Skip to main content

Advertisement

SpringerLink
Log in

The role of epithelial plasticity in prostate cancer dissemination and treatment resistance

  • Published:
Cancer and Metastasis Reviews Aims and scope Submit manuscript

Abstract

Nearly 30,000 men die annually in the USA of prostate cancer, nearly uniformly from metastatic dissemination. Despite recent advances in hormonal, immunologic, bone-targeted, and cytotoxic chemotherapies, treatment resistance and further dissemination are inevitable in men with metastatic disease. Emerging data suggests that the phenomenon of epithelial plasticity, encompassing both reversible mesenchymal transitions and acquisition of stemness traits, may underlie this lethal biology of dissemination and treatment resistance. Understanding the molecular underpinnings of this cellular plasticity from preclinical models of prostate cancer and from biomarker studies of human metastatic prostate cancer has provided clues to novel therapeutic approaches that may delay or prevent metastatic disease and lethality over time. This review will discuss the preclinical and clinical evidence for epithelial plasticity in this rapidly changing field and relate this to clinical phenotype and resistance in prostate cancer while suggesting novel therapeutic approaches.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Siegel, R., Naishadham, D., & Jemal, A. (2012). Cancer statistics, 2012. CA: A Cancer Journal for Clinicians, 62, 10–29.

    Google Scholar 

  2. Rini, B. I., & Small, E. J. (2002). Hormone-refractory prostate cancer. Current Treatment Options in Oncology, 3, 437–446.

    PubMed  Google Scholar 

  3. Chen, C. D., Welsbie, D. S., Tran, C., Baek, S. H., Chen, R., Vessella, R., Rosenfeld, M. G., & Sawyers, C. L. (2004). Molecular determinants of resistance to antiandrogen therapy. Nature Medicine, 10, 33–39.

    PubMed  Google Scholar 

  4. Dehm, S. M., Schmidt, L. J., Heemers, H. V., Vessella, R. L., & Tindall, D. J. (2008). Splicing of a novel androgen receptor exon generates a constitutively active androgen receptor that mediates prostate cancer therapy resistance. Cancer Research, 68, 5469–5477.

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Mostaghel, E. A., Page, S. T., Lin, D. W., Fazli, L., Coleman, I. M., True, L. D., Knudsen, B., Hess, D. L., Nelson, C. C., Matsumoto, A. M., Bremner, W. J., Gleave, M. E., & Nelson, P. S. (2007). Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: therapeutic implications for castration-resistant prostate cancer. Cancer Research, 67, 5033–5041.

    CAS  PubMed  Google Scholar 

  6. Shah, R. B., Mehra, R., Chinnaiyan, A. M., Shen, R., Ghosh, D., Zhou, M., Macvicar, G. R., Varambally, S., Harwood, J., Bismar, T. A., Kim, R., Rubin, M. A., & Pienta, K. J. (2004). Androgen-independent prostate cancer is a heterogeneous group of diseases: Lessons from a rapid autopsy program. Cancer Research, 64, 9209–9216.

    CAS  PubMed  Google Scholar 

  7. Rubin, M. A., Putzi, M., Mucci, N., Smith, D. C., Wojno, K., Korenchuk, S., & Pienta, K. J. (2000). Rapid (“warm”) autopsy study for procurement of metastatic prostate cancer. Clinical Cancer Research, 6, 1038–1045.

    CAS  PubMed  Google Scholar 

  8. Liu, W., Laitinen, S., Khan, S., Vihinen, M., Kowalski, J., Yu, G., Chen, L., Ewing, C. M., Eisenberger, M. A., Carducci, M. A., Nelson, W. G., Yegnasubramanian, S., Luo, J., Wang, Y., Xu, J., Isaacs, W. B., Visakorpi, T., & Bova, G. S. (2009). Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nature Medicine, 15, 559–565.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Aryee, M. J., Liu, W., Engelmann, J. C., Nuhn, P., Gurel, M., Haffner, M. C., Esopi, D., Irizarry, R. A., Getzenberg, R. H., Nelson, W. G., Luo, J., Xu, J., Isaacs, W. B., Bova, G. S., & Yegnasubramanian, S. (2013). “DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases,”. Science Translational Medicine, 5, 169ra10.

    PubMed Central  PubMed  Google Scholar 

  10. Mani, S. A., Guo, W., Liao, M. J., Eaton, E. N., Ayyanan, A., Zhou, A. Y., Brooks, M., Reinhard, F., Zhang, C. C., Shipitsin, M., Campbell, L. L., Polyak, K., Brisken, C., Yang, J., & Weinberg, R. A. (2008). The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell, 133, 704–715.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Thiery, J. P., & Sleeman, J. P. (2006). Complex networks orchestrate epithelial–mesenchymal transitions. Nature Reviews Molecular Cell Biology, 7, 131–142.

    CAS  PubMed  Google Scholar 

  12. Blick, T., Widodo, E., Hugo, H., Waltham, M., Lenburg, M. E., Neve, R. M., & Thompson, E. W. (2008). Epithelial mesenchymal transition traits in human breast cancer cell lines. Clinical & Experimental Metastasis, 25, 629–642.

    CAS  Google Scholar 

  13. Hugo, H., Ackland, M. L., Blick, T., Lawrence, M. G., Clements, J. A., Williams, E. D., & Thompson, E. W. (2007). Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. Journal of Cellular Physiology, 213, 374–383.

    CAS  PubMed  Google Scholar 

  14. Giannoni, E., Bianchini, F., Masieri, L., Serni, S., Torre, E., Calorini, L., & Chiarugi, P. (2010). Reciprocal activation of prostate cancer cells and cancer-associated fibroblasts stimulates epithelial–mesenchymal transition and cancer stemness. Cancer Research, 70, 6945–6956.

    CAS  PubMed  Google Scholar 

  15. Armstrong, A. J., Marengo, M. S., Oltean, S., Kemeny, G., Bitting, R. L., Turnbull, J. D., Herold, C. I., Marcom, P. K., George, D. J., & Garcia-Blanco, M. A. (2011). Circulating tumor cells from patients with advanced prostate and breast cancer display both epithelial and mesenchymal markers. Molecular Cancer Research, 9, 997–1007.

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Zhu, M. L., & Kyprianou, N. (2010). Role of androgens and the androgen receptor in epithelial–mesenchymal transition and invasion of prostate cancer cells. FASEB Journal, 24, 769–777.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Li, X., Lewis, M. T., Huang, J., Gutierrez, C., Osborne, C. K., Wu, M. F., Hilsenbeck, S. G., Pavlick, A., Zhang, X., Chamness, G. C., Wong, H., Rosen, J., & Chang, J. C. (2008). Intrinsic resistance of tumorigenic breast cancer cells to chemotherapy. Journal of the National Cancer Institute, 100, 672–679.

    CAS  PubMed  Google Scholar 

  18. Abraham, B. K., Fritz, P., McClellan, M., Hauptvogel, P., Athelogou, M., & Brauch, H. (2005). Prevalence of CD44+/CD24−/low cells in breast cancer may not be associated with clinical outcome but may favor distant metastasis. Clinical Cancer Research, 11, 1154–1159.

    CAS  PubMed  Google Scholar 

  19. Ginestier, C., Hur, M. H., Charafe-Jauffret, E., Monville, F., Dutcher, J., Brown, M., Jacquemier, J., Viens, P., Kleer, C. G., Liu, S., Schott, A., Hayes, D., Birnbaum, D., Wicha, M. S., & Dontu, G. (2007). ALDH1 is a marker of normal and malignant human mammary stem cells and a predictor of poor clinical outcome. Cell Stem Cell, 1, 555–567.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Taplin, M. E., George, D. J., Halabi, S., Sanford, B., Febbo, P. G., Hennessy, K. T., Mihos, C. G., Vogelzang, N. J., Small, E. J., & Kantoff, P. W. (2005). Prognostic significance of plasma chromogranin a levels in patients with hormone-refractory prostate cancer treated in Cancer and Leukemia Group B 9480 study. Urology, 66, 386–391.

    PubMed  Google Scholar 

  21. Aparicio, A. M., Harzstark, A., Corn, P. G., Wen, S., Araujo, J., Tu, S. M., Pagliaro, L., Kim, J., Millikan, R. E., Ryan, C. J., Tannir, N. M., Zurita, A., Mathew, P., Arap, W., Troncoso, P., Thall, P., & Logothetis, C. J. (2013). Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res, 19, 3621–3630.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Sequist, L. V., Waltman, B. A., Dias-Santagata, D., Digumarthy, S., Turke, A. B., Fidias, P., Bergethon, K., Shaw, A. T., Gettinger, S., Cosper, A. K., Akhavanfard, S., Heist, R. S., Temel, J., Christensen, J. G., Wain, J. C., Lynch, T. J., Vernovsky, K., Mark, E. J., Lanuti, M., Iafrate, A. J., Mino-Kenudson, M., & Engelman, J. A. (2011). Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Science Translational Medicine, 3, 75ra26.

    PubMed Central  PubMed  Google Scholar 

  23. Parwani, A. V., Kronz, J. D., Genega, E. M., Gaudin, P., Chang, S., & Epstein, J. I. (2004). Prostate carcinoma with squamous differentiation: An analysis of 33 cases. The American Journal of Surgical Pathology, 28, 651–657.

    PubMed  Google Scholar 

  24. di Sant’Agnese, P. A. (2001). Neuroendocrine differentiation in prostatic carcinoma: An update on recent developments. Annals of Oncology, 12(Suppl 2), S135–S140.

    PubMed  Google Scholar 

  25. Berruti, A., Mosca, A., Tucci, M., Terrone, C., Torta, M., Tarabuzzi, R., Russo, L., Cracco, C., Bollito, E., Scarpa, R. M., Angeli, A., & Dogliotti, L. (2005). Independent prognostic role of circulating chromogranin A in prostate cancer patients with hormone-refractory disease. Endocrine-Related Cancer, 12, 109–117.

    CAS  PubMed  Google Scholar 

  26. Wang, W., & Epstein, J. I. (2008). Small cell carcinoma of the prostate. A morphologic and immunohistochemical study of 95 cases. The American Journal of Surgical Pathology, 32, 65–71.

    PubMed  Google Scholar 

  27. Kalluri, R., & Weinberg, R. A. (2009). The basics of epithelial–mesenchymal transition. Journal of Clinical Investigation, 119, 1420–1428.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Beltran, H., Rickman, D. S., Park, K., Chae, S. S., Sboner, A., MacDonald, T. Y., Wang, Y., Sheikh, K. L., Terry, S., Tagawa, S. T., Dhir, R., Nelson, J. B., de la Taille, A., Allory, Y., Gerstein, M. B., Perner, S., Pienta, K. J., Chinnaiyan, A. M., Collins, C. C., Gleave, M. E., Demichelis, F., Nanus, D. M., & Rubin, M. A. (2011). Molecular characterization of neuroendocrine prostate cancer and identification of new drug targets. Cancer Discovery, 1, 487–495.

    CAS  PubMed Central  PubMed  Google Scholar 

  29. Giannoni, E., Taddei, M. L., Parri, M., Bianchini, F., Santosuosso, M., Grifantini, R., Fibbi, G., Mazzanti, B., Calorini, L., & Chiarugi, P. (2013). EphA2-mediated mesenchymal-amoeboid transition induced by endothelial progenitor cells enhances metastatic spread due to cancer-associated fibroblasts. Journal Molecules Medical (Berl), 91, 103–115.

    CAS  Google Scholar 

  30. Koeneman, K. S., Yeung, F., & Chung, L. W. (1999). Osteomimetic properties of prostate cancer cells: A hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate, 39, 246–261.

    CAS  PubMed  Google Scholar 

  31. Josson, S., Nomura, T., Lin, J. T., Huang, W. C., Wu, D., Zhau, H. E., Zayzafoon, M., Weizmann, M. N., Gururajan, M., & Chung, L. W. (2011). beta2-microglobulin induces epithelial to mesenchymal transition and confers cancer lethality and bone metastasis in human cancer cells. Cancer Research, 71, 2600–2610.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Zhau, H. E., He, H., Wang, C. Y., Zayzafoon, M., Morrissey, C., Vessella, R. L., Marshall, F. F., Chung, L. W., & Wang, R. (2011). Human prostate cancer harbors the stem cell properties of bone marrow mesenchymal stem cells. Clinical Cancer Research, 17, 2159–2169.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Yang, J., Fizazi, K., Peleg, S., Sikes, C. R., Raymond, A. K., Jamal, N., Hu, M., Olive, M., Martinez, L. A., Wood, C. G., Logothetis, C. J., Karsenty, G., & Navone, N. M. (2001). Prostate cancer cells induce osteoblast differentiation through a Cbfa1-dependent pathway. Cancer Research, 61, 5652–5659.

