CAS  Google Scholar 

  52. Comijn, J., Berx, G., Vermassen, P., Verschueren, K., van Grunsven, L., Bruyneel, E., et al. (2001). The two-handed E box binding zinc finger protein SIP1 downregulates E-cadherin and induces invasion. Molecular Cell, 7(6), 1267–1278. doi:S1097-2765(01)00260-X.

    PubMed  CAS  Google Scholar 

  53. Eger, A., Aigner, K., Sonderegger, S., Dampier, B., Oehler, S., Schreiber, M., et al. (2005). DeltaEF1 is a transcriptional repressor of E-cadherin and regulates epithelial plasticity in breast cancer cells. Oncogene, 24(14), 2375–2385. doi:10.1038/sj.onc.1208429.

    PubMed  CAS  Google Scholar 

  54. Remacle, J. E., Kraft, H., Lerchner, W., Wuytens, G., Collart, C., Verschueren, K., et al. (1999). New mode of DNA binding of multi-zinc finger transcription factors: deltaEF1 family members bind with two hands to two target sites. EMBO Journal, 18(18), 5073–5084. doi:10.1093/emboj/18.18.5073.

    PubMed  CAS  Google Scholar 

  55. Yang, J., Mani, S. A., Donaher, J. L., Ramaswamy, S., Itzykson, R. A., Come, C., et al. (2004). Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell, 117(7), 927–939. doi:10.1016/j.cell.2004.06.006S0092867404005768.

    PubMed  CAS  Google Scholar 

  56. Katoh, M. (2004). Human FOX gene family (review). International Journal of Oncology, 25(5), 1495–1500.

    PubMed  CAS  Google Scholar 

  57. Mani, S. A., Yang, J., Brooks, M., Schwaninger, G., Zhou, A., Miura, N., et al. (2007). Mesenchyme Forkhead 1 (FOXC2) plays a key role in metastasis and is associated with aggressive basal-like breast cancers. Proceedings of the National Academy of Sciences of the United States of America, 104(24), 10069–10074. doi:10.1073/pnas.0703900104.

    PubMed  CAS  Google Scholar 

  58. Bloushtain-Qimron, N., Yao, J., Snyder, E. L., Shipitsin, M., Campbell, L. L., Mani, S. A., et al. (2008). Cell type-specific DNA methylation patterns in the human breast. Proceedings of the National Academy of Sciences of the United States of America, 105(37), 14076–14081. doi:10.1073/pnas.0805206105.

    PubMed  CAS  Google Scholar 

  59. Ray, P. S., Wang, J., Qu, Y., Sim, M. S., Shamonki, J., Bagaria, S. P., et al. (2010). FOXC1 is a potential prognostic biomarker with functional significance in basal-like breast cancer. Cancer Research, 70(10), 3870–3876. doi:10.1158/0008-5472.CAN-09-4120.

    PubMed  CAS  Google Scholar 

  60. Feuerborn, A., Srivastava, P. K., Kuffer, S., Grandy, W. A., Sijmonsma, T. P., Gretz, N., et al. (2011). The Forkhead factor FoxQ1 influences epithelial differentiation. Journal of Cellular Physiology, 226(3), 710–719. doi:10.1002/jcp. 22385.

    PubMed  CAS  Google Scholar 

  61. Qiao, Y., Jiang, X., Lee, S. T., Karuturi, R. K., Hooi, S. C., & Yu, Q. (2011). FOXQ1 regulates epithelial–mesenchymal transition in human cancers. Cancer Research, 71(8), 3076–3086. doi:10.1158/0008-5472.CAN-10-2787.

    PubMed  CAS  Google Scholar 

  62. Zhang, H., Meng, F., Liu, G., Zhang, B., Zhu, J., Wu, F., et al. (2011). Forkhead transcription factor foxq1 promotes epithelial–mesenchymal transition and breast cancer metastasis. Cancer Research, 71(4), 1292–1301. doi:10.1158/0008-5472.CAN-10-2825.

    PubMed  CAS  Google Scholar 

  63. Tang, Y., Shu, G., Yuan, X., Jing, N., & Song, J. (2011). FOXA2 functions as a suppressor of tumor metastasis by inhibition of epithelial-to-mesenchymal transition in human lung cancers. Cell Research, 21(2), 316–326. doi:10.1038/cr.2010.126.

