Prostate cancer stem-like cells contribute to the development of castration-resistant prostate cancer

Cancers

Volumn 7, Issue 4, 2015, Pages 2290-2308

  Ojo, Diane ^a,b,c   Lin, Xiaozeng ^a,b,c   Wong, Nicholas ^a,b,c   Gu, Yan ^a,b,c   Tang, Damu ^a,b,c  

^a MCMASTER UNIVERSITY   (Canada)

^b Father Sean O'Sullivan Res Center   (Canada)

^c ST JOSEPH S HOSPITAL   (Canada)

Author keywords

Androgen receptor; Castration resistant prostate cancer; IL6; Prostate cancer; Prostate cancer stem like cells; STAT3

Indexed keywords

ABIRATERONE; ANDROGEN RECEPTOR; BETA CATENIN; ENZALUTAMIDE; INTERLEUKIN 6; JANUS KINASE; STAT3 PROTEIN; TESTOSTERONE; TRANSCRIPTION FACTOR NANOG; TRANSCRIPTION FACTOR SOX2;

ANDROGEN DEPRIVATION THERAPY; CANCER STEM CELL; CASTRATION RESISTANT PROSTATE CANCER; DRUG RESISTANCE; EPITHELIAL MESENCHYMAL TRANSITION; GENE EXPRESSION REGULATION; HUMAN; NANOG GENE; NONHUMAN; PROSTATE CANCER STEM LIKE CELL; REVIEW; SOX2 GENE; STEM CELL EXPANSION; TESTOSTERONE BLOOD LEVEL; UPREGULATION; WNT SIGNALING PATHWAY;

EID: 84947704120     PISSN: None     EISSN: 20726694     Source Type: Journal    
DOI: 10.3390/cancers7040890     Document Type: Review

References (163)