    CAS  PubMed  Google Scholar 

  34. Zhau, H. Y., Chang, S. M., Chen, B. Q., Wang, Y., Zhang, H., Kao, C., Sang, Q. A., Pathak, S. J., & Chung, L. W. (1996). Androgen-repressed phenotype in human prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 93, 15152–15157.

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Ke, X. S., Qu, Y., Goldfinger, N., Rostad, K., Hovland, R., Akslen, L. A., Rotter, V., Oyan, A. M., & Kalland, K. H. (2008). Epithelial to mesenchymal transition of a primary prostate cell line with switches of cell adhesion modules but without malignant transformation. PLoS One, 3, e3368.

    PubMed Central  PubMed  Google Scholar 

  36. Marian, C. O., Yang, L., Zou, Y. S., Gore, C., Pong, R. C., Shay, J. W., Kabbani, W., Hsieh, J. T., & Raj, G. V. (2011). Evidence of epithelial to mesenchymal transition associated with increased tumorigenic potential in an immortalized normal prostate epithelial cell line. Prostate, 71, 626–636.

    CAS  PubMed  Google Scholar 

  37. Celia-Terrassa, T., Meca-Cortes, O., Mateo, F., de Paz, A. M., Rubio, N., Arnal-Estape, A., Ell, B. J., Bermudo, R., Diaz, A., Guerra-Rebollo, M., Lozano, J. J., Estaras, C., Ulloa, C., Alvarez-Simon, D., Mila, J., Vilella, R., Paciucci, R., Martinez-Balbas, M., de Herreros, A. G., Gomis, R. R., Kang, Y., Blanco, J., Fernandez, P. L., & Thomson, T. M. (2012). Epithelial–mesenchymal transition can suppress major attributes of human epithelial tumor-initiating cells. The Journal of Clinical Investigation, 122, 1849–1868.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Moody, S. E., Perez, D., Pan, T. C., Sarkisian, C. J., Portocarrero, C. P., Sterner, C. J., Notorfrancesco, K. L., Cardiff, R. D., & Chodosh, L. A. (2005). The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell, 8, 197–209.

    CAS  PubMed  Google Scholar 

  39. Fan, F., Samuel, S., Evans, K. W., Lu, J., Xia, L., Zhou, Y., Sceusi, E., Tozzi, F., Ye, X. C., Mani, S. A., & Ellis, L. M. (2012). Overexpression of Snail induces epithelial–mesenchymal transition and a cancer stem cell-like phenotype in human colorectal cancer cells. Cancer Medical, 1, 5–16.

    CAS  Google Scholar 

  40. Emadi Baygi, M., Soheili, Z. S., Schmitz, I., Sameie, S., & Schulz, W. A. (2010). Snail regulates cell survival and inhibits cellular senescence in human metastatic prostate cancer cell lines. Cell Biology and Toxicology, 26, 553–567.

    CAS  PubMed  Google Scholar 

  41. McKeithen, D., Graham, T., Chung, L. W., & Odero-Marah, V. (2010). Snail transcription factor regulates neuroendocrine differentiation in LNCaP prostate cancer cells. Prostate, 70, 982–992.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Emadi Baygi, M., Soheili, Z. S., Essmann, F., Deezagi, A., Engers, R., Goering, W., & Schulz, W. A. (2010). Slug/SNAI2 regulates cell proliferation and invasiveness of metastatic prostate cancer cell lines. Tumour Biology, 31, 297–307.

    CAS  PubMed  Google Scholar 

  43. Wu, K., Gore, C., Yang, L., Fazli, L., Gleave, M., Pong, R. C., Xiao, G., Zhang, L., Yun, E. J., Tseng, S. F., Kapur, P., He, D., & Hsieh, J. T. (2012). Slug, a unique androgen-regulated transcription factor, coordinates androgen receptor to facilitate castration resistance in prostate cancer. Molecular Endocrinology, 26, 1496–1507.

    CAS  PubMed  Google Scholar 

  44. Graham, T. R., Zhau, H. E., Odero-Marah, V. A., Osunkoya, A. O., Kimbro, K. S., Tighiouart, M., Liu, T., Simons, J. W., & O’Regan, R. M. (2008). Insulin-like growth factor-I-dependent up-regulation of ZEB1 drives epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Research, 68, 2479–2488.

    CAS  PubMed  Google Scholar 

  45. Yang, J., Mani, S. A., Donaher, J. L., Ramaswamy, S., Itzykson, R. A., Come, C., Savagner, P., Gitelman, I., Richardson, A., & Weinberg, R. A. (2004). Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell, 117, 927–939.

    CAS  PubMed  Google Scholar 

  46. Liu, A. N., Zhu, Z. H., Chang, S. J., & Hang, X. S. (2012). Twist expression associated with the epithelial–mesenchymal transition in gastric cancer. Molecular and Cellular Biochemistry, 367, 195–203.

    CAS  PubMed  Google Scholar 

  47. Yang, M. H., Hsu, D. S., Wang, H. W., Wang, H. J., Lan, H. Y., Yang, W. H., Huang, C. H., Kao, S. Y., Tzeng, C. H., Tai, S. K., Chang, S. Y., Lee, O. K., & Wu, K. J. (2010). Bmi1 is essential in Twist1-induced epithelial–mesenchymal transition. Nature Cell Biology, 12, 982–992.

    PubMed  Google Scholar 

  48. Eckert, M. A., Lwin, T. M., Chang, A. T., Kim, J., Danis, E., Ohno-Machado, L., & Yang, J. (2011). Twist1-induced invadopodia formation promotes tumor metastasis. Cancer Cell, 19, 372–386.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. 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.

    CAS  PubMed  Google Scholar 

  50. Watson, M. A., Ylagan, L. R., Trinkaus, K. M., Gillanders, W. E., Naughton, M. J., Weilbaecher, K. N., Fleming, T. P., & Aft, R. L. (2007). Isolation and molecular profiling of bone marrow micrometastases identifies TWIST1 as a marker of early tumor relapse in breast cancer patients. Clinical Cancer Research, 13, 5001–5009.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Alexander, N. R., Tran, N. L., Rekapally, H., Summers, C. E., Glackin, C., & Heimark, R. L. (2006). N-Cadherin gene expression in prostate carcinoma is modulated by integrin-dependent nuclear translocation of Twist1. Cancer Research, 66, 3365–3369.

    CAS  PubMed  Google Scholar 

  52. Fridman, J. S., & Lowe, S. W. (2003). Control of apoptosis by p53. Oncogene, 22, 9030–9040.

    CAS  PubMed  Google Scholar 

  53. Vousden, K. H. (2000). p53: Death star. Cell, 103, 691–694.

    CAS  PubMed  Google Scholar 

  54. Sigal, A., & Rotter, V. (2000). Oncogenic mutations of the p53 tumor suppressor: the demons of the guardian of the genome. Cancer Research, 60, 6788–6793.

    CAS  PubMed  Google Scholar 

  55. Chang, C. J., Chao, C. H., Xia, W., Yang, J. Y., Xiong, Y., Li, C. W., Yu, W. H., Rehman, S. K., Hsu, J. L., Lee, H. H., Liu, M., Chen, C. T., Yu, D., & Hung, M. C. (2011). p53 regulates epithelial–mesenchymal transition and stem cell properties through modulating miRNAs. Nature Cell Biology, 13, 317–323.

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Perk, J., Iavarone, A., & Benezra, R. (2005). Id family of helix–loop–helix proteins in cancer. Nature Reviews Cancer, 5, 603–614.

    CAS  PubMed  Google Scholar 

  57. Ouyang, X. S., Wang, X., Lee, D. T., Tsao, S. W., & Wong, Y. C. (2002). Over expression of ID-1 in prostate cancer. The Journal of Urology, 167, 2598–2602.

    CAS  PubMed  Google Scholar 

  58. Zhang, X., Ling, M. T., Wang, Q., Lau, C. K., Leung, S. C., Lee, T. K., Cheung, A. L., Wong, Y. C., & Wang, X. (2007). Identification of a novel inhibitor of differentiation-1 (ID-1) binding partner, caveolin-1, and its role in epithelial–mesenchymal transition and resistance to apoptosis in prostate cancer cells. The Journal of Biological Chemistry, 282, 33284–33294.

    CAS  PubMed  Google Scholar 

  59. Williams, T. M., & Lisanti, M. P. (2005). Caveolin-1 in oncogenic transformation, cancer, and metastasis. American Journal of Physiology. Cell Physiology, 288, C494–C506.

    CAS  PubMed  Google Scholar 

  60. Yang, G., Truong, L. D., Wheeler, T. M., & Thompson, T. C. (1999). Caveolin-1 expression in clinically confined human prostate cancer: A novel prognostic marker. Cancer Research, 59, 5719–5723.

    CAS  PubMed  Google Scholar 

  61. Li, L., Ren, C. H., Tahir, S. A., Ren, C., & Thompson, T. C. (2003). Caveolin-1 maintains activated Akt in prostate cancer cells through scaffolding domain binding site interactions with and inhibition of serine/threonine protein phosphatases PP1 and PP2A. Molecular and Cellular Biology, 23, 9389–9404.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Wu, C., & Huang, J. (2007). Phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin pathway is essential for neuroendocrine differentiation of prostate cancer. The Journal of Biological Chemistry, 282, 3571–3583.

    CAS  PubMed  Google Scholar 

  63. Ciarlo, M., Benelli, R., Barbieri, O., Minghelli, S., Barboro, P., Balbi, C., & Ferrari, N. (2012). Regulation of neuroendocrine differentiation by AKT/hnRNPK/AR/beta-catenin signaling in prostate cancer cells. International Journal of Cancer, 131, 582–590.

    CAS  Google Scholar 

  64. Murthy, S., Wu, M., Bai, V. U., Hou, Z., Menon, M., Barrack, E. R., Kim, S. H., & Reddy, G. P. (2013). Role of androgen receptor in progression of LNCaP prostate cancer cells from G1 to S phase. PLoS One, 8, e56692.

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Sun, Y., Wang, B. E., Leong, K. G., Yue, P., Li, L., Jhunjhunwala, S., Chen, D., Seo, K., Modrusan, Z., Gao, W. Q., Settleman, J., & Johnson, L. (2012). Androgen deprivation causes epithelial–mesenchymal transition in the prostate: Implications for androgen-deprivation therapy. Cancer Research, 72, 527–536.

    CAS  PubMed  Google Scholar 

  66. Eide, T., Ramberg, H., Glackin, C., Tindall, D., & Tasken, K. A. (2013). TWIST1, A novel androgen-regulated gene, is a target for NKX3-1 in prostate cancer cells. Cancer Cell International, 13, 4.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Lu, T., Lin, W. J., Izumi, K., Wang, X., Xu, D., Fang, L. Y., Li, L., Jiang, Q., Jin, J., & Chang, C. (2012). Targeting androgen receptor to suppress macrophage-induced EMT and benign prostatic hyperplasia (BPH) development. Molecular Endocrinology, 26, 1707–1715.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Pourmand, G., Ziaee, A. A., Abedi, A. R., Mehrsai, A., Alavi, H. A., Ahmadi, A., & Saadati, H. R. (2007). Role of PTEN gene in progression of prostate cancer. Urology Journal, 4, 95–100. Spring.

    PubMed  Google Scholar 

  69. Mulholland, D. J., Kobayashi, N., Ruscetti, M., Zhi, A., Tran, L. M., Huang, J., Gleave, M., & Wu, H. (2012). Pten loss and RAS/MAPK activation cooperate to promote EMT and metastasis initiated from prostate cancer stem/progenitor cells. Cancer Research, 72, 1878–1889.