    PubMed  CAS  Google Scholar 

  64. Yori, J. L., Johnson, E., Zhou, G., Jain, M. K., & Keri, R. A. (2010). Kruppel-like factor 4 inhibits epithelial-to-mesenchymal transition through regulation of E-cadherin gene expression. Journal of Biological Chemistry, 285(22), 16854–16863. doi:10.1074/jbc.M110.114546.

    PubMed  CAS  Google Scholar 

  65. Gumireddy, K., Li, A., Gimotty, P. A., Klein-Szanto, A. J., Showe, L. C., Katsaros, D., et al. (2009). KLF17 is a negative regulator of epithelial–mesenchymal transition and metastasis in breast cancer. Nature Cell Biology, 11(11), 1297–1304. doi:10.1038/ncb1974.

    PubMed  CAS  Google Scholar 

  66. Wang, X., Zheng, M., Liu, G., Xia, W., McKeown-Longo, P. J., Hung, M. C., et al. (2007). Kruppel-like factor 8 induces epithelial to mesenchymal transition and epithelial cell invasion. Cancer Research, 67(15), 7184–7193. doi:10.1158/0008-5472.CAN-06-4729.

    PubMed  CAS  Google Scholar 

  67. Holian, J., Qi, W., Kelly, D. J., Zhang, Y., Mreich, E., Pollock, C. A., et al. (2008). Role of Kruppel-like factor 6 in transforming growth factor-beta1-induced epithelial–mesenchymal transition of proximal tubule cells. American Journal of Physiology. Renal Physiology, 295(5), F1388–F1396. doi:10.1152/ajprenal.00055.2008.

    PubMed  CAS  Google Scholar 

  68. Yu, M., Smolen, G. A., Zhang, J., Wittner, B., Schott, B. J., Brachtel, E., et al. (2009). A developmentally regulated inducer of EMT, LBX1, contributes to breast cancer progression. Genes & Development, 23(15), 1737–1742. doi:10.1101/gad.1809309.

    CAS  Google Scholar 

  69. Evdokimova, V., Tognon, C., Ng, T., Ruzanov, P., Melnyk, N., Fink, D., et al. (2009). Translational activation of snail1 and other developmentally regulated transcription factors by YB-1 promotes an epithelial–mesenchymal transition. Cancer Cell, 15(5), 402–415. doi:10.1016/j.ccr.2009.03.017.

    PubMed  CAS  Google Scholar 

  70. Fernando, R. I., Litzinger, M., Trono, P., Hamilton, D. H., Schlom, J., & Palena, C. (2010). The T-box transcription factor Brachyury promotes epithelial–mesenchymal transition in human tumor cells. The Journal of Clinical Investigation, 120(2), 533–544. doi:10.1172/JCI38379.

    PubMed  CAS  Google Scholar 

  71. Beltran, M., Puig, I., Pena, C., Garcia, J. M., Alvarez, A. B., Pena, R., et al. (2008). A natural antisense transcript regulates Zeb2/Sip1 gene expression during Snail1-induced epithelial–mesenchymal transition. Genes & Development, 22(6), 756–769. doi:10.1101/gad.455708.

    CAS  Google Scholar 

  72. Cano, A., & Nieto, M. A. (2008). Non-coding RNAs take centre stage in epithelial-to-mesenchymal transition. Trends in Cell Biology, 18(8), 357–359. doi:10.1016/j.tcb.2008.05.005.

    PubMed  CAS  Google Scholar 

  73. Gregory, P. A., Bert, A. G., Paterson, E. L., Barry, S. C., Tsykin, A., Farshid, G., et al. (2008). The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nature Cell Biology, 10(5), 593–601. doi:10.1038/ncb1722.

    PubMed  CAS  Google Scholar 

  74. Gregory, P. A., Bracken, C. P., Bert, A. G., & Goodall, G. J. (2008). MicroRNAs as regulators of epithelial–mesenchymal transition. Cell Cycle, 7(20), 3112–3118.

    PubMed  CAS  Google Scholar 

  75. Park, S. M., Gaur, A. B., Lengyel, E., & Peter, M. E. (2008). The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes & Development, 22(7), 894–907. doi:10.1101/gad.1640608.

    CAS  Google Scholar 

  76. Gebeshuber, C. A., Zatloukal, K., & Martinez, J. (2009). miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Reports, 10(4), 400–405. doi:10.1038/embor.2009.9.

