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Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer

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Abstract

Epithelial-to-mesenchymal transition (EMT) is a process that plays essential roles in development and wound healing that is characterized by loss of homotypic adhesion and cell polarity and increased invasion and migration. At the molecular level, EMT is characterized by loss of E-cadherin and increased expression of several transcriptional repressors of E-cadherin expression (Zeb-1, Zeb-2, Twist, Snail, and Slug). Early work established that loss of E-cadherin and increased expression of MMP-9 was associated with a poor clinical outcome in patients with urothelial tumors, suggesting that EMT might also be associated with bladder cancer progression and metastasis. More recently, we have used global gene expression profiling to characterize the molecular heterogeneity in human urothelial cancer cell lines (n = 20) and primary patient tumors, and unsupervised clustering analyses revealed that the cells naturally segregate into two discrete “epithelial” and “mesenchymal” subsets, the latter consisting entirely of muscle-invasive tumors. Importantly, sensitivity to inhibitors of the epidermal growth factor receptor (EGFR) or type-3 fibroblast growth factor receptor (FGFR3) was confined to the “epithelial” subset, and sensitivity to EGFR inhibitors could be reestablished by micro-RNA-mediated molecular reversal of EMT. The results suggest that EMT coordinately regulates drug resistance and muscle invasion/metastasis in urothelial cancer and is a dominant feature of overall cancer biology.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. De Donatis, A., Comito, G., Buricchi, F., et al. (2008). Proliferation versus migration in platelet-derived growth factor signaling: the key role of endocytosis. Journal of Biological Chemistry, 283, 19948–19956.

    Article  PubMed  CAS  Google Scholar 

  3. Giese, A., Loo, M. A., Tran, N., Haskett, D., Coons, S. W., & Berens, M. E. (1996). Dichotomy of astrocytoma migration and proliferation. International Journal of Cancer, 67, 275–282.

    Article  CAS  Google Scholar 

  4. Engel, M. E., Datta, P. K., & Moses, H. L. (1998). Signal transduction by transforming growth factor-beta: a cooperative paradigm with extensive negative regulation. Journal of Cellular Biochemistry. Supplement, 30–31, 111–122.

    PubMed  Google Scholar 

  5. Horiguchi, K., Shirakihara, T., Nakano, A., Imamura, T., Miyazono, K., & Saitoh, M. (2009). Role of Ras signaling in the induction of snail by transforming growth factor-beta. Journal of Biological Chemistry, 284, 245–253.

    Article  CAS  PubMed  Google Scholar 

  6. Davis, B. N., Hilyard, A. C., Lagna, G., & Hata, A. (2008). SMAD proteins control DROSHA-mediated microRNA maturation. Nature, 454, 56–61.

    Article  CAS  PubMed  Google Scholar 

  7. Levy, L., & Hill, C. S. (2005). Smad4 dependency defines two classes of transforming growth factor beta (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Molecular and Cellular Biology, 25, 8108–8125.

    Article  CAS  PubMed  Google Scholar 

  8. 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.

    Article  CAS  PubMed  Google Scholar 

  9. Gregory, P. A., Bert, A. G., Paterson, E. L., 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.

    Article  CAS  PubMed  Google Scholar 

  10. 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 and Development, 22, 894–907.

    Article  CAS  PubMed  Google Scholar 

  11. Adam, L., Zhong, M., Choi, W., et al. (2009). miR-200 expression regulates epithelial-to-mesenchymal transition in bladder cancer cells and reverses resistance to epidermal growth factor receptor therapy. Clinical Cancer Research, 15, 5060–5072.

    Article  CAS  PubMed  Google Scholar 

  12. Honn, K. V., & Tang, D. G. (1992). Adhesion molecules and tumor cell interaction with endothelium and subendothelial matrix. Cancer and Metastasis Reviews, 11, 353–375.