    CAS  PubMed Central  PubMed  Google Scholar 

  70. Dubrovska, A., Kim, S., Salamone, R. J., Walker, J. R., Maira, S. M., Garcia-Echeverria, C., Schultz, P. G., & Reddy, V. A. (2009). The role of PTEN/Akt/PI3K signaling in the maintenance and viability of prostate cancer stem-like cell populations. Proceedings of the National Academy of Sciences of the United States of America, 106, 268–273.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Taylor, B. S., Schultz, N., Hieronymus, H., Gopalan, A., Xiao, Y., Carver, B. S., Arora, V. K., Kaushik, P., Cerami, E., Reva, B., Antipin, Y., Mitsiades, N., Landers, T., Dolgalev, I., Major, J. E., Wilson, M., Socci, N. D., Lash, A. E., Heguy, A., Eastham, J. A., Scher, H. I., Reuter, V. E., Scardino, P. T., Sander, C., Sawyers, C. L., & Gerald, W. L. (2010). Integrative genomic profiling of human prostate cancer. Cancer Cell, 18, 11–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Nusse, R., & Varmus, H. (2012). Three decades of Wnts: A personal perspective on how a scientific field developed. EMBO Journal, 31, 2670–2684.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Yee, D. S., Tang, Y., Li, X., Liu, Z., Guo, Y., Ghaffar, S., McQueen, P., Atreya, D., Xie, J., Simoneau, A. R., Hoang, B. H., & Zi, X. (2010). The Wnt inhibitory factor 1 restoration in prostate cancer cells was associated with reduced tumor growth, decreased capacity of cell migration and invasion and a reversal of epithelial to mesenchymal transition. Molecular Cancer, 9, 162.

    PubMed Central  PubMed  Google Scholar 

  74. Clevers, H. (2006). Wnt/beta-catenin signaling in development and disease. Cell, 127, 469–480.

    CAS  PubMed  Google Scholar 

  75. Truica, C. I., Byers, S., & Gelmann, E. P. (2000). Beta-catenin affects androgen receptor transcriptional activity and ligand specificity. Cancer Research, 60, 4709–4713.

    CAS  PubMed  Google Scholar 

  76. Whitaker, H. C., Girling, J., Warren, A. Y., Leung, H., Mills, I. G., & Neal, D. E. (2008). Alterations in beta-catenin expression and localization in prostate cancer. Prostate, 68, 1196–1205.

    CAS  PubMed  Google Scholar 

  77. Wan, X., Liu, J., Lu, J. F., Tzelepi, V., Yang, J., Starbuck, M. W., Diao, L., Wang, J., Efstathiou, E., Vazquez, E. S., Troncoso, P., Maity, S. N., & Navone, N. M. (2012). Activation of beta-catenin signaling in androgen receptor-negative prostate cancer cells. Clinical Cancer Research, 18, 726–736.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Cao, J., Chiarelli, C., Richman, O., Zarrabi, K., Kozarekar, P., & Zucker, S. (2008). Membrane type 1 matrix metalloproteinase induces epithelial-to-mesenchymal transition in prostate cancer. The Journal of Biological Chemistry, 283, 6232–6240.

    CAS  PubMed  Google Scholar 

  79. Xie, D., Gore, C., Liu, J., Pong, R. C., Mason, R., Hao, G., Long, M., Kabbani, W., Yu, L., Zhang, H., Chen, H., Sun, X., Boothman, D. A., Min, W., & Hsieh, J. T. (2010). “Role of DAB2IP in modulating epithelial-to-mesenchymal transition and prostate cancer metastasis,“. Proceedings of the National Academy of Sciences of the United States of America, 107, 2485–2490.

    CAS  PubMed Central  PubMed  Google Scholar 

  80. Min, J., Zaslavsky, A., Fedele, G., McLaughlin, S. K., Reczek, E. E., De Raedt, T., Guney, I., Strochlic, D. E., Macconaill, L. E., Beroukhim, R., Bronson, R. T., Ryeom, S., Hahn, W. C., Loda, M., & Cichowski, K. (2010). ”An oncogene-tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factor-kappaB. Nature Medicine, 16, 286–294.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. K. Wu, J. Liu, S. F. Tseng, C. Gore, Z. Ning, N. Sharifi, L. Fazli, M. Gleave, P. Kapur, G. Xiao, X. Sun, O. K. Oz, W. Min, G. Alexandrakis, C. R. Yang, C. L. Hsieh, H. C. Wu, D. He, D. Xie, and J. T. Hsieh,”The role of DAB2IP in androgen receptor activation during prostate cancer progression,“Oncogene, Apr 22 2013.

  82. Jain, G., Cronauer, M. V., Schrader, M., Moller, P., & Marienfeld, R. B. (2012). NF-kappaB signaling in prostate cancer: a promising therapeutic target? World Journal of Urology, 30, 303–310.

    CAS  PubMed  Google Scholar 

  83. McCall, P., Bennett, L., Ahmad, I., Mackenzie, L. M., Forbes, I. W., Leung, H. Y., Sansom, O. J., Orange, C., Seywright, M., Underwood, M. A., & Edwards, J. (2012). NFkappaB signalling is upregulated in a subset of castrate-resistant prostate cancer patients and correlates with disease progression. British Journal of Cancer, 107, 1554–1563.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. 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, 733–744.

    CAS  PubMed  Google Scholar 

  85. Luo, J. L., Tan, W., Ricono, J. M., Korchynskyi, O., Zhang, M., Gonias, S. L., Cheresh, D. A., & Karin, M. (2007). Nuclear cytokine-activated IKKalpha controls prostate cancer metastasis by repressing Maspin. Nature, 446, 690–694.

    CAS  PubMed  Google Scholar 

  86. Odero-Marah, V. A., Wang, R., Chu, G., Zayzafoon, M., Xu, J., Shi, C., Marshall, F. F., Zhau, H. E., & Chung, L. W. (2008). Receptor activator of NF-kappaB Ligand (RANKL) expression is associated with epithelial to mesenchymal transition in human prostate cancer cells. Cell Research, 18, 858–870.

    CAS  PubMed  Google Scholar 

  87. Kuo, P. L., Shen, K. H., Hung, S. H., & Hsu, Y. L. (2012). CXCL1/GROalpha increases cell migration and invasion of prostate cancer by decreasing fibulin-1 expression through NF-kappaB/HDAC1 epigenetic regulation. Carcinogenesis, 33, 2477–2487.

    CAS  PubMed  Google Scholar 

  88. Bolitho, C., Hahn, M. A., Baxter, R. C., & Marsh, D. J. (2010). The chemokine CXCL1 induces proliferation in epithelial ovarian cancer cells by transactivation of the epidermal growth factor receptor. Endocrine-Related Cancer, 17, 929–940.

    CAS  PubMed  Google Scholar 

  89. Shiota, M., Zardan, A., Takeuchi, A., Kumano, M., Beraldi, E., Naito, S., Zoubeidi, A., & Gleave, M. E. (2012). Clusterin mediates TGF-beta-induced epithelial–mesenchymal transition and metastasis via Twist1 in prostate cancer cells. Cancer Research, 72, 5261–5272.

    CAS  PubMed  Google Scholar 

  90. Mak, P., Leav, I., Pursell, B., Bae, D., Yang, X., Taglienti, C. A., Gouvin, L. M., Sharma, V. M., & Mercurio, A. M. (2010). ERbeta impedes prostate cancer EMT by destabilizing HIF-1alpha and inhibiting VEGF-mediated snail nuclear localization: implications for Gleason grading. Cancer Cell, 17, 319–332.

    CAS  PubMed Central  PubMed  Google Scholar 

  91. Poon, S., Easterbrook-Smith, S. B., Rybchyn, M. S., Carver, J. A., & Wilson, M. R. (2000). Clusterin is an ATP-independent chaperone with very broad substrate specificity that stabilizes stressed proteins in a folding-competent state. Biochemistry, 39, 15953–15960.

    CAS  PubMed  Google Scholar 

  92. Chi, K. N., Hotte, S. J., Yu, E. Y., Tu, D., Eigl, B. J., Tannock, I., Saad, F., North, S., Powers, J., Gleave, M. E., & Eisenhauer, E. A. (2010). Randomized phase II study of docetaxel and prednisone with or without OGX-011 in patients with metastatic castration-resistant prostate cancer. Journal of Clinical Oncology, 28, 4247–4254.

    CAS  PubMed  Google Scholar 

  93. Zoubeidi, A., Chi, K., & Gleave, M. (2010). Targeting the cytoprotective chaperone, clusterin, for treatment of advanced cancer. Clinical Cancer Research, 16, 1088–1093.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Turley, R. S., Finger, E. C., Hempel, N., How, T., Fields, T. A., & Blobe, G. C. (2007). The type III transforming growth factor-beta receptor as a novel tumor suppressor gene in prostate cancer. Cancer Research, 67, 1090–1098.

    CAS  PubMed  Google Scholar 

  95. Ikushima, H., & Miyazono, K. (2010). TGFbeta signalling: a complex web in cancer progression. Nature Reviews Cancer, 10, 415–424.

    CAS  PubMed  Google Scholar 

  96. Adorno, M., Cordenonsi, M., Montagner, M., Dupont, S., Wong, C., Hann, B., Solari, A., Bobisse, S., Rondina, M. B., Guzzardo, V., Parenti, A. R., Rosato, A., Bicciato, S., Balmain, A., & Piccolo, S. (2009). A Mutant-p53/Smad complex opposes p63 to empower TGFbeta-induced metastasis. Cell, 137, 87–98.

    CAS  PubMed  Google Scholar 

  97. Ding, Z., Wu, C. J., Chu, G. C., Xiao, Y., Ho, D., Zhang, J., Perry, S. R., Labrot, E. S., Wu, X., Lis, R., Hoshida, Y., Hiller, D., Hu, B., Jiang, S., Zheng, H., Stegh, A. H., Scott, K. L., Signoretti, S., Bardeesy, N., Wang, Y. A., Hill, D. E., Golub, T. R., Stampfer, M. J., Wong, W. H., Loda, M., Mucci, L., Chin, L., & DePinho, R. A. (2011). SMAD4-dependent barrier constrains prostate cancer growth and metastatic progression. Nature, 470, 269–273.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Qin, J., Wu, S. P., Creighton, C. J., Dai, F., Xie, X., Cheng, C. M., Frolov, A., Ayala, G., Lin, X., Feng, X. H., Ittmann, M. M., Tsai, S. J., Tsai, M. J., & Tsai, S. Y. (2013). COUP-TFII inhibits TGF-beta-induced growth barrier to promote prostate tumorigenesis. Nature, 493, 236–240.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Buijs, J. T., Henriquez, N. V., van Overveld, P. G., van der Horst, G., ten Dijke, P., & van der Pluijm, G. (2007). TGF-beta and BMP7 interactions in tumour progression and bone metastasis. Clinical & Experimental Metastasis, 24, 609–617.

    CAS  Google Scholar 

  100. Grivennikov, S., Karin, E., Terzic, J., Mucida, D., Yu, G. Y., Vallabhapurapu, S., Scheller, J., Rose-John, S., Cheroutre, H., Eckmann, L., & Karin, M. (2009). IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell, 15, 103–113.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Bollrath, J., Phesse, T. J., von Burstin, V. A., Putoczki, T., Bennecke, M., Bateman, T., Nebelsiek, T., Lundgren-May, T., Canli, O., Schwitalla, S., Matthews, V., Schmid, R. M., Kirchner, T., Arkan, M. C., Ernst, M., & Greten, F. R. (2009). gp130-mediated Stat3 activation in enterocytes regulates cell survival and cell-cycle progression during colitis-associated tumorigenesis. Cancer Cell, 15, 91–102.

    CAS  PubMed  Google Scholar 

  102. Yadav, A., Kumar, B., Datta, J., Teknos, T. N., & Kumar, P. (2011). IL-6 promotes head and neck tumor metastasis by inducing epithelial–mesenchymal transition via the JAK-STAT3-SNAIL signaling pathway. Molecular Cancer Research, 9, 1658–1667.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Yao, Z., Fenoglio, S., Gao, D. C., Camiolo, M., Stiles, B., Lindsted, T., Schlederer, M., Johns, C., Altorki, N., Mittal, V., Kenner, L., & Sordella, R. (2010). TGF-beta IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer. Proceedings of the National Academy of Sciences of the United States of America, 107, 15535–15540.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Sullivan, N. J., Sasser, A. K., Axel, A. E., Vesuna, F., Raman, V., Ramirez, N., Oberyszyn, T. M., & Hall, B. M. (2009). Interleukin-6 induces an epithelial–mesenchymal transition phenotype in human breast cancer cells. Oncogene, 28, 2940–2947.