    PubMed  CAS  Google Scholar 

  77. Kong, W., Yang, H., He, L., Zhao, J. J., Coppola, D., Dalton, W. S., et al. (2008). MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Molecular and Cellular Biology, 28(22), 6773–6784. doi:10.1128/MCB.00941-08.

    PubMed  CAS  Google Scholar 

  78. Dong, P., Kaneuchi, M., Watari, H., Hamada, J., Sudo, S., Ju, J., et al. (2011). MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Molecular Cancer, 10, 99. doi:10.1186/1476-4598-10-99.

    PubMed  CAS  Google Scholar 

  79. Kumarswamy, R., Mudduluru, G., Ceppi, P., Muppala, S., Kozlowski, M., Niklinski, J., et al. (2012). MicroRNA-30a inhibits epithelial-to-mesenchymal transition by targeting Snai1 and is downregulated in non-small cell lung cancer. International Journal of Cancer, 130, 2044–2053. doi:10.1002/ijc.26218.

    CAS  Google Scholar 

  80. Liu, X., Wang, C., Chen, Z., Jin, Y., Wang, Y., Kolokythas, A., et al. (2011). MicroRNA-138 suppresses epithelial–mesenchymal transition in squamous cell carcinoma cell lines. Biochemistry Journal, 440(1), 23–31. doi:10.1042/BJ20111006.

    CAS  Google Scholar 

  81. Stinson, S., Lackner, M. R., Adai, A. T., Yu, N., Kim, H. J., O’Brien, C., et al. (2011). TRPS1 targeting by miR-221/222 promotes the epithelial-to-mesenchymal transition in breast cancer. Science Signaling, 4(177), ra41. doi:10.1126/scisignal.2001538.

    PubMed  Google Scholar 

  82. Aigner, A. (2011). MicroRNAs (miRNAs) in cancer invasion and metastasis: Therapeutic approaches based on metastasis-related miRNAs. J Mol Med (Berl), 89(5), 445–457. doi:10.1007/s00109-010-0716-0.

    CAS  Google Scholar 

  83. Cortez, M. A., Ivan, C., Zhou, P., Wu, X., Ivan, M., & Calin, G. A. (2010). microRNAs in cancer: From bench to bedside. Advances in Cancer Research, 108, 113–157. doi:10.1016/B978-0-12-380888-2.00004-2.

    PubMed  CAS  Google Scholar 

  84. Garofalo, M., & Croce, C. M. (2011). microRNAs: Master regulators as potential therapeutics in cancer. Annual Review of Pharmacology and Toxicology, 51, 25–43. doi:10.1146/annurev-pharmtox-010510-100517.

    PubMed  CAS  Google Scholar 

  85. Wright, J. A., Richer, J. K., & Goodall, G. J. (2010). microRNAs and EMT in mammary cells and breast cancer. Journal of Mammary Gland Biology and Neoplasia, 15(2), 213–223. doi:10.1007/s10911-010-9183-z.

    PubMed  Google Scholar 

  86. Lombaerts, M., van Wezel, T., Philippo, K., Dierssen, J. W., Zimmerman, R. M., Oosting, J., et al. (2006). E-cadherin transcriptional downregulation by promoter methylation but not mutation is related to epithelial-to-mesenchymal transition in breast cancer cell lines. British Journal of Cancer, 94(5), 661–671. doi:10.1038/sj.bjc.6602996.

    PubMed  CAS  Google Scholar 

  87. Tryndyak, V. P., Beland, F. A., & Pogribny, I. P. (2010). 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. International Journal of Cancer, 126(11), 2575–2583.

    CAS  Google Scholar 

  88. Vrba, L., Jensen, T. J., Garbe, J. C., Heimark, R. L., Cress, A. E., Dickinson, S., et al. (2010). Role for DNA methylation in the regulation of miR-200c and miR-141 expression in normal and cancer cells. PLoS One, 5(1), e8697.

    PubMed  Google Scholar 

  89. Ke, X. S., Qu, Y., Cheng, Y., Li, W. C., Rotter, V., Oyan, A. M., et al. (2010). Global profiling of histone and DNA methylation reveals epigenetic-based regulation of gene expression during epithelial to mesenchymal transition in prostate cells. BMC Genomics, 11, 669. doi:10.1186/1471-2164-11-669.