1. Siegel, R.; Ward, E.; Brawley, O.; Jemal, A. Cancer statistics, 2011: The impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J. Clin. 2011, 61, 212–236. [CrossRef][PubMed]
2. Ross, J.S. The androgen receptor in prostate cancer: Therapy target in search of an integrated diagnostic test. Adv. Anat. Pathol. 2007, 14, 353–357. [CrossRef][PubMed]
3. Moon, C.; Park, J.C.; Chae, Y.K.; Yun, J.H.; Kim, S. Current status of experimental therapeutics for prostate cancer. Cancer Lett. 2008, 266, 116–134. [CrossRef][PubMed]
4. Lytton, B. Prostate cancer: A brief history and the discovery of hormonal ablation treatment. J. Urol. 2001, 165, 1859–1862. [CrossRef]
5. Wong, Y.N.; Ferraldeschi, R.; Attard, G.; de Bono, J. Evolution of androgen receptor targeted therapy for advanced prostate cancer. Nat. Rev. Clin. Oncol. 2014, 11, 365–376. [CrossRef][PubMed]
6. Heinlein, C.A.; Chang, C. Androgen receptor in prostate cancer. Endocr. Rev. 2004, 25, 276–308. [CrossRef][PubMed]
7. Tannock, I.F.; de Wit, R.; Berry, W.R.; Horti, J.; Pluzanska, A.; Chi, K.N.; Oudard, S.; Theodore, C.; James, N.D.; Turesson, I., et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N. Engl. J. Med. 2004, 351, 1502–1512. [CrossRef][PubMed]
8. Berthold, D.R.; Pond, G.R.; Soban, F.; de Wit, R.; Eisenberger, M.; Tannock, I.F. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer: Updated survival in the tax 327 study. J. Clin. Oncol. 2008, 26, 242–245. [CrossRef][PubMed]
9. Mitsiades, N. A road map to comprehensive androgen receptor axis targeting for castration-resistant prostate cancer. Cancer Res. 2013, 73, 4599–4605. [CrossRef][PubMed]
10. Mateo, J.; Smith, A.; Ong, M.; de Bono, J.S. Novel drugs targeting the androgen receptor pathway in prostate cancer. Cancer Metastasis Rev. 2014, 33, 567–579. [CrossRef][PubMed]
11. 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., et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl. J. Med. 2011, 364, 1995–2005. [CrossRef][PubMed]
12. Scher, H.I.; Fizazi, K.; Saad, F.; Taplin, M.E.; Sternberg, C.N.; Miller, K.; de Wit, R.; Mulders, P.; Chi, K.N.; Shore, N.D., et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N. Engl. J. Med. 2012, 367, 1187–1197. [PubMed]
13. Li, Y.; Chan, S.C.; Brand, L.J.; Hwang, T.H.; Silverstein, K.A.; Dehm, S.M. Androgen receptor splice variants mediate enzalutamide resistance in castration-resistant prostate cancer cell lines. Cancer Res. 2013, 73, 483–489. [CrossRef][PubMed]
14. Antonarakis, E.S.; Lu, C.; Wang, H.; Luber, B.; Nakazawa, M.; Roeser, J.C.; Chen, Y.; Mohammad, T.A.; Chen, Y.; Fedor, H.L., et al. Ar-v7 and resistance to enzalutamide and abiraterone in prostate cancer. N. Engl. J. Med. 2014, 371, 1028–1038. [CrossRef][PubMed]
15. Pienta, K.J.; Walia, G.; Simons, J.W.; Soule, H.R. Beyond the androgen receptor: New approaches to treating metastatic prostate cancer. Report of the 2013 prouts neck prostate cancer meeting. Prostate 2014, 74, 314–320. [CrossRef][PubMed]
16. Ramadan, W.H.; Kabbara, W.K.; Al Basiouni., Al Masri, H.S. Enzalutamide for patients with metastatic castration-resistant prostate cancer. OncoTargets Ther. 2015, 8, 871–876. [CrossRef][PubMed]
17. Oudard, S. Progress in emerging therapies for advanced prostate cancer. Cancer Treat. Rev. 2013, 39, 275–289. [CrossRef][PubMed]
18. 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., et al. Intraprostatic androgens and androgen-regulated gene expression persist after testosterone suppression: Therapeutic implications for castration-resistant prostate cancer. Cancer Res. 2007, 67, 5033–5041. [CrossRef][PubMed]
19. Montgomery, R.B.; Mostaghel, E.A.; Vessella, R.; Hess, D.L.; Kalhorn, T.F.; Higano, C.S.; True, L.D.; Nelson, P.S. Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth. Cancer Res. 2008, 68, 4447–4454. [CrossRef][PubMed]