    CAS  PubMed  Google Scholar 

  105. Tenniswood, M. P., Guenette, R. S., Lakins, J., Mooibroek, M., Wong, P., & Welsh, J. E. (1992). Active cell death in hormone-dependent tissues. Cancer Metastasis Reviews, 11, 197–220.

    CAS  PubMed  Google Scholar 

  106. Paul, C., Manero, F., Gonin, S., Kretz-Remy, C., Virot, S., & Arrigo, A. P. (2002). Hsp27 as a negative regulator of cytochrome C release. Molecular and Cellular Biology, 22, 816–834.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Zoubeidi, A., & Gleave, M. (2012). Small heat shock proteins in cancer therapy and prognosis. The International Journal of Biochemistry & Cell Biology, 44, 1646–1656.

    CAS  Google Scholar 

  108. Shiota, M., Bishop, J. L., Nip, K. M., Zardan, A., Takeuchi, A., Cordonnier, T., Beraldi, E., Bazov, J., Fazli, L., Chi, K., Gleave, M., & Zoubeidi, A. (2013). Hsp27 regulates epithelial mesenchymal transition, metastasis, and circulating tumor cells in prostate cancer. Cancer Research, 73, 3109–3119.

    CAS  PubMed  Google Scholar 

  109. Lue, H. W., Yang, X., Wang, R., Qian, W., Xu, R. Z., Lyles, R., Osunkoya, A. O., Zhou, B. P., Vessella, R. L., Zayzafoon, M., Liu, Z. R., Zhau, H. E., & Chung, L. W. (2011). LIV-1 promotes prostate cancer epithelial-to-mesenchymal transition and metastasis through HB-EGF shedding and EGFR-mediated ERK signaling. PLoS One, 6, e27720.

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Mimeault, M., & Batra, S. K. (2010). Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer. Journal of Cellular Physiology, 224, 626–635.

    CAS  PubMed Central  PubMed  Google Scholar 

  111. Cheung, P. K., Woolcock, B., Adomat, H., Sutcliffe, M., Bainbridge, T. C., Jones, E. C., Webber, D., Kinahan, T., Sadar, M., Gleave, M. E., & Vielkind, J. (2004). Protein profiling of microdissected prostate tissue links growth differentiation factor 15 to prostate carcinogenesis. Cancer Research, 64, 5929–5933.

    CAS  PubMed  Google Scholar 

  112. Nakamura, T., Scorilas, A., Stephan, C., Yousef, G. M., Kristiansen, G., Jung, K., & Diamandis, E. P. (2003). Quantitative analysis of macrophage inhibitory cytokine-1 (MIC-1) gene expression in human prostatic tissues. British Journal of Cancer, 88, 1101–1104.

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Veveris-Lowe, T. L., Lawrence, M. G., Collard, R. L., Bui, L., Herington, A. C., Nicol, D. L., & Clements, J. A. (2005). Kallikrein 4 (hK4) and prostate-specific antigen (PSA) are associated with the loss of E-cadherin and an epithelial–mesenchymal transition (EMT)-like effect in prostate cancer cells. Endocrine-Related Cancer, 12, 631–643.

    CAS  PubMed  Google Scholar 

  114. Jang, M. J., Baek, S. H., & Kim, J. H. (2011). UCH-L1 promotes cancer metastasis in prostate cancer cells through EMT induction. Cancer Letters, 302, 128–135.

    CAS  PubMed  Google Scholar 

  115. Wesche, J., Haglund, K., & Haugsten, E. M. (2011). Fibroblast growth factors and their receptors in cancer. The Biochemical Journal, 437, 199–213.

    CAS  PubMed  Google Scholar 

  116. Feng, S., Wang, F., Matsubara, A., Kan, M., & McKeehan, W. L. (1997). Fibroblast growth factor receptor 2 limits and receptor 1 accelerates tumorigenicity of prostate epithelial cells. Cancer Research, 57, 5369–5378.

    CAS  PubMed  Google Scholar 

  117. Kwabi-Addo, B., Ropiquet, F., Giri, D., & Ittmann, M. (2001). Alternative splicing of fibroblast growth factor receptors in human prostate cancer. Prostate, 46, 163–172.

    CAS  PubMed  Google Scholar 

  118. Carstens, R. P., Wagner, E. J., & Garcia-Blanco, M. A. (2000). An intronic splicing silencer causes skipping of the IIIb exon of fibroblast growth factor receptor 2 through involvement of polypyrimidine tract binding protein. Molecular and Cellular Biology, 20, 7388–7400.

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Baraniak, A. P., Chen, J. R., & Garcia-Blanco, M. A. (2006). Fox-2 mediates epithelial cell-specific fibroblast growth factor receptor 2 exon choice. Molecular and Cellular Biology, 26, 1209–1222.

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Warzecha, C. C., Sato, T. K., Nabet, B., Hogenesch, J. B., & Carstens, R. P. (2009). ESRP1 and ESRP2 are epithelial cell-type-specific regulators of FGFR2 splicing. Molecular Cell, 33, 591–601.

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Shapiro, I. M., Cheng, A. W., Flytzanis, N. C., Balsamo, M., Condeelis, J. S., Oktay, M. H., Burge, C. B., & Gertler, F. B. (2011). An EMT-driven alternative splicing program occurs in human breast cancer and modulates cellular phenotype. PLoS Genetics, 7, e1002218.

    CAS  PubMed Central  PubMed  Google Scholar 

  122. Acevedo, V. D., Gangula, R. D., Freeman, K. W., Li, R., Zhang, Y., Wang, F., Ayala, G. E., Peterson, L. E., Ittmann, M., & Spencer, D. M. (2007). Inducible FGFR-1 activation leads to irreversible prostate adenocarcinoma and an epithelial-to-mesenchymal transition. Cancer Cell, 12, 559–571.

    CAS  PubMed  Google Scholar 

  123. Bao, B., Ahmad, A., Kong, D., Ali, S., Azmi, A. S., Li, Y., Banerjee, S., Padhye, S., & Sarkar, F. H. (2012). Hypoxia induced aggressiveness of prostate cancer cells is linked with deregulated expression of VEGF, IL-6 and miRNAs that are attenuated by CDF. PLoS One, 7, e43726.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Wang, G. L., & Semenza, G. L. (1993). General involvement of hypoxia-inducible factor 1 in transcriptional response to hypoxia. Proceedings of the National Academy of Sciences of the United States of America, 90, 4304–4308.

    CAS  PubMed Central  PubMed  Google Scholar 

  125. 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, 377–382.

    CAS  PubMed  Google Scholar 

  126. Luo, Y., He, D. L., Ning, L., Shen, S. L., Li, L., & Li, X. (2006). Hypoxia-inducible factor-1alpha induces the epithelial–mesenchymal transition of human prostatecancer cells. Chinese Medical Journal, 119, 713–718.

    CAS  PubMed  Google Scholar 

  127. Yang, M. H., Wu, M. Z., Chiou, S. H., Chen, P. M., Chang, S. Y., Liu, C. J., Teng, S. C., & Wu, K. J. (2008). Direct regulation of TWIST by HIF-1alpha promotes metastasis. Nature Cell Biology, 10, 295–305.

    CAS  PubMed  Google Scholar 

  128. Sun, S., Ning, X., Zhang, Y., Lu, Y., Nie, Y., Han, S., Liu, L., Du, R., Xia, L., He, L., & Fan, D. (2009). Hypoxia-inducible factor-1alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-to-mesenchymal transition. Kidney International, 75, 1278–1287.

    CAS  PubMed  Google Scholar 

  129. Song, X., Wang, H., Logsdon, C. D., Rashid, A., Fleming, J. B., Abbruzzese, J. L., Gomez, H. F., & Evans, D. B. (2011). Overexpression of receptor tyrosine kinase Axl promotes tumor cell invasion and survival in pancreatic ductal adenocarcinoma. Cancer, 117, 734–743.

    CAS  PubMed  Google Scholar 

  130. Mudduluru, G., Vajkoczy, P., & Allgayer, H. (2010). Myeloid zinc finger 1 induces migration, invasion, and in vivo metastasis through Axl gene expression in solid cancer. Molecular Cancer Research, 8, 159–169.

    CAS  PubMed  Google Scholar 

  131. Gustafsson, A., Bostrom, A. K., Ljungberg, B., Axelson, H., & Dahlback, B. (2009). Gas6 and the receptor tyrosine kinase Axl in clear cell renal cell carcinoma. PLoS One, 4, e7575.

    PubMed Central  PubMed  Google Scholar 

  132. Gjerdrum, C., Tiron, C., Hoiby, T., Stefansson, I., Haugen, H., Sandal, T., Collett, K., Li, S., McCormack, E., Gjertsen, B. T., Micklem, D. R., Akslen, L. A., Glackin, C., & Lorens, J. B. (2010). Axl is an essential epithelial-to-mesenchymal transition-induced regulator of breast cancer metastasis and patient survival. Proceedings of the National Academy of Sciences of the United States of America, 107, 1124–1129.

    CAS  PubMed Central  PubMed  Google Scholar 

  133. Vajkoczy, P., Knyazev, P., Kunkel, A., Capelle, H. H., Behrndt, S., von Tengg-Kobligk, H., Kiessling, F., Eichelsbacher, U., Essig, M., Read, T. A., Erber, R., & Ullrich, A. (2006). Dominant-negative inhibition of the Axl receptor tyrosine kinase suppresses brain tumor cell growth and invasion and prolongs survival. Proceedings of the National Academy of Sciences of the United States of America, 103, 5799–5804.

    CAS  PubMed Central  PubMed  Google Scholar 

  134. Hector, A., Montgomery, E. A., Karikari, C., Canto, M., Dunbar, K. B., Wang, J. S., Feldmann, G., Hong, S. M., Haffner, M. C., Meeker, A. K., Holland, S. J., Yu, J., Heckrodt, T. J., Zhang, J., Ding, P., Goff, D., Singh, R., Roa, J. C., Marimuthu, A., Riggins, G. J., Eshleman, J. R., Nelkin, B. D., Pandey, A., & Maitra, A. (2010). The Axl receptor tyrosine kinase is an adverse prognostic factor and a therapeutic target in esophageal adenocarcinoma. Cancer Biology & Therapy, 10, 1009–1018.

    Google Scholar 

  135. Koorstra, J. B., Karikari, C. A., Feldmann, G., Bisht, S., Rojas, P. L., Offerhaus, G. J., Alvarez, H., & Maitra, A. (2009). The Axl receptor tyrosine kinase confers an adverse prognostic influence in pancreatic cancer and represents a new therapeutic target. Cancer Biology & Therapy, 8, 618–626.

    CAS  Google Scholar 

  136. Gustafsson, A., Martuszewska, D., Johansson, M., Ekman, C., Hafizi, S., Ljungberg, B., & Dahlback, B. (2009). Differential expression of Axl and Gas6 in renal cell carcinoma reflecting tumor advancement and survival. Clinical Cancer Research, 15, 4742–4749.

    CAS  PubMed  Google Scholar 

  137. Zhang, Y. X., Knyazev, P. G., Cheburkin, Y. V., Sharma, K., Knyazev, Y. P., Orfi, L., Szabadkai, I., Daub, H., Keri, G., & Ullrich, A. (2008). AXL is a potential target for therapeutic intervention in breast cancer progression. Cancer Research, 68, 1905–1915.

    CAS  PubMed  Google Scholar 

  138. Hutterer, M., Knyazev, P., Abate, A., Reschke, M., Maier, H., Stefanova, N., Knyazeva, T., Barbieri, V., Reindl, M., Muigg, A., Kostron, H., Stockhammer, G., & Ullrich, A. (2008). Axl and growth arrest-specific gene 6 are frequently overexpressed in human gliomas and predict poor prognosis in patients with glioblastoma multiforme. Clinical Cancer Research, 14, 130–138.

    CAS  PubMed  Google Scholar 

  139. Mishra, A., Wang, J., Shiozawa, Y., McGee, S., Kim, J., Jung, Y., Joseph, J., Berry, J. E., Havens, A., Pienta, K. J., & Taichman, R. S. (2012). Hypoxia stabilizes GAS6/Axl signaling in metastatic prostate cancer. Molecular Cancer Research, 10, 703–712.