    PubMed  Google Scholar 

  90. Bernstein, B. E., Mikkelsen, T. S., Xie, X., Kamal, M., Huebert, D. J., Cuff, J., et al. (2006). A bivalent chromatin structure marks key developmental genes in embryonic stem cells. Cell, 125(2), 315–326. doi:10.1016/j.cell.2006.02.041.

    PubMed  CAS  Google Scholar 

  91. Cedar, H., & Bergman, Y. (2009). Linking DNA methylation and histone modification: patterns and paradigms. Nature Reviews Genetics, 10(5), 295–304. doi:10.1038/nrg2540.

    PubMed  CAS  Google Scholar 

  92. Kaimori, A., Potter, J. J., Choti, M., Ding, Z., Mezey, E., & Koteish, A. A. (2010). Histone deacetylase inhibition suppresses the transforming growth factor beta1-induced epithelial-to-mesenchymal transition in hepatocytes. Hepatology, 52(3), 1033–1045.

    PubMed  CAS  Google Scholar 

  93. Yoshikawa, M., Hishikawa, K., Marumo, T., & Fujita, T. (2007). Inhibition of histone deacetylase activity suppresses epithelial-to-mesenchymal transition induced by TGF-beta1 in human renal epithelial cells. Journal of the American Society of Nephrology, 18(1), 58–65.

    PubMed  CAS  Google Scholar 

  94. Jordan, N. V., Johnson, G. L., & Abell, A. N. (2011). Tracking the intermediate stages of epithelial–mesenchymal transition in epithelial stem cells and cancer. Cell Cycle, 10(17), 2865–2873.

    PubMed  CAS  Google Scholar 

  95. Abell, A. N., Jordan, N. V., Huang, W., Prat, A., Midland, A. A., Johnson, N. L., et al. (2011). MAP3K4/CBP-regulated H2B acetylation controls epithelial–mesenchymal transition in trophoblast stem cells. Cell Stem Cell, 8(5), 525–537.

    PubMed  CAS  Google Scholar 

  96. Wels, C., Joshi, S., Koefinger, P., Bergler, H., & Schaider, H. (2011). Transcriptional activation of ZEB1 by Slug leads to cooperative regulation of the epithelial–mesenchymal transition-like phenotype in melanoma. The Journal of Investigative Dermatology, 131(9), 1877–1885. doi:10.1038/jid.2011.142.

    PubMed  CAS  Google Scholar 

  97. Casas, E., Kim, J., Bendesky, A., Ohno-Machado, L., Wolfe, C. J., & Yang, J. (2011). Snail2 is an essential mediator of Twist1-induced epithelial mesenchymal transition and metastasis. Cancer Research, 71(1), 245–254. doi:10.1158/0008-5472.CAN-10-2330.

    PubMed  CAS  Google Scholar 

  98. Taube, J. H., Herschkowitz, J. I., Komurov, K., Zhou, A. Y., Gupta, S., Yang, J., et al. (2010). Core epithelial-to-mesenchymal transition interactome gene-expression signature is associated with claudin-low and metaplastic breast cancer subtypes. Proceedings of the National Academy of Sciences of the United States of America, 107(35), 15449–15454. doi:10.1073/pnas.1004900107.

    PubMed  CAS  Google Scholar 

  99. 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(23), 11271–11278. doi:10.1158/0008-5472.CAN-06-2044.

    PubMed  CAS  Google Scholar 

  100. Korpal, M., Ell, B. J., Buffa, F. M., Ibrahim, T., Blanco, M. A., Celia-Terrassa, T., et al. (2011). Direct targeting of Sec23a by miR-200 s influences cancer cell secretome and promotes metastatic colonization. Nature Medicine, 17(9), 1101–1108. doi:10.1038/nm.2401.

    PubMed  CAS  Google Scholar 

  101. 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.

    PubMed  Google Scholar 

  102. Jeschke, U., Mylonas, I., Kuhn, C., Shabani, N., Kunert-Keil, C., Schindlbeck, C., et al. (2007). Expression of E-cadherin in human ductal breast cancer carcinoma in situ, invasive carcinomas, their lymph node metastases, their distant metastases, carcinomas with recurrence and in recurrence. Anticancer Research, 27(4A), 1969–1974.