    Article  CAS  PubMed  Google Scholar 

  13. Herrera, C. A., Xu, L., Bucana, C. D., et al. (2002). Expression of metastasis-related genes in human epithelial ovarian tumors. International Journal of Oncology, 20, 5–13.

    CAS  PubMed  Google Scholar 

  14. Kim, S. J., Uehara, H., Karashima, T., McCarty, M., Shih, N., & Fidler, I. J. (2001). Expression of interleukin-8 correlates with angiogenesis, tumorigenicity, and metastasis of human prostate cancer cells implanted orthotopically in nude mice. Neoplasia, 3, 33–42.

    Article  CAS  PubMed  Google Scholar 

  15. Slaton, J. W., Inoue, K., Perrotte, P., et al. (2001). Expression levels of genes that regulate metastasis and angiogenesis correlate with advanced pathological stage of renal cell carcinoma. American Journal of Pathology, 158, 735–743.

    CAS  PubMed  Google Scholar 

  16. Kuniyasu, H., Troncoso, P., Johnston, D., et al. (2000). Relative expression of type IV collagenase, E-cadherin, and vascular endothelial growth factor/vascular permeability factor in prostatectomy specimens distinguishes organ-confined from pathologically advanced prostate cancers. Clinical Cancer Research, 6, 2295–2308.

    CAS  PubMed  Google Scholar 

  17. Herbst, R. S., Yano, S., Kuniyasu, H., et al. (2000). Differential expression of E-cadherin and type IV collagenase genes predicts outcome in patients with stage I non-small cell lung carcinoma. Clinical Cancer Research, 6, 790–797.

    CAS  PubMed  Google Scholar 

  18. Kuniyasu, H., Ellis, L. M., Evans, D. B., et al. (1999). Relative expression of E-cadherin and type IV collagenase genes predicts disease outcome in patients with resectable pancreatic carcinoma. Clinical Cancer Research, 5, 25–33.

    CAS  PubMed  Google Scholar 

  19. Anzai, H., Kitadai, Y., Bucana, C. D., Sanchez, R., Omoto, R., & Fidler, I. J. (1998). Expression of metastasis-related genes in surgical specimens of human gastric cancer can predict disease recurrence. European Journal of Cancer, 34, 558–565.

    Article  CAS  PubMed  Google Scholar 

  20. Greene, G. F., Kitadai, Y., Pettaway, C. A., von Eschenbach, A. C., Bucana, C. D., & Fidler, I. J. (1997). Correlation of metastasis-related gene expression with metastatic potential in human prostate carcinoma cells implanted in nude mice using an in situ messenger RNA hybridization technique. American Journal of Pathology, 150, 1571–1582.

    CAS  PubMed  Google Scholar 

  21. Kitadai, Y., Ellis, L. M., Tucker, S. L., et al. (1996). Multiparametric in situ mRNA hybridization analysis to predict disease recurrence in patients with colon carcinoma. American Journal of Pathology, 149, 1541–1551.

    CAS  PubMed  Google Scholar 

  22. Kitadai, Y., Ellis, L. M., Takahashi, Y., et al. (1995). Multiparametric in situ messenger RNA hybridization analysis to detect metastasis-related genes in surgical specimens of human colon carcinomas. Clinical Cancer Research, 1, 1095–1102.

    CAS  PubMed  Google Scholar 

  23. Slaton, J. W., Millikan, R., Inoue, K., et al. (2004). Correlation of metastasis related gene expression and relapse-free survival in patients with locally advanced bladder cancer treated with cystectomy and chemotherapy. Journal of Urology, 171, 570–574.

    Article  CAS  PubMed  Google Scholar 

  24. Onder, T. T., Gupta, P. B., Mani, S. A., Yang, J., Lander, E. S., & Weinberg, R. A. (2008). Loss of E-cadherin promotes metastasis via multiple downstream transcriptional pathways. Cancer Research, 68, 3645–3654.

