Cancer and Metastasis Reviews

, Volume 28, Issue 3–4, pp 335–344 | Cite as

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

  • David J. McConkey
  • Woonyoung Choi
  • Lauren Marquis
  • Frances Martin
  • Michael B. Williams
  • Jay Shah
  • Robert Svatek
  • Aditi Das
  • Liana Adam
  • Ashish Kamat
  • Arlene Siefker-Radtke
  • Colin Dinney


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.


Epithelial-to-mesenchymal transition Epidermal growth factor receptor Type-3 fibroblast growth factor receptor Micro-RNA-mediated molecular reversal Urothelial tumor 


  1. 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.CrossRefPubMedGoogle Scholar
  2. 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.CrossRefPubMedGoogle Scholar
  3. 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.CrossRefGoogle Scholar
  4. 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.PubMedGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 6.
    Davis, B. N., Hilyard, A. C., Lagna, G., & Hata, A. (2008). SMAD proteins control DROSHA-mediated microRNA maturation. Nature, 454, 56–61.CrossRefPubMedGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 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.CrossRefPubMedGoogle Scholar
  13. 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.PubMedGoogle Scholar
  14. 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.CrossRefPubMedGoogle Scholar
  15. 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.PubMedGoogle Scholar
  16. 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.PubMedGoogle Scholar
  17. 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.PubMedGoogle Scholar
  18. 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.PubMedGoogle Scholar
  19. 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.CrossRefPubMedGoogle Scholar
  20. 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.PubMedGoogle Scholar
  21. 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.PubMedGoogle Scholar
  22. 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.PubMedGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedGoogle Scholar
  25. 25.
    Hajra, K. M., & Fearon, E. R. (2002). Cadherin and catenin alterations in human cancer. Genes Chromosomes Cancer, 34, 255–268.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 27.
    Strathdee, G. (2002). Epigenetic versus genetic alterations in the inactivation of E-cadherin. Seminars in Cancer Biology, 12, 373–379.CrossRefPubMedGoogle Scholar
  28. 28.
    Dinney, C. P., McConkey, D. J., Millikan, R. E., et al. (2004). Focus on bladder cancer. Cancer Cell, 6, 111–116.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 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.CrossRefPubMedGoogle Scholar
  31. 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.CrossRefPubMedGoogle Scholar
  32. 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.CrossRefPubMedGoogle Scholar
  33. 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.PubMedGoogle Scholar
  34. 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.PubMedGoogle Scholar
  35. 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.CrossRefPubMedGoogle Scholar
  36. 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.PubMedGoogle Scholar
  37. 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. 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.PubMedGoogle Scholar
  39. 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.CrossRefPubMedGoogle Scholar
  40. 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.CrossRefPubMedGoogle Scholar
  41. 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.PubMedGoogle Scholar
  42. 42.
    Signoretti, S., & Loda, M. (2006). Defining cell lineages in the prostate epithelium. Cell Cycle, 5, 138–141.PubMedGoogle Scholar
  43. 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.CrossRefPubMedGoogle Scholar
  44. 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.PubMedGoogle Scholar
  45. 45.
    Blanpain, C., & Fuchs, E. (2007). p63: revving up epithelial stem-cell potential. Nature Cell Biology, 9, 731–733.CrossRefPubMedGoogle Scholar
  46. 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.CrossRefPubMedGoogle Scholar
  47. 47.
    Mendelsohn, J., & Baselga, J. (2006). Epidermal growth factor receptor targeting in cancer. Seminars in Oncology, 33, 369–385.CrossRefPubMedGoogle Scholar
  48. 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.PubMedGoogle Scholar
  49. 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.PubMedGoogle Scholar
  50. 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.PubMedGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.CrossRefPubMedGoogle Scholar
  53. 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.CrossRefPubMedGoogle Scholar
  54. 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.CrossRefPubMedGoogle Scholar
  55. 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).Google Scholar
  56. 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.CrossRefPubMedGoogle Scholar
  57. 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. 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.CrossRefPubMedGoogle Scholar
  59. 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.CrossRefPubMedGoogle Scholar
  60. 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.CrossRefPubMedGoogle Scholar
  61. 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.CrossRefPubMedGoogle Scholar
  62. 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.CrossRefPubMedGoogle Scholar
  63. 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.CrossRefPubMedGoogle Scholar
  64. 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.CrossRefPubMedGoogle Scholar
  65. 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.CrossRefPubMedGoogle Scholar
  66. 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.CrossRefPubMedGoogle Scholar
  67. 67.
    Sibley, K., Stern, P., & Knowles, M. A. (2001). Frequency of fibroblast growth factor receptor 3 mutations in sporadic tumours. Oncogene, 20, 4416–4418.CrossRefPubMedGoogle Scholar
  68. 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.CrossRefPubMedGoogle Scholar
  69. 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.CrossRefPubMedGoogle Scholar
  70. 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.CrossRefPubMedGoogle Scholar
  71. 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.CrossRefPubMedGoogle Scholar
  72. 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.CrossRefPubMedGoogle Scholar
  73. 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.PubMedGoogle Scholar
  74. 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.CrossRefPubMedGoogle Scholar
  75. 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.CrossRefPubMedGoogle Scholar
  76. 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.CrossRefPubMedGoogle Scholar
  77. 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.CrossRefPubMedGoogle Scholar
  78. 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.PubMedGoogle Scholar
  79. 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.CrossRefPubMedGoogle Scholar
  80. 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.PubMedCrossRefGoogle Scholar
  81. 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.CrossRefPubMedGoogle Scholar
  82. 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.CrossRefPubMedGoogle Scholar
  83. 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.PubMedGoogle Scholar
  84. 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.PubMedGoogle Scholar
  85. 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.PubMedGoogle Scholar
  86. 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.PubMedGoogle Scholar
  87. 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.CrossRefPubMedGoogle Scholar
  88. 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.CrossRefPubMedGoogle Scholar
  89. 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.CrossRefPubMedGoogle Scholar
  90. 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.CrossRefPubMedGoogle Scholar
  91. 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.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • David J. McConkey
    • 1
    • 2
  • Woonyoung Choi
    • 1
    • 2
  • Lauren Marquis
    • 1
    • 2
  • Frances Martin
    • 1
  • Michael B. Williams
    • 1
  • Jay Shah
    • 1
  • Robert Svatek
    • 1
  • Aditi Das
    • 1
    • 2
  • Liana Adam
    • 1
    • 2
  • Ashish Kamat
    • 1
  • Arlene Siefker-Radtke
    • 3
  • Colin Dinney
    • 1
  1. 1.Department of UrologyU.T. M.D. Anderson Cancer CenterHoustonUSA
  2. 2.Department of Cancer BiologyU.T. M.D. Anderson Cancer CenterHoustonUSA
  3. 3.Department of Genitourinary Medical OncologyU.T. M.D. Anderson Cancer CenterHoustonUSA

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