    PubMed  CAS  Google Scholar 

  103. Park, D., Karesen, R., Axcrona, U., Noren, T., & Sauer, T. (2007). Expression pattern of adhesion molecules (E-cadherin, alpha-, beta-, gamma-catenin and claudin-7), their influence on survival in primary breast carcinoma, and their corresponding axillary lymph node metastasis. APMIS, 115(1), 52–65.

    PubMed  CAS  Google Scholar 

  104. Christiansen, J. J., & Rajasekaran, A. K. (2006). Reassessing epithelial to mesenchymal transition as a prerequisite for carcinoma invasion and metastasis. Cancer Research, 66(17), 8319–8326. doi:10.1158/0008-5472.CAN-06-0410.

    PubMed  CAS  Google Scholar 

  105. Garber, K. (2008). Epithelial-to-mesenchymal transition is important to metastasis, but questions remain. Journal of the National Cancer Institute, 100(4), 232–233. doi:10.1093/jnci/djn032.

    PubMed  Google Scholar 

  106. Tarin, D., Thompson, E. W., & Newgreen, D. F. (2005). The fallacy of epithelial mesenchymal transition in neoplasia. Cancer Research, 65(14), 5996–6000. doi:10.1158/0008-5472.CAN-05-0699. discussion 6000–5991.

    PubMed  CAS  Google Scholar 

  107. Thompson, E. W., Newgreen, D. F., & Tarin, D. (2005). Carcinoma invasion and metastasis: a role for epithelial–mesenchymal transition? Cancer Research, 65(14), 5991–5995. doi:10.1158/0008-5472.CAN-05-0616. discussion 5995.

    PubMed  CAS  Google Scholar 

  108. Aslakson, C. J., & Miller, F. R. (1992). Selective events in the metastatic process defined by analysis of the sequential dissemination of subpopulations of a mouse mammary tumor. Cancer Research, 52(6), 1399–1405.

    PubMed  CAS  Google Scholar 

  109. Zhang, H., Meng, F., Wu, S., Kreike, B., Sethi, S., Chen, W., et al. (2011). Engagement of I-branching beta}-1, 6-N-acetylglucosaminyltransferase 2 in breast cancer metastasis and TGF-{beta signaling. Cancer Research, 71(14), 4846–4856. doi:10.1158/0008-5472.CAN-11-0414.

    PubMed  CAS  Google Scholar 

  110. Lou, Y., Preobrazhenska, O., auf dem Keller, U., Sutcliffe, M., Barclay, L., McDonald, P. C., et al. (2008). Epithelial–mesenchymal transition (EMT) is not sufficient for spontaneous murine breast cancer metastasis. Developmental Dynamics, 237(10), 2755–2768. doi:10.1002/dvdy.21658.

    PubMed  CAS  Google Scholar 

  111. Futterman, M. A., Garcia, A. J., & Zamir, E. A. (2011). Evidence for partial epithelial-to-mesenchymal transition (pEMT) and recruitment of motile blastoderm edge cells during avian epiboly. Developmental Dynamics, 240(6), 1502–1511. doi:10.1002/dvdy.22607.

    PubMed  CAS  Google Scholar 

  112. Chao, Y., Wu, Q., Acquafondata, M., Dhir, R., & Wells, A. (2011). Partial mesenchymal to epithelial reverting transition in breast and prostate cancer metastases. Cancer Microenviron, 5, 19–28. doi:10.1007/s12307-011-0085-4.

    PubMed  Google Scholar 

  113. Bruewer, M., Hopkins, A. M., Hobert, M. E., Nusrat, A., & Madara, J. L. (2004). RhoA, Rac1, and Cdc42 exert distinct effects on epithelial barrier via selective structural and biochemical modulation of junctional proteins and F-actin. American Journal of Physiology. Cell Physiology, 287(2), C327–C335. doi:10.1152/ajpcell.00087.200400087.2004.

    PubMed  CAS  Google Scholar 

  114. Hay, E. D., & Zuk, A. (1995). Transformations between epithelium and mesenchyme: normal, pathological, and experimentally induced. American Journal of Kidney Diseases, 26(4), 678–690. doi:0272-6386(95)90610-X.