    Article  CAS  PubMed  Google Scholar 

  25. Hajra, K. M., & Fearon, E. R. (2002). Cadherin and catenin alterations in human cancer. Genes Chromosomes Cancer, 34, 255–268.

    Article  CAS  PubMed  Google Scholar 

  26. Gibbons, D. L., Lin, W., Creighton, C. J., et al. (2009). Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. Genes and Development, 23, 2140–2151.

    Article  CAS  PubMed  Google Scholar 

  27. Strathdee, G. (2002). Epigenetic versus genetic alterations in the inactivation of E-cadherin. Seminars in Cancer Biology, 12, 373–379.

    Article  CAS  PubMed  Google Scholar 

  28. Dinney, C. P., McConkey, D. J., Millikan, R. E., et al. (2004). Focus on bladder cancer. Cancer Cell, 6, 111–116.

    Article  CAS  PubMed  Google Scholar 

  29. Blaveri, E., Simko, J. P., Korkola, J. E., et al. (2005). Bladder cancer outcome and subtype classification by gene expression. Clinical Cancer Research, 11, 4044–4055.

    Article  CAS  PubMed  Google Scholar 

  30. Sanchez-Carbayo, M., Socci, N. D., Lozano, J., Saint, F., & Cordon-Cardo, C. (2006). Defining molecular profiles of poor outcome in patients with invasive bladder cancer using oligonucleotide microarrays. Journal of Clinical Oncology, 24, 778–789.

    Article  CAS  PubMed  Google Scholar 

  31. Baumgart, E., Cohen, M. S., Silva Neto, B., et al. (2007). Identification and prognostic significance of an epithelial-mesenchymal transition expression profile in human bladder tumors. Clinical Cancer Research, 13, 1685–1694.

    Article  CAS  PubMed  Google Scholar 

  32. 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.

    Article  CAS  PubMed  Google Scholar 

  33. Urist, M. J., Di Como, C. J., Lu, M. L., et al. (2002). Loss of p63 expression is associated with tumor progression in bladder cancer. American Journal of Pathology, 161, 1199–1206.

    CAS  PubMed  Google Scholar 

  34. Di Como, C. J., Urist, M. J., Babayan, I., et al. (2002). p63 expression profiles in human normal and tumor tissues. Clinical Cancer Research, 8, 494–501.

    PubMed  Google Scholar 

  35. Comperat, E., Camparo, P., Haus, R., et al. (2006). Immunohistochemical expression of p63, p53 and MIB-1 in urinary bladder carcinoma. A tissue microarray study of 158 cases. Virchows Archiv, 448, 319–324.

    Article  CAS  PubMed  Google Scholar 

  36. Koga, F., Kawakami, S., Fujii, Y., et al. (2003). Impaired p63 expression associates with poor prognosis and uroplakin III expression in invasive urothelial carcinoma of the bladder. Clinical Cancer Research, 9, 5501–5507.

    CAS  PubMed  Google Scholar 

  37. Moll, U. M. (2003). The Role of p63 and p73 in tumor formation and progression: coming of age toward clinical usefulness. Commentary re: F. Koga et al., Impaired p63 expression associates with poor prognosis and uroplakin III expression in invasive urothelial carcinoma of the bladder. Clinical Cancer Research, 9, 5501–5507.

    Google Scholar 

  38. Puig, P., et al. (2003). p73 Expression in human normal and tumor tissues: loss of p73alpha expression is associated with tumor progression in bladder Cancer. Clinical Cancer Research, 9, 5642–5651. Clin Cancer Res 2003; 9: 5437–5441.

    CAS  PubMed  Google Scholar 

  39. Reis-Filho, J. S., Simpson, P. T., Martins, A., Preto, A., Gartner, F., & Schmitt, F. C. (2003). Distribution of p63, cytokeratins 5/6 and cytokeratin 14 in 51 normal and 400 neoplastic human tissue samples using TARP-4 multi-tumor tissue microarray. Virchows Archiv, 443, 122–132.