20. Mitsiades, N.; Sung, C.C.; Schultz, N.; Danila, D.C.; He, B.; Eedunuri, V.K.; Fleisher, M.; Sander, C.; Sawyers, C.L.; Scher, H.I. Distinct patterns of dysregulated expression of enzymes involved in androgen synthesis and metabolism in metastatic prostate cancer tumors. Cancer Res. 2012, 72, 6142–6152. [CrossRef][PubMed]
21. Levesque, E.; Huang, S.P.; Audet-Walsh, E.; Lacombe, L.; Bao, B.Y.; Fradet, Y.; Laverdiere, I.; Rouleau, M.; Huang, C.Y.; Yu, C.C., et al. Molecular markers in key steroidogenic pathways, circulating steroid levels, and prostate cancer progression. Clin. Cancer Res. 2013, 19, 699–709. [CrossRef][PubMed]
22. Salem, M.; Garcia, J.A. Abiraterone acetate, a novel adrenal inhibitor in metastatic castration-resistant prostate cancer. Curr. Oncol. Rep. 2011, 13, 92–96. [CrossRef][PubMed]
23. Vasaitis, T.S.; Bruno, R.D.; Njar, V.C. Cyp17 inhibitors for prostate cancer therapy. J. Steroid biochem. Mol. Biol. 2011, 125, 23–31. [CrossRef][PubMed]
24. Labrie, F. Adrenal androgens and intracrinology. Semin. Reprod. Med. 2004, 22, 299–309. [CrossRef][PubMed]
25. Fizazi, K.; Scher, H.I.; Molina, A.; Logothetis, C.J.; Chi, K.N.; Jones, R.J.; Staffurth, J.N.; North, S.; Vogelzang, N.J.; Saad, F., et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: Final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012, 13, 983–992. [CrossRef]
26. Ryan, C.J.; Smith, M.R.; Fizazi, K.; Saad, F.; Mulders, P.F.; Sternberg, C.N.; Miller, K.; Logothetis, C.J.; Shore, N.D.; Small, E.J., et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): Final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015, 16, 152–160. [CrossRef]
27. Augello, M.A.; Hickey, T.E.; Knudsen, K.E. Foxa1: Master of steroid receptor function in cancer. EMBO J. 2011, 30, 3885–3894. [CrossRef][PubMed]
28. Wang, Q.; Li, W.; Zhang, Y.; Yuan, X.; Xu, K.; Yu, J.; Chen, Z.; Beroukhim, R.; Wang, H.; Lupien, M., et al. Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 2009, 138, 245–256. [CrossRef][PubMed]
29. Robinson, J.L.; Hickey, T.E.; Warren, A.Y.; Vowler, S.L.; Carroll, T.; Lamb, A.D.; Papoutsoglou, N.; Neal, D.E.; Tilley, W.D.; Carroll, J.S. Elevated levels of foxa1 facilitate androgen receptor chromatin binding resulting in a crpc-like phenotype. Oncogene 2014, 33, 5666–5674. [CrossRef][PubMed]
30. Taylor, B.S.; Schultz, N.; Hieronymus, H.; Gopalan, A.; Xiao, Y.; Carver, B.S.; Arora, V.K.; Kaushik, P.; Cerami, E.; Reva, B., et al. Integrative genomic profiling of human prostate cancer. Cancer Cell 2010, 18, 11–22. [CrossRef][PubMed]
31. Visakorpi, T.; Hyytinen, E.; Koivisto, P.; Tanner, M.; Keinanen, R.; Palmberg, C.; Palotie, A.; Tammela, T.; Isola, J.; Kallioniemi, O.P. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat. Genet. 1995, 9, 401–406. [CrossRef][PubMed]
32. Edwards, J.; Krishna, N.S.; Grigor, K.M.; Bartlett, J.M. Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br. J. Cancer 2003, 89, 552–556. [CrossRef][PubMed]
33. Robinson, D.; van Allen, E.M.; Wu, Y.M.; Schultz, N.; Lonigro, R.J.; Mosquera, J.M.; Montgomery, B.; Taplin, M.E.; Pritchard, C.C.; Attard, G., et al. Integrative clinical genomics of advanced prostate cancer. Cell 2015, 161, 1215–1228. [CrossRef][PubMed]
34. Dehm, S.M.; Tindall, D.J. Alternatively spliced androgen receptor variants. Endocr. Relat. Cancer 2011, 18, R183–R196. [CrossRef][PubMed]
35. Hu, R.; Dunn, T.A.; Wei, S.; Isharwal, S.; Veltri, R.W.; Humphreys, E.; Han, M.; Partin, A.W.; Vessella, R.L.; Isaacs, W.B., et al. Ligand-independent androgen receptor variants derived from splicing of cryptic exons signify hormone-refractory prostate cancer. Cancer Res. 2009, 69, 16–22. [CrossRef][PubMed]