    PubMed  CAS  Google Scholar 

  115. Pinkas, J., & Leder, P. (2002). MEK1 signaling mediates transformation and metastasis of EpH4 mammary epithelial cells independent of an epithelial to mesenchymal transition. Cancer Research, 62(16), 4781–4790.

    PubMed  CAS  Google Scholar 

  116. Xue, C., Plieth, D., Venkov, C., Xu, C., & Neilson, E. G. (2003). The gatekeeper effect of epithelial–mesenchymal transition regulates the frequency of breast cancer metastasis. Cancer Research, 63(12), 3386–3394.

    PubMed  CAS  Google Scholar 

  117. Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., et al. (2008). The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell, 133(4), 704–715. doi:10.1016/j.cell.2008.03.027.

    PubMed  CAS  Google Scholar 

  118. Morel, A. P., Lievre, M., Thomas, C., Hinkal, G., Ansieau, S., & Puisieux, A. (2008). Generation of breast cancer stem cells through epithelial–mesenchymal transition. PLoS One, 3(8), e2888. doi:10.1371/journal.pone.0002888.

    PubMed  Google Scholar 

  119. Aktas, B., Tewes, M., Fehm, T., Hauch, S., Kimmig, R., & Kasimir-Bauer, S. (2009). Stem cell and epithelial–mesenchymal transition markers are frequently overexpressed in circulating tumor cells of metastatic breast cancer patients. Breast Cancer Research, 11(4), R46. doi:10.1186/bcr2333.

    PubMed  Google Scholar 

  120. Raimondi, C., Gradilone, A., Naso, G., Vincenzi, B., Petracca, A., Nicolazzo, C., et al. (2011). Epithelial–mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Research and Treatment, 130(2), 449–455. doi:10.1007/s10549-011-1373-x.

    PubMed  CAS  Google Scholar 

  121. Kallergi, G., Papadaki, M. A., Politaki, E., Mavroudis, D., Georgoulias, V., & Agelaki, S. (2011). Epithelial to mesenchymal transition markers expressed in circulating tumour cells of early and metastatic breast cancer patients. Breast Cancer Research, 13(3), R59. doi:10.1186/bcr2896.

    PubMed  Google Scholar 

  122. Armstrong, A. J., Marengo, M. S., Oltean, S., Kemeny, G., Bitting, R. L., Turnbull, J. D., et al. (2011). Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Molecular Cancer Research, 9(8), 997–1007. doi:10.1158/1541-7786.MCR-10-0490.

    PubMed  CAS  Google Scholar 

  123. Li, R., Liang, J., Ni, S., Zhou, T., Qing, X., Li, H., et al. (2010). A mesenchymal-to-epithelial transition initiates and is required for the nuclear reprogramming of mouse fibroblasts. Cell Stem Cell, 7(1), 51–63. doi:10.1016/j.stem.2010.04.014.

    PubMed  CAS  Google Scholar 

  124. Samavarchi-Tehrani, P., Golipour, A., David, L., Sung, H. K., Beyer, T. A., Datti, A., et al. (2010). Functional genomics reveals a BMP-driven mesenchymal-to-epithelial transition in the initiation of somatic cell reprogramming. Cell Stem Cell, 7(1), 64–77. doi:10.1016/j.stem.2010.04.015.

    PubMed  CAS  Google Scholar 

  125. Blick, T., Widodo, E., Hugo, H., Waltham, M., Lenburg, M. E., Neve, R. M., et al. (2008). Epithelial mesenchymal transition traits in human breast cancer cell lines. Clinical & Experimental Metastasis, 25(6), 629–642. doi:10.1007/s10585-008-9170-6.

    CAS  Google Scholar 

  126. Neve, R. M., Chin, K., Fridlyand, J., Yeh, J., Baehner, F. L., Fevr, T., et al. (2006). A collection of breast cancer cell lines for the study of functionally distinct cancer subtypes. Cancer Cell, 10(6), 515–527. doi:10.1016/j.ccr.2006.10.008.

    PubMed  CAS  Google Scholar 

  127. Sayan, A. E., Griffiths, T. R., Pal, R., Browne, G. J., Ruddick, A., Yagci, T., 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(35), 14884–14889. doi:10.1073/pnas.0902042106.