    Article  CAS  PubMed  Google Scholar 

  40. Koga, F., Kawakami, S., Kumagai, J., et al. (2003). Impaired Delta Np63 expression associates with reduced beta-catenin and aggressive phenotypes of urothelial neoplasms. British Journal of Cancer, 88, 740–747.

    Article  CAS  PubMed  Google Scholar 

  41. Park, B. J., Lee, S. J., Kim, J. I., et al. (2000). Frequent alteration of p63 expression in human primary bladder carcinomas. Cancer Research, 60, 3370–3374.

    CAS  PubMed  Google Scholar 

  42. Signoretti, S., & Loda, M. (2006). Defining cell lineages in the prostate epithelium. Cell Cycle, 5, 138–141.

    CAS  PubMed  Google Scholar 

  43. Signoretti, S., Pires, M. M., Lindauer, M., et al. (2005). p63 regulates commitment to the prostate cell lineage. Proceedings of the National Academy of Sciences of the United States of America, 102, 11355–11360.

    Article  CAS  PubMed  Google Scholar 

  44. Signoretti, S., Waltregny, D., Dilks, J., et al. (2000). p63 is a prostate basal cell marker and is required for prostate development. American Journal of Pathology, 157, 1769–1775.

    CAS  PubMed  Google Scholar 

  45. Blanpain, C., & Fuchs, E. (2007). p63: revving up epithelial stem-cell potential. Nature Cell Biology, 9, 731–733.

    Article  CAS  PubMed  Google Scholar 

  46. Kurzrock, E. A., Lieu, D. K., Degraffenried, L. A., Chan, C. W., & Isseroff, R. R. (2008). Label-retaining cells of the bladder: candidate urothelial stem cells. American Journal of Physiology. Renal Physiology, 294, F1415–F1421.

    Article  CAS  PubMed  Google Scholar 

  47. Mendelsohn, J., & Baselga, J. (2006). Epidermal growth factor receptor targeting in cancer. Seminars in Oncology, 33, 369–385.

    Article  CAS  PubMed  Google Scholar 

  48. Lipponen, P., & Eskelinen, M. (1994). Expression of epidermal growth factor receptor in bladder cancer as related to established prognostic factors, oncoprotein (c-erbB-2, p53) expression and long-term prognosis. British Journal of Cancer, 69, 1120–1125.

    CAS  PubMed  Google Scholar 

  49. Izawa, J. I., Slaton, J. W., Kedar, D., et al. (2001). Differential expression of progression-related genes in the evolution of superficial to invasive transitional cell carcinoma of the bladder. Oncology Reports, 8, 9–15.

    CAS  PubMed  Google Scholar 

  50. Perrotte, P., Matsumoto, T., Inoue, K., et al. (1999). Anti-epidermal growth factor receptor antibody C225 inhibits angiogenesis in human transitional cell carcinoma growing orthotopically in nude mice. Clinical Cancer Research, 5, 257–265.

    CAS  PubMed  Google Scholar 

  51. Cheng, J., Huang, H., Zhang, Z. T., et al. (2002). Overexpression of epidermal growth factor receptor in urothelium elicits urothelial hyperplasia and promotes bladder tumor growth. Cancer Research, 62, 4157–4163.

    CAS  PubMed  Google Scholar 

  52. Janne, P. A., Engelman, J. A., & Johnson, B. E. (2005). Epidermal growth factor receptor mutations in non-small-cell lung cancer: implications for treatment and tumor biology. Journal of Clinical Oncology, 23, 3227–3234.

    Article  CAS  PubMed  Google Scholar 

  53. Eberhard, D. A., Giaccone, G., & Johnson, B. E. (2008). Biomarkers of response to epidermal growth factor receptor inhibitors in Non-Small-Cell Lung Cancer Working Group: standardization for use in the clinical trial setting. Journal of Clinical Oncology, 26, 983–994.