    CAS  PubMed Central  PubMed  Google Scholar 

  140. Kalluri, R., & Zeisberg, M. (2006). Fibroblasts in cancer. Nature Reviews Cancer, 6, 392–401.

    CAS  PubMed  Google Scholar 

  141. Liotta, L. A., & Kohn, E. C. (2001). The microenvironment of the tumour–host interface. Nature, 411, 375–379.

    CAS  PubMed  Google Scholar 

  142. Chung, L. W., Baseman, A., Assikis, V., & Zhau, H. E. (2005). Molecular insights into prostate cancer progression: The missing link of tumor microenvironment. The Journal of Urology, 173, 10–20.

    PubMed  Google Scholar 

  143. Kaminski, A., Hahne, J. C., Haddouti el, M., Florin, A., Wellmann, A., & Wernert, N. (2006). Tumour–stroma interactions between metastatic prostate cancer cells and fibroblasts. International Journal of Molecular Medicine, 18, 941–950.

    CAS  PubMed  Google Scholar 

  144. Giannoni, E., Bianchini, F., Calorini, L., & Chiarugi, P. (2011). Cancer associated fibroblasts exploit reactive oxygen species through a proinflammatory signature leading to epithelial mesenchymal transition and stemness. Antioxidants & Redox Signaling, 14, 2361–2371.

    CAS  Google Scholar 

  145. Lafon, C., Mathieu, C., Guerrin, M., Pierre, O., Vidal, S., & Valette, A. (1996). Transforming growth factor beta 1-induced apoptosis in human ovarian carcinoma cells: protection by the antioxidant N-acetylcysteine and bcl-2. Cell Growth & Differentiation, 7, 1095–1104.

    CAS  Google Scholar 

  146. Rhyu, D. Y., Yang, Y., Ha, H., Lee, G. T., Song, J. S., Uh, S. T., & Lee, H. B. (2005). Role of reactive oxygen species in TGF-beta1-induced mitogen-activated protein kinase activation and epithelial–mesenchymal transition in renal tubular epithelial cells. Journal of the American Society of Nephrology, 16, 667–675.

    CAS  PubMed  Google Scholar 

  147. Radisky, D. C., Levy, D. D., Littlepage, L. E., Liu, H., Nelson, C. M., Fata, J. E., Leake, D., Godden, E. L., Albertson, D. G., Nieto, M. A., Werb, Z., & Bissell, M. J. (2005). Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature, 436, 123–127.

    CAS  PubMed Central  PubMed  Google Scholar 

  148. Barnett, P., Arnold, R. S., Mezencev, R., Chung, L. W., Zayzafoon, M., & Odero-Marah, V. (2011). Snail-mediated regulation of reactive oxygen species in ARCaP human prostate cancer cells. Biochemical and Biophysical Research Communications, 404, 34–39.

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Das, T. P., Suman, S., & Damodaran, C. (2013). Reactive oxygen species generation inhibits epithelial–mesenchymal transition and promotes growth arrest in prostate cancer cells. Molecular Carcinogenesis. doi:10.1002/mc.22014.

  150. Sun, Y., Campisi, J., Higano, C., Beer, T. M., Porter, P., Coleman, I., True, L., & Nelson, P. S. (2012). Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nature Medicine, 18, 1359–1368.

    CAS  PubMed Central  PubMed  Google Scholar 

  151. Zhang, Y., Daquinag, A., Traktuev, D. O., Amaya-Manzanares, F., Simmons, P. J., March, K. L., Pasqualini, R., Arap, W., & Kolonin, M. G. (2009). White adipose tissue cells are recruited by experimental tumors and promote cancer progression in mouse models. Cancer Research, 69, 5259–5266.

    CAS  PubMed  Google Scholar 

  152. Chao, Y., Wu, Q., Shepard, C., & Wells, A. (2012). Hepatocyte induced re-expression of E-cadherin in breast and prostate cancer cells increases chemoresistance. Clinical & Experimental Metastasis, 29, 39–50.

    CAS  Google Scholar 

  153. Yates, C. C., Shepard, C. R., Stolz, D. B., & Wells, A. (2007). Co-culturing human prostate carcinoma cells with hepatocytes leads to increased expression of E-cadherin. British Journal of Cancer, 96, 1246–1252.

    CAS  PubMed Central  PubMed  Google Scholar 

  154. S. Josson, S. Sharp, S. Y. Sung, P. A. Johnstone, R. Aneja, R. Wang, M. Gururajan, T. Turner, L. W. Chung, and C. Yates (2010) Tumor–stromal interactions influence radiation sensitivity in epithelial- versus mesenchymal-like prostate cancer cells. Journal of Oncology, 2010. doi:10.1155/2010/232831.

  155. Oltean, S., Sorg, B. S., Albrecht, T., Bonano, V. I., Brazas, R. M., Dewhirst, M. W., & Garcia-Blanco, M. A. (2006). Alternative inclusion of fibroblast growth factor receptor 2 exon IIIc in Dunning prostate tumors reveals unexpected epithelial mesenchymal plasticity. Proceedings of the National Academy of Sciences of the United States of America, 103, 14116–14121.

    CAS  PubMed Central  PubMed  Google Scholar 

  156. Giannini, G., Cabri, W., Fattorusso, C., & Rodriquez, M. (2012). Histone deacetylase inhibitors in the treatment of cancer: Overview and perspectives. Future Medicinal Chemistry, 4, 1439–1460.

    CAS  PubMed  Google Scholar 

  157. Kong, D., Ahmad, A., Bao, B., Li, Y., Banerjee, S., & Sarkar, F. H. (2012). Histone deacetylase inhibitors induce epithelial-to-mesenchymal transition in prostate cancer cells. PLoS One, 7, e45045.

    CAS  PubMed Central  PubMed  Google Scholar 

  158. Bradley, D., Rathkopf, D., Dunn, R., Stadler, W. M., Liu, G., Smith, D. C., Pili, R., Zwiebel, J., Scher, H., & Hussain, M. (2009). Vorinostat in advanced prostate cancer patients progressing on prior chemotherapy (National Cancer Institute Trial 6862): trial results and interleukin-6 analysis: A study by the Department of Defense Prostate Cancer Clinical Trial Consortium and University of Chicago Phase 2 Consortium. Cancer, 115, 5541–5549.

    CAS  PubMed Central  PubMed  Google Scholar 

  159. Martinez-Garcia, E., Popovic, R., Min, D. J., Sweet, S. M., Thomas, P. M., Zamdborg, L., Heffner, A., Will, C., Lamy, L., Staudt, L. M., Levens, D. L., Kelleher, N. L., & Licht, J. D. (2011). The MMSET histone methyl transferase switches global histone methylation and alters gene expression in t(4;14) multiple myeloma cells. Blood, 117, 211–220.

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Hudlebusch, H. R., Skotte, J., Santoni-Rugiu, E., Zimling, Z. G., Lees, M. J., Simon, R., Sauter, G., Rota, R., De Ioris, M. A., Quarto, M., Johansen, J. V., Jorgensen, M., Rechnitzer, C., Maroun, L. L., Schroder, H., Petersen, B. L., & Helin, K. (2011). MMSET is highly expressed and associated with aggressiveness in neuroblastoma. Cancer Research, 71, 4226–4235.

    CAS  PubMed  Google Scholar 

  161. Kassambara, A., Klein, B., & Moreaux, J. (2009). MMSET is overexpressed in cancers: link with tumor aggressiveness. Biochemical and Biophysical Research Communications, 379, 840–845.

    CAS  PubMed  Google Scholar 

  162. Ezponda, T., Popovic, R., Shah, M. Y., Martinez-Garcia, E., Zheng, Y., Min, D. J., Will, C., Neri, A., Kelleher, N. L., Yu, J., & Licht, J. D. (2013). The histone methyltransferase MMSET/WHSC1 activates TWIST1 to promote an epithelial–mesenchymal transition and invasive properties of prostate cancer. Oncogene, 32, 2882–2890.

    CAS  PubMed Central  PubMed  Google Scholar 

  163. Smith, J. (2002). Human Sir2 and the “silencing” of p53 activity. Trends in Cell Biology, 12, 404–406.

    CAS  PubMed  Google Scholar 

  164. Giannakou, M. E., & Partridge, L. (2004). The interaction between FOXO and SIRT1: Tipping the balance towards survival. Trends in Cell Biology, 14, 408–412.

    CAS  PubMed  Google Scholar 

  165. Byles, V., Zhu, L., Lovaas, J. D., Chmilewski, L. K., Wang, J., Faller, D. V., & Dai, Y. (2012). SIRT1 induces EMT by cooperating with EMT transcription factors and enhances prostate cancer cell migration and metastasis. Oncogene, 31, 4619–4629.

    CAS  PubMed  Google Scholar 

  166. Cao, Q., Yu, J., Dhanasekaran, S. M., Kim, J. H., Mani, R. S., Tomlins, S. A., Mehra, R., Laxman, B., Cao, X., Kleer, C. G., Varambally, S., & Chinnaiyan, A. M. (2008). Repression of E-cadherin by the polycomb group protein EZH2 in cancer. Oncogene, 27, 7274–7284.

    CAS  PubMed Central  PubMed  Google Scholar 

  167. Saha, B., Kaur, P., Tsao-Wei, D., Naritoku, W. Y., Groshen, S., Datar, R. H., Jones, L. W., & Imam, S. A. (2008). Unmethylated E-cadherin gene expression is significantly associated with metastatic human prostate cancer cells in bone. Prostate, 68, 1681–1688.

    CAS  PubMed  Google Scholar 

  168. Jansson, M. D., & Lund, A. H. (2012). MicroRNA and cancer. Molecular Oncology, 6, 590–610.

    CAS  PubMed  Google Scholar 

  169. Bartel, D. P. (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116, 281–297.

    CAS  PubMed  Google Scholar 

  170. Bullock, M. D., Sayan, A. E., Packham, G. K., & Mirnezami, A. H. (2012). MicroRNAs: critical regulators of epithelial to mesenchymal (EMT) and mesenchymal to epithelial transition (MET) in cancer progression. Biology of the Cell, 104, 3–12.

    CAS  PubMed  Google Scholar 

  171. Liu, Y. N., Yin, J. J., Abou-Kheir, W., Hynes, P. G., Casey, O. M., Fang, L., Yi, M., Stephens, R. M., Seng, V., Sheppard-Tillman, H., Martin, P., & Kelly, K. (2013). MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms. Oncogene, 32, 296–306.

    CAS  PubMed  Google Scholar 

  172. Kong, D., Li, Y., Wang, Z., Banerjee, S., Ahmad, A., Kim, H. R., & Sarkar, F. H. (2009). miR-200 regulates PDGF-D-mediated epithelial–mesenchymal transition, adhesion, and invasion of prostate cancer cells. Stem Cells, 27, 1712–1721.

    CAS  PubMed Central  PubMed  Google Scholar 

  173. Kong, D., Banerjee, S., Ahmad, A., Li, Y., Wang, Z., Sethi, S., & Sarkar, F. H. (2010). Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells. PLoS One, 5, e12445.

    PubMed Central  PubMed  Google Scholar 

  174. Puhr, M., Hoefer, J., Schafer, G., Erb, H. H., Oh, S. J., Klocker, H., Heidegger, I., Neuwirt, H., & Culig, Z. (2012). Epithelial-to-mesenchymal transition leads to docetaxel resistance in prostate cancer and is mediated by reduced expression of miR-200c and miR-205. The American Journal of Pathology, 181, 2188–2201.

    CAS  PubMed  Google Scholar 

  175. Qu, Y., Li, W. C., Hellem, M. R., Rostad, K., Popa, M., McCormack, E., Oyan, A. M., Kalland, K. H., & Ke, X. S. (2013). MiR-182 and miR-203 induce mesenchymal to epithelial transition and self-sufficiency of growth signals via repressing SNAI2 in prostate cells. International Journal of Cancer, 133, 544–555.

    CAS  Google Scholar 

  176. Coppola, V., Musumeci, M., Patrizii, M., Cannistraci, A., Addario, A., Maugeri-Sacca, M., Biffoni, M., Francescangeli, F., Cordenonsi, M., Piccolo, S., Memeo, L., Pagliuca, A., Muto, G., Zeuner, A., De Maria, R., & Bonci, D. (2013). BTG2 loss and miR-21 upregulation contribute to prostate cell transformation by inducing luminal markers expression and epithelial–mesenchymal transition. Oncogene, 32, 1843–1853.