    PubMed  CAS  Google Scholar 

  128. Fuchs, B. C., Fujii, T., Dorfman, J. D., Goodwin, J. M., Zhu, A. X., Lanuti, M., et al. (2008). Epithelial-to-mesenchymal transition and integrin-linked kinase mediate sensitivity to epidermal growth factor receptor inhibition in human hepatoma cells. Cancer Research, 68(7), 2391–2399. doi:10.1158/0008-5472.CAN-07-2460.

    PubMed  CAS  Google Scholar 

  129. Li, L. N., Zhang, H. D., Yuan, S. J., Yang, D. X., Wang, L., & Sun, Z. X. (2008). Differential sensitivity of colorectal cancer cell lines to artesunate is associated with expression of beta-catenin and E-cadherin. European Journal of Pharmacology, 588(1), 1–8. doi:10.1016/j.ejphar.2008.03.041.

    PubMed  CAS  Google Scholar 

  130. Sokol, J. P., Neil, J. R., Schiemann, B. J., & Schiemann, W. P. (2005). The use of cystatin C to inhibit epithelial–mesenchymal transition and morphological transformation stimulated by transforming growth factor-beta. Breast Cancer Research, 7(5), R844–R853. doi:10.1186/bcr1312.

    PubMed  CAS  Google Scholar 

  131. Feldmann, G., Dhara, S., Fendrich, V., Bedja, D., Beaty, R., Mullendore, M., et al. (2007). Blockade of hedgehog signaling inhibits pancreatic cancer invasion and metastases: A new paradigm for combination therapy in solid cancers. Cancer Research, 67(5), 2187–2196. doi:10.1158/0008-5472.CAN-06-3281.

    PubMed  CAS  Google Scholar 

  132. Feldmann, G., Fendrich, V., McGovern, K., Bedja, D., Bisht, S., Alvarez, H., et al. (2008). An orally bioavailable small-molecule inhibitor of Hedgehog signaling inhibits tumor initiation and metastasis in pancreatic cancer. Molecular Cancer Therapeutics, 7(9), 2725–2735. doi:10.1158/1535-7163.MCT-08-0573.

    PubMed  CAS  Google Scholar 

  133. Yauch, R. L., Januario, T., Eberhard, D. A., Cavet, G., Zhu, W., Fu, L., 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(24 Pt 1), 8686–8698. doi:10.1158/1078-0432.CCR-05-1492.

    PubMed  CAS  Google Scholar 

  134. Kajiyama, H., Shibata, K., Terauchi, M., Yamashita, M., Ino, K., Nawa, A., et al. (2007). Chemoresistance to paclitaxel induces epithelial–mesenchymal transition and enhances metastatic potential for epithelial ovarian carcinoma cells. International Journal of Oncology, 31(2), 277–283.

    PubMed  CAS  Google Scholar 

  135. Konecny, G. E., Venkatesan, N., Yang, G., Dering, J., Ginther, C., Finn, R., et al. (2008). Activity of lapatinib a novel HER2 and EGFR dual kinase inhibitor in human endometrial cancer cells. British Journal of Cancer, 98(6), 1076–1084. doi:10.1038/sj.bjc.6604278.

    PubMed  CAS  Google Scholar 

  136. Yang, Y., Pan, X., Lei, W., Wang, J., & Song, J. (2006). Transforming growth factor-beta1 induces epithelial-to-mesenchymal transition and apoptosis via a cell cycle-dependent mechanism. Oncogene, 25(55), 7235–7244.

    PubMed  CAS  Google Scholar 

  137. 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(10), 1131–1143.

    CAS  Google Scholar 

  138. Mejlvang, J., Kriajevska, M., Vandewalle, C., Chernova, T., Sayan, A. E., Berx, G., 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(11), 4615–4624.

    PubMed  CAS  Google Scholar 

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Acknowledgment

The authors would like to thank Ms. Elizabeth A. Katz of the Barbara Ann Karmanos Cancer Institute’s Marketing & Communications Department for editing our manuscript. We also want to thank Dr. Cecilia Speyer of the Department of Surgery, WSU for her insightful discussions. This work was supported in part by the Susan G. Komen grant KG080465 (G. Wu) and the NOMIC grant from the Karmanos Cancer Institute (G. Wu).

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Meng, F., Wu, G. The rejuvenated scenario of epithelial–mesenchymal transition (EMT) and cancer metastasis. Cancer Metastasis Rev 31, 455–467 (2012). https://doi.org/10.1007/s10555-012-9379-3

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