    Article  PubMed  Google Scholar 

  54. Heymach, J. V., Nilsson, M., Blumenschein, G., Papadimitrakopoulou, V., & Herbst, R. (2006). Epidermal growth factor receptor inhibitors in development for the treatment of non-small cell lung cancer. Clinical Cancer Research, 12, 4441s–4445s.

    Article  CAS  PubMed  Google Scholar 

  55. Lara-Guerra, H., Waddell, T. K., Salvarrey, M. A., et al. (2009). Phase II study of preoperative gefitinib in clinical stage i non-small-cell lung cancer. Journal of Clinical Oncology (in press).

  56. Hirsch, F. R., Scagliotti, G. V., Langer, C. J., Varella-Garcia, M., & Franklin, W. A. (2003). Epidermal growth factor family of receptors in preneoplasia and lung cancer: perspectives for targeted therapies. Lung Cancer, 41(Suppl 1), S29–S42.

    Article  PubMed  Google Scholar 

  57. Laurent-Puig, P., Cayre, A., Manceau, G., et al. (2009). Analysis of PTEN, BRAF, and EGFR status in determining benefit from cetuximab therapy in wild-type KRAS metastatic colon cancer. Journal of Clinical Oncology, 27(35), 5924–5930.

    Google Scholar 

  58. Zhu, C. Q., da Cunha Santos, G., Ding, K., et al. (2008). Role of KRAS and EGFR as biomarkers of response to erlotinib in National Cancer Institute of Canada Clinical Trials Group Study BR.21. Journal of Clinical Oncology, 26, 4268–4275.

    Article  CAS  PubMed  Google Scholar 

  59. Miller, V. A., Riely, G. J., Zakowski, M. F., et al. (2008). Molecular characteristics of bronchioloalveolar carcinoma and adenocarcinoma, bronchioloalveolar carcinoma subtype, predict response to erlotinib. Journal of Clinical Oncology, 26, 1472–1478.

    Article  CAS  PubMed  Google Scholar 

  60. Amado, R. G., Wolf, M., Peeters, M., et al. (2008). Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. Journal of Clinical Oncology, 26, 1626–1634.

    Article  CAS  PubMed  Google Scholar 

  61. Eberhard, D. A., Johnson, B. E., Amler, L. C., et al. (2005). Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. Journal of Clinical Oncology, 23, 5900–5909.

    Article  CAS  PubMed  Google Scholar 

  62. Kassouf, W., Dinney, C. P., Brown, G., et al. (2005). Uncoupling between epidermal growth factor receptor and downstream signals defines resistance to the antiproliferative effect of Gefitinib in bladder cancer cells. Cancer Research, 65, 10524–10535.

    Article  CAS  PubMed  Google Scholar 

  63. Shrader, M., Pino, M. S., Lashinger, L., et al. (2007). Gefitinib reverses TRAIL resistance in human bladder cancer cell lines via inhibition of AKT-mediated X-linked inhibitor of apoptosis protein expression. Cancer Research, 67, 1430–1435.

    Article  CAS  PubMed  Google Scholar 

  64. Shrader, M., Pino, M. S., Brown, G., et al. (2007). Molecular correlates of gefitinib responsiveness in human bladder cancer cells. Molecular Cancer Therapeutics, 6, 277–285.

    Article  CAS  PubMed  Google Scholar 

  65. Black, P. C., Brown, G. A., Inamoto, T., et al. (2008). Sensitivity to epidermal growth factor receptor inhibitor requires E-cadherin expression in urothelial carcinoma cells. Clinical Cancer Research, 14, 1478–1486.

    Article  CAS  PubMed  Google Scholar 

  66. Tomlinson, D. C., Baldo, O., Harnden, P., & Knowles, M. A. (2007). FGFR3 protein expression and its relationship to mutation status and prognostic variables in bladder cancer. Journal of Pathology, 213, 91–98.