    CAS  PubMed  Google Scholar 

  177. Watahiki, A., Macfarlane, R. J., Gleave, M. E., Crea, F., Wang, Y., Helgason, C. D., & Chi, K. N. (2013). Plasma miRNAs as biomarkers to identify patients with castration-resistant metastatic prostate cancer. International Journal of Molecular Sciences, 14, 7757–7770.

    CAS  PubMed Central  PubMed  Google Scholar 

  178. Ru, P., Steele, R., Newhall, P., Phillips, N. J., Toth, K., & Ray, R. B. (2012). miRNA-29b suppresses prostate cancer metastasis by regulating epithelial–mesenchymal transition signaling. Molecular Cancer Therapeutics, 11, 1166–1173.

    CAS  PubMed  Google Scholar 

  179. Tucci, P., Agostini, M., Grespi, F., Markert, E. K., Terrinoni, A., Vousden, K. H., Muller, P. A., Dotsch, V., Kehrloesser, S., Sayan, B. S., Giaccone, G., Lowe, S. W., Takahashi, N., Vandenabeele, P., Knight, R. A., Levine, A. J., & Melino, G. (2012). Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer. Proceedings of the National Academy of Sciences of the United States of America, 109, 15312–15317.

    CAS  PubMed Central  PubMed  Google Scholar 

  180. Zi, X., & Agarwal, R. (1999). Silibinin decreases prostate-specific antigen with cell growth inhibition via G1 arrest, leading to differentiation of prostate carcinoma cells: Implications for prostate cancer intervention. Proceedings of the National Academy of Sciences of the United States of America, 96, 7490–7495.

    CAS  PubMed Central  PubMed  Google Scholar 

  181. Tyagi, A. K., Singh, R. P., Agarwal, C., Chan, D. C., & Agarwal, R. (2002). Silibinin strongly synergizes human prostate carcinoma DU145 cells to doxorubicin-induced growth Inhibition, G2-M arrest, and apoptosis. Clinical Cancer Research, 8, 3512–3519.

    CAS  PubMed  Google Scholar 

  182. Dhanalakshmi, S., Agarwal, P., Glode, L. M., & Agarwal, R. (2003). Silibinin sensitizes human prostate carcinoma DU145 cells to cisplatin- and carboplatin-induced growth inhibition and apoptotic death. International Journal of Cancer, 106, 699–705.

    CAS  Google Scholar 

  183. Flaig, T. W., Su, L. J., Harrison, G., Agarwal, R., & Glode, L. M. (2007). Silibinin synergizes with mitoxantrone to inhibit cell growth and induce apoptosis in human prostate cancer cells. International Journal of Cancer, 120, 2028–2033.

    CAS  Google Scholar 

  184. Tyagi, A., Bhatia, N., Condon, M. S., Bosland, M. C., Agarwal, C., & Agarwal, R. (2002). Antiproliferative and apoptotic effects of silibinin in rat prostate cancer cells. Prostate, 53, 211–217.

    CAS  PubMed  Google Scholar 

  185. Agarwal, C., Tyagi, A., Kaur, M., & Agarwal, R. (2007). Silibinin inhibits constitutive activation of Stat3, and causes caspase activation and apoptotic death of human prostate carcinoma DU145 cells. Carcinogenesis, 28, 1463–1470.

    CAS  PubMed  Google Scholar 

  186. Zhu, W., Zhang, J. S., & Young, C. Y. (2001). Silymarin inhibits function of the androgen receptor by reducing nuclear localization of the receptor in the human prostate cancer cell line LNCaP. Carcinogenesis, 22, 1399–1403.

    CAS  PubMed  Google Scholar 

  187. Mokhtari, M. J., Motamed, N., & Shokrgozar, M. A. (2008). Evaluation of silibinin on the viability, migration and adhesion of the human prostate adenocarcinoma (PC-3) cell line. Cell Biology International, 32, 888–892.

    CAS  PubMed  Google Scholar 

  188. Wu, K. J., Zeng, J., Zhu, G. D., Zhang, L. L., Zhang, D., Li, L., Fan, J. H., Wang, X. Y., & He, D. L. (2009). Silibinin inhibits prostate cancer invasion, motility and migration by suppressing vimentin and MMP-2 expression. Acta Pharmacologica Sinica, 30, 1162–1168.

    CAS  PubMed  Google Scholar 

  189. Wu, K., Zeng, J., Li, L., Fan, J., Zhang, D., Xue, Y., Zhu, G., Yang, L., Wang, X., & He, D. (2010). Silibinin reverses epithelial-to-mesenchymal transition in metastatic prostate cancer cells by targeting transcription factors. Oncology Reports, 23, 1545–1552.

    CAS  PubMed  Google Scholar 

  190. Jung, H. J., Park, J. W., Lee, J. S., Lee, S. R., Jang, B. C., Suh, S. I., Suh, M. H., & Baek, W. K. (2009). Silibinin inhibits expression of HIF-1alpha through suppression of protein translation in prostate cancer cells. Biochemical and Biophysical Research Communications, 390, 71–76.

    CAS  PubMed  Google Scholar 

  191. Zhang, L. L., Li, L., Wu, D. P., Fan, J. H., Li, X., Wu, K. J., Wang, X. Y., & He, D. L. (2008). A novel anti-cancer effect of genistein: reversal of epithelial mesenchymal transition in prostate cancer cells. Acta Pharmacologica Sinica, 29, 1060–1068.

    CAS  PubMed  Google Scholar 

  192. Zhang, L., Li, L., Jiao, M., Wu, D., Wu, K., Li, X., Zhu, G., Yang, L., Wang, X., Hsieh, J. T., & He, D. (2012). Genistein inhibits the stemness properties of prostate cancer cells through targeting Hedgehog-Gli1 pathway. Cancer Letters, 323, 48–57.

    CAS  PubMed  Google Scholar 

  193. Chiyomaru, T., Yamamura, S., Fukuhara, S., Hidaka, H., Majid, S., Saini, S., Arora, S., Deng, G., Shahryari, V., Chang, I., Tanaka, Y., Tabatabai, Z. L., Enokida, H., Seki, N., Nakagawa, M., & Dahiya, R. (2013). Genistein up-regulates tumor suppressor microRNA-574-3p in prostate cancer. PLoS One, 8, e58929.

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Baritaki, S., Chapman, A., Yeung, K., Spandidos, D. A., Palladino, M., & Bonavida, B. (2009). Inhibition of epithelial to mesenchymal transition in metastatic prostate cancer cells by the novel proteasome inhibitor, NPI-0052: pivotal roles of Snail repression and RKIP induction. Oncogene, 28, 3573–3585.

    CAS  PubMed  Google Scholar 

  195. 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, e2888.

    PubMed Central  PubMed  Google Scholar 

  196. Lan, L., Luo, Y., Cui, D., Shi, B. Y., Deng, W., Huo, L. L., Chen, H. L., Zhang, G. Y., & Deng, L. L. (2013). Epithelial–mesenchymal transition triggers cancer stem cell generation in human thyroid cancer cells. International Journal of Oncology, 43, 113–120.

    CAS  PubMed  Google Scholar 

  197. Klarmann, G. J., Hurt, E. M., Mathews, L. A., Zhang, X., Duhagon, M. A., Mistree, T., Thomas, S. B., & Farrar, W. L. (2009). Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature. Clinical & Experimental Metastasis, 26, 433–446.

    CAS  Google Scholar 

  198. Albino, D., Longoni, N., Curti, L., Mello-Grand, M., Pinton, S., Civenni, G., Thalmann, G., D’Ambrosio, G., Sarti, M., Sessa, F., Chiorino, G., Catapano, C. V., & Carbone, G. M. (2012). ESE3/EHF controls epithelial cell differentiation and its loss leads to prostate tumors with mesenchymal and stem-like features. Cancer Research, 72, 2889–2900.

    CAS  PubMed  Google Scholar 

  199. Lukacs, R. U., Memarzadeh, S., Wu, H., & Witte, O. N. (2010). Bmi-1 is a crucial regulator of prostate stem cell self-renewal and malignant transformation. Cell Stem Cell, 7, 682–693.

    CAS  PubMed Central  PubMed  Google Scholar 

  200. Domingo-Domenech, J., Vidal, S. J., Rodriguez-Bravo, V., Castillo-Martin, M., Quinn, S. A., Rodriguez-Barrueco, R., Bonal, D. M., Charytonowicz, E., Gladoun, N., de la Iglesia-Vicente, J., Petrylak, D. P., Benson, M. C., Silva, J. M., & Cordon-Cardo, C. (2012). Suppression of acquired docetaxel resistance in prostate cancer through depletion of Notch- and Hedgehog-dependent tumor-initiating cells. Cancer Cell, 22, 373–388.

    CAS  PubMed  Google Scholar 

  201. Bae, K. M., Su, Z., Frye, C., McClellan, S., Allan, R. W., Andrejewski, J. T., Kelley, V., Jorgensen, M., Steindler, D. A., Vieweg, J., & Siemann, D. W. (2010). Expression of pluripotent stem cell reprogramming factors by prostate tumor initiating cells. The Journal of Urology, 183, 2045–2053.

    CAS  PubMed  Google Scholar 

  202. Yan, H., Chen, X., Zhang, Q., Qin, J., Li, H., Liu, C., Calhoun-Davis, T., Coletta, L. D., Klostergaard, J., Fokt, I., Skora, S., Priebe, W., Bi, Y., & Tang, D. G. (2011). Drug-tolerant cancer cells show reduced tumor-initiating capacity: Depletion of CD44 cells and evidence for epigenetic mechanisms. PLoS One, 6, e24397.

    CAS  PubMed Central  PubMed  Google Scholar 

  203. Wang, Z. A., & Shen, M. M. (2011). Revisiting the concept of cancer stem cells in prostate cancer. Oncogene, 30, 1261–1271.

    PubMed  Google Scholar 

  204. Gupta, P. B., Onder, T. T., Jiang, G., Tao, K., Kuperwasser, C., Weinberg, R. A., & Lander, E. S. (2009). Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell, 138, 645–659.

    CAS  PubMed  Google Scholar 

  205. Allard, W. J., Matera, J., Miller, M. C., Repollet, M., Connelly, M. C., Rao, C., Tibbe, A. G., Uhr, J. W., & Terstappen, L. W. (2004). Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clinical Cancer Research, 10, 6897–6904.

    PubMed  Google Scholar 

  206. Cristofanilli, M., Budd, G. T., Ellis, M. J., Stopeck, A., Matera, J., Miller, M. C., Reuben, J. M., Doyle, G. V., Allard, W. J., Terstappen, L. W., & Hayes, D. F. (2004). Circulating tumor cells, disease progression, and survival in metastatic breast cancer. The New England Journal of Medicine, 351, 781–791.

    CAS  PubMed  Google Scholar 

  207. de Bono, J. S., Scher, H. I., Montgomery, R. B., Parker, C., Miller, M. C., Tissing, H., Doyle, G. V., Terstappen, L. W., Pienta, K. J., & Raghavan, D. (2008). Circulating tumor cells predict survival benefit from treatment in metastatic castration-resistant prostate cancer. Clinical Cancer Research, 14, 6302–6309.

    PubMed  Google Scholar 

  208. Cohen, S. J., Punt, C. J., Iannotti, N., Saidman, B. H., Sabbath, K. D., Gabrail, N. Y., Picus, J., Morse, M., Mitchell, E., Miller, M. C., Doyle, G. V., Tissing, H., Terstappen, L. W., & Meropol, N. J. (2008). Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. Journal of Clinical Oncology, 26, 3213–3221.

    PubMed  Google Scholar 

  209. Khan, M. S., Kirkwood, A., Tsigani, T., Garcia-Hernandez, J., Hartley, J. A., Caplin, M. E., & Meyer, T. (2013). Circulating tumor cells as prognostic markers in neuroendocrine tumors. Journal of Clinical Oncology, 31, 365–372.

    CAS  PubMed  Google Scholar 

  210. Scher, H. I., Morris, M. J., Basch, E., & Heller, G. (2011). End points and outcomes in castration-resistant prostate cancer: From clinical trials to clinical practice. Journal of Clinical Oncology, 29, 3695–3704.