    Article  CAS  PubMed  Google Scholar 

  67. Sibley, K., Stern, P., & Knowles, M. A. (2001). Frequency of fibroblast growth factor receptor 3 mutations in sporadic tumours. Oncogene, 20, 4416–4418.

    Article  CAS  PubMed  Google Scholar 

  68. Tomlinson, D. C., Hurst, C. D., & Knowles, M. A. (2007). Knockdown by shRNA identifies S249C mutant FGFR3 as a potential therapeutic target in bladder cancer. Oncogene, 26, 5889–5899.

    Article  CAS  PubMed  Google Scholar 

  69. Qing, J., Du, X., Chen, Y., et al. (2009). Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. Journal of Clinical Investigation, 119, 1216–1229.

    Article  CAS  PubMed  Google Scholar 

  70. Huang, P. H., Mukasa, A., Bonavia, R., et al. (2007). Quantitative analysis of EGFRvIII cellular signaling networks reveals a combinatorial therapeutic strategy for glioblastoma. Proceedings of the National Academy of Sciences of the United States of America, 104, 12867–12872.

    Article  CAS  PubMed  Google Scholar 

  71. Mellinghoff, I. K., Wang, M. Y., Vivanco, I., et al. (2005). Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. New England Journal of Medicine, 353, 2012–2024.

    Article  CAS  PubMed  Google Scholar 

  72. Blehm, K. N., Spiess, P. E., Bondaruk, J. E., et al. (2006). Mutations within the kinase domain and truncations of the epidermal growth factor receptor are rare events in bladder cancer: implications for therapy. Clinical Cancer Research, 12, 4671–4677.

    Article  CAS  PubMed  Google Scholar 

  73. Simons, M. P., O'Donnell, M. A., & Griffith, T. S. (2008). Role of neutrophils in BCG immunotherapy for bladder cancer. Urologic Oncology, 26, 341–345.

    CAS  PubMed  Google Scholar 

  74. Simons, M. P., Nauseef, W. M., & Griffith, T. S. (2007). Neutrophils and TRAIL: insights into BCG immunotherapy for bladder cancer. Immunologic Research, 39, 79–93.

    Article  CAS  PubMed  Google Scholar 

  75. Simons, M. P., Moore, J. M., Kemp, T. J., & Griffith, T. S. (2007). Identification of the mycobacterial subcomponents involved in the release of tumor necrosis factor-related apoptosis-inducing ligand from human neutrophils. Infection and Immunity, 75, 1265–1271.

    Article  CAS  PubMed  Google Scholar 

  76. Kemp, T. J., Ludwig, A. T., Earel, J. K., et al. (2005). Neutrophil stimulation with Mycobacterium bovis bacillus Calmette-Guerin (BCG) results in the release of functional soluble TRAIL/Apo-2L. Blood, 106, 3474–3482.

    Article  CAS  PubMed  Google Scholar 

  77. Ludwig, A. T., Moore, J. M., Luo, Y., et al. (2004). Tumor necrosis factor-related apoptosis-inducing ligand: a novel mechanism for Bacillus Calmette-Guerin-induced antitumor activity. Cancer Research, 64, 3386–3390.

    Article  CAS  PubMed  Google Scholar 

  78. Logothetis, C. J., Hossan, E., Recondo, G., et al. (1994). 5-Fluorouracil and interferon-alpha in chemotherapy refractory bladder carcinoma: an effective regimen. Anticancer Research, 14, 1265–1269.

    CAS  PubMed  Google Scholar 

  79. Logothetis, C. J., Hossan, E., Sella, A., Dexeus, F. H., & Amato, R. J. (1991). Fluorouracil and recombinant human interferon alfa-2a in the treatment of metastatic chemotherapy-refractory urothelial tumors. Journal of the National Cancer Institute, 83, 285–288.

    Article  CAS  PubMed  Google Scholar 

  80. Papageorgiou, A., Dinney, C. P., & McConkey, D. J. (2007). Interferon-alpha induces TRAIL expression and cell death via an IRF-1-dependent mechanism in human bladder cancer cells. Cancer Biology and Therapy, 6, 872–879.