    PubMed Central  PubMed  Google Scholar 

  211. Lecharpentier, A., Vielh, P., Perez-Moreno, P., Planchard, D., Soria, J. C., & Farace, F. (2011). Detection of circulating tumour cells with a hybrid (epithelial/mesenchymal) phenotype in patients with metastatic non-small cell lung cancer. British Journal of Cancer, 105, 1338–1341.

    CAS  PubMed Central  PubMed  Google Scholar 

  212. Krebs, M. G., Hou, J. M., Sloane, R., Lancashire, L., Priest, L., Nonaka, D., Ward, T. H., Backen, A., Clack, G., Hughes, A., Ranson, M., Blackhall, F. H., & Dive, C. (2012). Analysis of circulating tumor cells in patients with non-small cell lung cancer using epithelial marker-dependent and -independent approaches. Journal of Thoracic Oncology, 7, 306–315.

    PubMed  Google Scholar 

  213. Bellizzi, A., Sebastian, S., Ceglia, P., Centonze, M., Divella, R., Manzillo, E. F., Azzariti, A., Silvestris, N., Montemurro, S., Caliandro, C., De Luca, R., Cicero, G., Rizzo, S., Russo, A., Quaranta, M., Simone, G., & Paradiso, A. (2013). Co-expression of CD133(+)/CD44(+) in human colon cancer and liver metastasis. Journal of Cellular Physiology, 228, 408–415.

    CAS  PubMed  Google Scholar 

  214. Barriere, G., Riouallon, A., Renaudie, J., Tartary, M., & Rigaud, M. (2012). Mesenchymal and stemness circulating tumor cells in early breast cancer diagnosis. BMC Cancer, 12, 114.

    CAS  PubMed Central  PubMed  Google Scholar 

  215. Sieuwerts, A. M., Kraan, J., Bolt, J., van der Spoel, P., Elstrodt, F., Schutte, M., Martens, J. W., Gratama, J. W., Sleijfer, S., & Foekens, J. A. (2009). Anti-epithelial cell adhesion molecule antibodies and the detection of circulating normal-like breast tumor cells. Journal of the National Cancer Institute, 101, 61–66.

    CAS  PubMed Central  PubMed  Google Scholar 

  216. Raimondi, C., Gradilone, A., Naso, G., Vincenzi, B., Petracca, A., Nicolazzo, C., Palazzo, A., Saltarelli, R., Spremberg, F., Cortesi, E., & Gazzaniga, P. (2011). Epithelial–mesenchymal transition and stemness features in circulating tumor cells from breast cancer patients. Breast Cancer Research and Treatment, 130, 449–455.

    CAS  PubMed  Google Scholar 

  217. Ozkumur, E., Shah, A. M., Ciciliano, J. C., Emmink, B. L., Miyamoto, D. T., Brachtel, E., Yu, M., Chen, P. I., Morgan, B., Trautwein, J., Kimura, A., Sengupta, S., Stott, S. L., Karabacak, N. M., Barber, T. A., Walsh, J. R., Smith, K., Spuhler, P. S., Sullivan, J. P., Lee, R. J., Ting, D. T., Luo, X., Shaw, A. T., Bardia, A., Sequist, L. V., Louis, D. N., Maheswaran, S., Kapur, R., Haber, D. A., & Toner, M. (2013). “Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells,”. Science Translational Medicine, 5, 179ra47.

    PubMed Central  PubMed  Google Scholar 

  218. Ryan, C. J., Shah, S., Efstathiou, E., Smith, M. R., Taplin, M. E., Bubley, G. J., Logothetis, C. J., Kheoh, T., Kilian, C., Haqq, C. M., Molina, A., & Small, E. J. (2011). Phase II study of abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer displaying bone flare discordant with serologic response. Clinical Cancer Research, 17, 4854–4861.

    CAS  PubMed Central  PubMed  Google Scholar 

  219. Smith, D. C., Smith, M. R., Sweeney, C., Elfiky, A. A., Logothetis, C., Corn, P. G., Vogelzang, N. J., Small, E. J., Harzstark, A. L., Gordon, M. S., Vaishampayan, U. N., Haas, N. B., Spira, A. I., Lara, P. N., Jr., Lin, C. C., Srinivas, S., Sella, A., Schoffski, P., Scheffold, C., Weitzman, A. L., & Hussain, M. (2013). Cabozantinib in patients with advanced prostate cancer: Results of a phase II randomized discontinuation trial. Journal of Clinical Oncology, 31, 412–419.

    CAS  PubMed  Google Scholar 

  220. R. J. Lee, P. J. Saylor, M. D. Michaelson, S. M. Rothenberg, M. E. Smas, D. T. Miyamoto, C. A. Gurski, W. Xie, S. Maheswaran, D. A. Haber, J. G. Goldin, and M. R. Smith, “A Dose-Ranging Study of Cabozantinib in Men with Castration-Resistant Prostate Cancer and Bone Metastases,” Clin Cancer Res, May 15 2013

  221. Kwok, W. K., Ling, M. T., Lee, T. W., Lau, T. C., Zhou, C., Zhang, X., Chua, C. W., Chan, K. W., Chan, F. L., Glackin, C., Wong, Y. C., & Wang, X. (2005). Up-regulation of TWIST in prostate cancer and its implication as a therapeutic target. Cancer Research, 65, 5153–5162.

    CAS  PubMed  Google Scholar 

  222. Sethi, S., Macoska, J., Chen, W., & Sarkar, F. H. (2010). Molecular signature of epithelial–mesenchymal transition (EMT) in human prostate cancer bone metastasis. American Journal of Translational Research, 3, 90–99.

    PubMed Central  PubMed  Google Scholar 

  223. Gravdal, K., Halvorsen, O. J., Haukaas, S. A., & Akslen, L. A. (2007). A switch from E-cadherin to N-cadherin expression indicates epithelial to mesenchymal transition and is of strong and independent importance for the progress of prostate cancer. Clinical Cancer Research, 13, 7003–7011.

    CAS  PubMed  Google Scholar 

  224. Behnsawy, H. M., Miyake, H., Harada, K., & Fujisawa, M. (2013). Expression patterns of epithelial–mesenchymal transition markers in localized prostate cancer: Significance in clinicopathological outcomes following radical prostatectomy. BJU International, 111, 30–37.

    PubMed  Google Scholar 

  225. Tomlins, S. A., Rhodes, D. R., Perner, S., Dhanasekaran, S. M., Mehra, R., Sun, X. W., Varambally, S., Cao, X., Tchinda, J., Kuefer, R., Lee, C., Montie, J. E., Shah, R. B., Pienta, K. J., Rubin, M. A., & Chinnaiyan, A. M. (2005). Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science, 310, 644–648.

    CAS  PubMed  Google Scholar 

  226. Tomlins, S. A., Laxman, B., Dhanasekaran, S. M., Helgeson, B. E., Cao, X., Morris, D. S., Menon, A., Jing, X., Cao, Q., Han, B., Yu, J., Wang, L., Montie, J. E., Rubin, M. A., Pienta, K. J., Roulston, D., Shah, R. B., Varambally, S., Mehra, R., & Chinnaiyan, A. M. (2007). Distinct classes of chromosomal rearrangements create oncogenic ETS gene fusions in prostate cancer. Nature, 448, 595–599.

    CAS  PubMed  Google Scholar 

  227. Gupta, S., Iljin, K., Sara, H., Mpindi, J. P., Mirtti, T., Vainio, P., Rantala, J., Alanen, K., Nees, M., & Kallioniemi, O. (2010). FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Research, 70, 6735–6745.

    CAS  PubMed  Google Scholar 

  228. Leshem, O., Madar, S., Kogan-Sakin, I., Kamer, I., Goldstein, I., Brosh, R., Cohen, Y., Jacob-Hirsch, J., Ehrlich, M., Ben-Sasson, S., Goldfinger, N., Loewenthal, R., Gazit, E., Rotter, V., & Berger, R. (2011). TMPRSS2/ERG promotes epithelial to mesenchymal transition through the ZEB1/ZEB2 axis in a prostate cancer model. PLoS One, 6, e21650.

    CAS  PubMed Central  PubMed  Google Scholar 

  229. Demichelis, F., Fall, K., Perner, S., Andren, O., Schmidt, F., Setlur, S. R., Hoshida, Y., Mosquera, J. M., Pawitan, Y., Lee, C., Adami, H. O., Mucci, L. A., Kantoff, P. W., Andersson, S. O., Chinnaiyan, A. M., Johansson, J. E., & Rubin, M. A. (2007). TMPRSS2:ERG gene fusion associated with lethal prostate cancer in a watchful waiting cohort. Oncogene, 26, 4596–4599.

    CAS  PubMed  Google Scholar 

  230. Nam, R. K., Sugar, L., Yang, W., Srivastava, S., Klotz, L. H., Yang, L. Y., Stanimirovic, A., Encioiu, E., Neill, M., Loblaw, D. A., Trachtenberg, J., Narod, S. A., & Seth, A. (2007). Expression of the TMPRSS2:ERG fusion gene predicts cancer recurrence after surgery for localised prostate cancer. British Journal of Cancer, 97, 1690–1695.

    CAS  PubMed Central  PubMed  Google Scholar 

  231. Attard, G., Clark, J., Ambroisine, L., Fisher, G., Kovacs, G., Flohr, P., Berney, D., Foster, C. S., Fletcher, A., Gerald, W. L., Moller, H., Reuter, V., De Bono, J. S., Scardino, P., Cuzick, J., & Cooper, C. S. (2008). Duplication of the fusion of TMPRSS2 to ERG sequences identifies fatal human prostate cancer. Oncogene, 27, 253–263.

    CAS  PubMed Central  PubMed  Google Scholar 

  232. Pettersson, A., Graff, R. E., Bauer, S. R., Pitt, M. J., Lis, R. T., Stack, E. C., Martin, N. E., Kunz, L., Penney, K. L., Ligon, A. H., Suppan, C., Flavin, R., Sesso, H. D., Rider, J. R., Sweeney, C., Stampfer, M. J., Fiorentino, M., Kantoff, P. W., Sanda, M. G., Giovannucci, E. L., Ding, E. L., Loda, M., & Mucci, L. A. (2012). The TMPRSS2:ERG rearrangement, ERG expression, and prostate cancer outcomes: A cohort study and meta-analysis. Cancer Epidemiology, Biomarkers & Prevention, 21, 1497–1509.

    Google Scholar 

  233. Chen, C. L., Mahalingam, D., Osmulski, P., Jadhav, R. R., Wang, C. M., Leach, R. J., Chang, T. C., Weitman, S. D., Kumar, A. P., Sun, L., Gaczynska, M. E., Thompson, I. M., & Huang, T. H. (2013). Single-cell analysis of circulating tumor cells identifies cumulative expression patterns of EMT-related genes in metastatic prostate cancer. Prostate, 73, 813–826.

    PubMed  Google Scholar 

  234. Jennbacken, K., Tesan, T., Wang, W., Gustavsson, H., Damber, J. E., & Welen, K. (2010). N-Cadherin increases after androgen deprivation and is associated with metastasis in prostate cancer. Endocrine-Related Cancer, 17, 469–479.

    CAS  PubMed  Google Scholar 

  235. Tanaka, H., Kono, E., Tran, C. P., Miyazaki, H., Yamashiro, J., Shimomura, T., Fazli, L., Wada, R., Huang, J., Vessella, R. L., An, J., Horvath, S., Gleave, M., Rettig, M. B., Wainberg, Z. A., & Reiter, R. E. (2010). Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nature Medicine, 16, 1414–1420.

    CAS  PubMed Central  PubMed  Google Scholar 

  236. Putzke, A. P., Ventura, A. P., Bailey, A. M., Akture, C., Opoku-Ansah, J., Celiktas, M., Hwang, M. S., Darling, D. S., Coleman, I. M., Nelson, P. S., Nguyen, H. M., Corey, E., Tewari, M., Morrissey, C., Vessella, R. L., & Knudsen, B. S. (2011). Metastatic progression of prostate cancer and e-cadherin regulation by zeb1 and SRC family kinases. The American Journal of Pathology, 179, 400–410.