    Article  CAS  PubMed  Google Scholar 

  81. Papageorgiou, A., Kamat, A., Benedict, W. F., Dinney, C., & McConkey, D. J. (2006). Combination therapy with IFN-alpha plus bortezomib induces apoptosis and inhibits angiogenesis in human bladder cancer cells. Molecular Cancer Therapeutics, 5, 3032–3041.

    Article  CAS  PubMed  Google Scholar 

  82. Papageorgiou, A., Lashinger, L., Millikan, R., et al. (2004). Role of tumor necrosis factor-related apoptosis-inducing ligand in interferon-induced apoptosis in human bladder cancer cells. Cancer Research, 64, 8973–8979.

    Article  CAS  PubMed  Google Scholar 

  83. Izawa, J. I., Sweeney, P., Perrotte, P., et al. (2002). Inhibition of tumorigenicity and metastasis of human bladder cancer growing in athymic mice by interferon-beta gene therapy results partially from various antiangiogenic effects including endothelial cell apoptosis. Clinical Cancer Research, 8, 1258–1270.

    CAS  PubMed  Google Scholar 

  84. Slaton, J. W., Karashima, T., Perrotte, P., et al. (2001). Treatment with low-dose interferon-alpha restores the balance between matrix metalloproteinase-9 and E-cadherin expression in human transitional cell carcinoma of the bladder. Clinical Cancer Research, 7, 2840–2853.

    CAS  PubMed  Google Scholar 

  85. Slaton, J. W., Perrotte, P., Inoue, K., Dinney, C. P., & Fidler, I. J. (1999). Interferon-alpha-mediated down-regulation of angiogenesis-related genes and therapy of bladder cancer are dependent on optimization of biological dose and schedule. Clinical Cancer Research, 5, 2726–2734.

    CAS  PubMed  Google Scholar 

  86. Dinney, C. P., Bielenberg, D. R., Perrotte, P., et al. (1998). Inhibition of basic fibroblast growth factor expression, angiogenesis, and growth of human bladder carcinoma in mice by systemic interferon-alpha administration. Cancer Research, 58, 808–814.

    CAS  PubMed  Google Scholar 

  87. Wagner, K. W., Punnoose, E. A., Januario, T., et al. (2007). Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL. Nature Medicine, 13, 1070–1077.

    Article  CAS  PubMed  Google Scholar 

  88. Witta, S. E., Gemmill, R. M., Hirsch, F. R., et al. (2006). Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Research, 66, 944–950.

    Article  CAS  PubMed  Google Scholar 

  89. 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.

    Article  CAS  PubMed  Google Scholar 

  90. Arumugam, T., Ramachandran, V., Fournier, K. F., et al. (2009). Epithelial to mesenchymal transition contributes to drug resistance in pancreatic cancer. Cancer Research, 69, 5820–5828.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Urology, U.T. M.D. Anderson Cancer Center, P.O. Box 1373, 1515 Holcombe Boulevard, Houston, TX, 77030, USA

    David J. McConkey, Woonyoung Choi, Lauren Marquis, Frances Martin, Michael B. Williams, Jay Shah, Robert Svatek, Aditi Das, Liana Adam, Ashish Kamat & Colin Dinney

  2. Department of Cancer Biology, U.T. M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    David J. McConkey, Woonyoung Choi, Lauren Marquis, Aditi Das & Liana Adam

  3. Department of Genitourinary Medical Oncology, U.T. M.D. Anderson Cancer Center, Houston, TX, 77030, USA

    Arlene Siefker-Radtke

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  1. David J. McConkey
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McConkey, D.J., Choi, W., Marquis, L. et al. Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer Metastasis Rev 28, 335–344 (2009). https://doi.org/10.1007/s10555-009-9194-7

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  • DOI: https://doi.org/10.1007/s10555-009-9194-7

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