    CAS  PubMed Central  PubMed  Google Scholar 

  237. Giampieri, S., Manning, C., Hooper, S., Jones, L., Hill, C. S., & Sahai, E. (2009). Localized and reversible TGFbeta signalling switches breast cancer cells from cohesive to single cell motility. Nature Cell Biology, 11, 1287–1296.

    CAS  PubMed Central  PubMed  Google Scholar 

  238. Armstrong, A. J., Tannock, I. F., de Wit, R., George, D. J., Eisenberger, M., & Halabi, S. (2010). The development of risk groups in men with metastatic castration-resistant prostate cancer based on risk factors for PSA decline and survival. European Journal of Cancer, 46, 517–525.

    CAS  PubMed  Google Scholar 

  239. Qin, J., Liu, X., Laffin, B., Chen, X., Choy, G., Jeter, C. R., Calhoun-Davis, T., Li, H., Palapattu, G. S., Pang, S., Lin, K., Huang, J., Ivanov, I., Li, W., Suraneni, M. V., & Tang, D. G. (2012). The PSA(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell, 10, 556–569.

    CAS  PubMed Central  PubMed  Google Scholar 

  240. Kottke, T., Errington, F., Pulido, J., Galivo, F., Thompson, J., Wongthida, P., Diaz, R. M., Chong, H., Ilett, E., Chester, J., Pandha, H., Harrington, K., Selby, P., Melcher, A., & Vile, R. (2011). Broad antigenic coverage induced by vaccination with virus-based cDNA libraries cures established tumors. Nature Medicine, 17, 854–859.

    CAS  PubMed Central  PubMed  Google Scholar 

  241. Kantoff, P. W., Higano, C. S., Shore, N. D., Berger, E. R., Small, E. J., Penson, D. F., Redfern, C. H., Ferrari, A. C., Dreicer, R., Sims, R. B., Xu, Y., Frohlich, M. W., & Schellhammer, P. F. (2010). Sipuleucel-T immunotherapy for castration-resistant prostate cancer. The New England Journal of Medicine, 363, 411–422.

    CAS  PubMed  Google Scholar 

  242. Kantoff, P. W., Schuetz, T. J., Blumenstein, B. A., Glode, L. M., Bilhartz, D. L., Wyand, M., Manson, K., Panicali, D. L., Laus, R., Schlom, J., Dahut, W. L., Arlen, P. M., Gulley, J. L., & Godfrey, W. R. (2010). Overall survival analysis of a phase II randomized controlled trial of a Poxviral-based PSA-targeted immunotherapy in metastatic castration-resistant prostate cancer. Journal of Clinical Oncology, 28, 1099–1105.

    CAS  PubMed Central  PubMed  Google Scholar 

  243. Yuan, T. C., Veeramani, S., & Lin, M. F. (2007). Neuroendocrine-like prostate cancer cells: neuroendocrine transdifferentiation of prostate adenocarcinoma cells. Endocrine-Related Cancer, 14, 531–547.

    CAS  PubMed  Google Scholar 

  244. Carver, B. S., Chapinski, C., Wongvipat, J., Hieronymus, H., Chen, Y., Chandarlapaty, S., Arora, V. K., Le, C., Koutcher, J., Scher, H., Scardino, P. T., Rosen, N., & Sawyers, C. L. (2011). Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell, 19, 575–586.

    CAS  PubMed Central  PubMed  Google Scholar 

  245. Bitting, R. L., & Armstrong, A. J. (2013). Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer. Endocrine-Related Cancer, 20, R83–R99.

    CAS  PubMed  Google Scholar 

  246. Glickman, M. S., & Sawyers, C. L. (2012). Converting cancer therapies into cures: lessons from infectious diseases. Cell, 148, 1089–1098.

    CAS  PubMed Central  PubMed  Google Scholar 

  247. Goldstein, A. S., Huang, J., Guo, C., Garraway, I. P., & Witte, O. N. (2010). Identification of a cell of origin for human prostate cancer. Science, 329, 568–571.

    CAS  PubMed Central  PubMed  Google Scholar 

  248. Cottard, F., Asmane, I., Erdmann, E., Bergerat, J. P., Kurtz, J. E., & Ceraline, J. (2013). Constitutively active androgen receptor variants upregulate expression of mesenchymal markers in prostate cancer cells. PLoS One, 8, p. e63466.

  249. Brennen, W. N., Rosen, D. M., Wang, H., Isaacs, J. T., & Denmeade, S. R. (2012). Targeting carcinoma-associated fibroblasts within the tumor stroma with a fibroblast activation protein-activated prodrug. Journal of the National Cancer Institute, 104, 1320–1334.

    CAS  PubMed Central  PubMed  Google Scholar 

  250. Li, Y., Maitah, M. Y., Ahmad, A., Kong, D., Bao, B., & Sarkar, F. H. (2012). Targeting the Hedgehog signaling pathway for cancer therapy. Expert Opinion on Therapeutic Targets, 16, 49–66.

    Google Scholar 

  251. Groth, C., & Fortini, M. E. (2012). Therapeutic approaches to modulating Notch signaling: Current challenges and future prospects. Seminars in Cell & Developmental Biology, 23, 465–472.

    CAS  Google Scholar 

  252. Smith, A. L., Robin, T. P., & Ford, H. L. (2012). Molecular pathways: Targeting the TGF-beta pathway for cancer therapy. Clinical Cancer Research, 18, 4514–4521.

    CAS  PubMed  Google Scholar 

  253. Liu, G., Sprenger, C., Sun, S., Epilepsia, K. S., Haugk, K., Zhang, X., et al. (2013). AR variant ARv567es induces carcinogenesis in a novel transgenic mouse model of prostate cancer. Neoplasia, 15, pp. 1009–1017.

    Google Scholar 

  254. Bitting, R. L., & Armstrong, A. J. (2013). Potential predictive biomarkers for individualizing treatment for men with castration-resistant prostate cancer. Cancer Journal, 19, 25–33.

    CAS  Google Scholar 

  255. Othus, M., Barlogie, B., Leblanc, M. L., & Crowley, J. J. (2012). Cure models as a useful statistical tool for analyzing survival. Clinical Cancer Research, 18, 3731–3736.

    PubMed Central  PubMed  Google Scholar 

  256. Scher, H. I., Fizazi, K., Saad, F., Taplin, M. E., Sternberg, C. N., Miller, K., et al. (2012). Increased survival with enzalutamide in prostate cancer after chemotherapy. The New England Journal of Medicine, 367, 1187–1197.

    Google Scholar 

  257. Clegg, N. J., Wongvipat, J., Joseph, J. D., Tran, C., Ouk, S., Dilhas, A., Chen, Y., Grillot, K., Bischoff, E. D., Cai, L., Aparicio, A., Dorow, S., Arora, V., Shao, G., Qian, J., Zhao, H., Yang, G., Cao, C., Sensintaffar, J., Wasielewska, T., Herbert, M. R., Bonnefous, C., Darimont, B., Scher, H. I., Smith-Jones, P., Klang, M., Smith, N. D., De Stanchina, E., Wu, N., Ouerfelli, O., Rix, P. J., Heyman, R. A., Jung, M. E., Sawyers, C. L., & Hager, J. H. (2012). ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Research, 72, 1494–1503.

    CAS  PubMed Central  PubMed  Google Scholar 

  258. Montgomery, R. B., Eisenberger, M. A., Rettig, M., Chu, F., Pili, R., Stephenson, J., Vogelzang, N. J., Morrison, J., & Taplin, M. (2012). Phase I clinical trial of galeterone (TOK-001), a multifunctional antiandrogen and CYP17 inhibitor in castration resistant prostate cancer. Journal of Clinical Oncology, 30, abstr 4665.

    Google Scholar 

  259. de Bono, J. S., Logothetis, C. J., Molina, A., Fizazi, K., North, S., Chu, L., Chi, K. N., Jones, R. J., Goodman, O. B., Jr., Saad, F., Staffurth, J. N., Mainwaring, P., Harland, S., Flaig, T. W., Hutson, T. E., Cheng, T., Patterson, H., Hainsworth, J. D., Ryan, C. J., Sternberg, C. N., Ellard, S. L., Flechon, A., Saleh, M., Scholz, M., Efstathiou, E., Zivi, A., Bianchini, D., Loriot, Y., Chieffo, N., Kheoh, T., Haqq, C. M., & Scher, H. I. (2011). Abiraterone and increased survival in metastatic prostate cancer. The New England Journal of Medicine, 364, 1995–2005.

    PubMed Central  PubMed  Google Scholar 

  260. Ryan, C. J., Smith, M. R., de Bono, J. S., Molina, A., Logothetis, C. J., de Souza, P., Fizazi, K., Mainwaring, P., Piulats, J. M., Ng, S., Carles, J., Mulders, P. F., Basch, E., Small, E. J., Saad, F., Schrijvers, D., Van Poppel, H., Mukherjee, S. D., Suttmann, H., Gerritsen, W. R., Flaig, T. W., George, D. J., Yu, E. Y., Efstathiou, E., Pantuck, A., Winquist, E., Higano, C. S., Taplin, M. E., Park, Y., Kheoh, T., Griffin, T., Scher, H. I., & Rathkopf, D. E. (2013). Abiraterone in metastatic prostate cancer without previous chemotherapy. The New England Journal of Medicine, 368, 138–148.

    CAS  PubMed Central  PubMed  Google Scholar 

  261. Kaku, T., Hitaka, T., Ojida, A., Matsunaga, N., Adachi, M., Tanaka, T., Hara, T., Yamaoka, M., Kusaka, M., Okuda, T., Asahi, S., Furuya, S., & Tasaka, A. (2011). Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer. Bioorganic & Medicinal Chemistry, 19, 6383–6399.

    CAS  Google Scholar 

  262. Yarom, N., Stewart, D., Malik, R., Wells, J., Avruch, L., & Jonker, D. J. (2013). Phase I clinical trial of Exherin (ADH-1) in patients with advanced solid tumors. Current Clinical Pharmacology, 8, 81–88.

    CAS  PubMed  Google Scholar 

  263. Austin, P., Freeman, S. A., Gray, C. A., Gold, M. R., Vogl, A. W., Andersen, R. J., Roberge, M., & Roskelley, C. D. (2013). The invasion inhibitor sarasinoside A1 reverses mesenchymal tumor transformation in an e-cadherin-independent manner. Molecular Cancer Research, 11, 530–540.

    CAS  PubMed  Google Scholar 

  264. Feng, S., Shao, L., Yu, W., Gavine, P., & Ittmann, M. (2012). Targeting fibroblast growth factor receptor signaling inhibits prostate cancer progression. Clinical Cancer Research, 18, 3880–3888.

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We acknowledge grant support from NIGMS grant R01 GM63090 (M.A. Garcia-Blanco); National Cancer Institute grant R01 CA127727, (M.A. Garcia-Blanco), Robert B. Goergen Prostate Cancer Foundation Young Investigator Award (A.J. Armstrong), Department of Defense Physician Research Training Award W81XWH-10-1-0483 (A.J. Armstrong).

Author information

Authors and Affiliations

  1. Division of Medical Oncology, Duke Cancer Institute, Duke University, DUMC Box 102002, Durham, NC, 27710, USA

    Rhonda L. Bitting & Andrew J. Armstrong

  2. Department of Medicine, Duke University, Durham, NC, USA

    Rhonda L. Bitting, Mariano A. Garcia-Blanco & Andrew J. Armstrong

  3. Center for RNA Biology, Duke University, Durham, NC, USA

    Rhonda L. Bitting, Daneen Schaeffer, Jason A. Somarelli, Mariano A. Garcia-Blanco & Andrew J. Armstrong

  4. Department of Molecular Genetics and Microbiology, Duke University, Durham, NC, USA

    Daneen Schaeffer, Jason A. Somarelli, Mariano A. Garcia-Blanco & Andrew J. Armstrong

Authors
  1. Rhonda L. Bitting
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daneen Schaeffer
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jason A. Somarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mariano A. Garcia-Blanco
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Andrew J. Armstrong
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Andrew J. Armstrong.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bitting, R.L., Schaeffer, D., Somarelli, J.A. et al. The role of epithelial plasticity in prostate cancer dissemination and treatment resistance. Cancer Metastasis Rev 33, 441–468 (2014). https://doi.org/10.1007/s10555-013-9483-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10555-013-9483-z

Keywords

Search

Navigation