36. Guo, Z.; Yang, X.; Sun, F.; Jiang, R.; Linn, D.E.; Chen, H.; Chen, H.; Kong, X.; Melamed, J.; Tepper, C.G., et al. A novel androgen receptor splice variant is up-regulated during prostate cancer progression and promotes androgen depletion-resistant growth. Cancer Res. 2009, 69, 2305–2313. [CrossRef][PubMed]
37. Liu, W.; Laitinen, S.; Khan, S.; Vihinen, M.; Kowalski, J.; Yu, G.; Chen, L.; Ewing, C.M.; Eisenberger, M.A.; Carducci, M.A., et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat. Med. 2009, 15, 559–565. [CrossRef][PubMed]
38. Barbieri, C.E.; Demichelis, F.; Rubin, M.A. Molecular genetics of prostate cancer: Emerging appreciation of genetic complexity. Histopathology 2012, 60, 187–198. [CrossRef][PubMed]
39. Lin, P.C.; Giannopoulou, E.G.; Park, K.; Mosquera, J.M.; Sboner, A.; Tewari, A.K.; Garraway, L.A.; Beltran, H.; Rubin, M.A.; Elemento, O. Epigenomic alterations in localized and advanced prostate cancer. Neoplasia 2013, 15, 373–383. [CrossRef][PubMed]
40. Pellacani, D.; Kestoras, D.; Droop, A.P.; Frame, F.M.; Berry, P.A.; Lawrence, M.G.; Stower, M.J.; Simms, M.S.; Mann, V.M.; Collins, A.T., et al. DNA hypermethylation in prostate cancer is a consequence of aberrant epithelial differentiation and hyperproliferation. Cell Death Differ. 2014, 21, 761–773. [CrossRef][PubMed]
41. Logothetis, C.J.; Gallick, G.E.; Maity, S.N.; Kim, J.; Aparicio, A.; Efstathiou, E.; Lin, S.H. Molecular classification of prostate cancer progression: Foundation for marker-driven treatment of prostate cancer. Cancer Discov. 2013, 3, 849–861. [CrossRef][PubMed]
42. Bianchini, D.; Lorente, D.; Rodriguez-Vida, A.; Omlin, A.; Pezaro, C.; Ferraldeschi, R.; Zivi, A.; Attard, G.; Chowdhury, S.; de Bono, J.S. Antitumour activity of enzalutamide (MDV3100) in patients with metastatic castration-resistant prostate cancer (CRPC) pre-treated with docetaxel and abiraterone. Eur. J. Cancer 2014, 50, 78–84. [CrossRef][PubMed]
43. Schrader, A.J.; Boegemann, M.; Ohlmann, C.H.; Schnoeller, T.J.; Krabbe, L.M.; Hajili, T.; Jentzmik, F.; Stoeckle, M.; Schrader, M.; Herrmann, E., et al. Enzalutamide in castration-resistant prostate cancer patients progressing after docetaxel and abiraterone. Eur. Urol. 2014, 65, 30–36. [CrossRef][PubMed]
44. Azad, A.A.; Eigl, B.J.; Murray, R.N.; Kollmannsberger, C.; Chi, K.N. Efficacy of enzalutamide following abiraterone acetate in chemotherapy-naive metastatic castration-resistant prostate cancer patients. Eur. Urol. 2015, 67, 23–29. [CrossRef][PubMed]
45. Noonan, K.L.; North, S.; Bitting, R.L.; Armstrong, A.J.; Ellard, S.L.; Chi, K.N. Clinical activity of abiraterone acetate in patients with metastatic castration-resistant prostate cancer progressing after enzalutamide. Ann. Oncol. 2013, 24, 1802–1807. [CrossRef][PubMed]
46. Verras, M.; Lee, J.; Xue, H.; Li, T.H.; Wang, Y.; Sun, Z. The androgen receptor negatively regulates the expression of c-Met: Implications for a novel mechanism of prostate cancer progression. Cancer Res. 2007, 67, 967–975. [CrossRef][PubMed]
47. Carver, B.S.; Chapinski, C.; Wongvipat, J.; Hieronymus, H.; Chen, Y.; Chandarlapaty, S.; Arora, V.K.; Le, C.; Koutcher, J.; Scher, H., et al. Reciprocal feedback regulation of PI3k and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell 2011, 19, 575–586. [CrossRef][PubMed]
48. Mulholland, D.J.; Tran, L.M.; Li, Y.; Cai, H.; Morim, A.; Wang, S.; Plaisier, S.; Garraway, I.P.; Huang, J.; Graeber, T.G., et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell 2011, 19, 792–804. [CrossRef][PubMed]
49. Collins, A.T.; Berry, P.A.; Hyde, C.; Stower, M.J.; Maitland, N.J. Prospective identification of tumorigenic prostate cancer stem cells. Cancer Res. 2005, 65, 10946–10951. [CrossRef][PubMed]
50. Rane, J.K.; Greener, S.; Frame, F.M.; Mann, V.M.; Simms, M.S.; Collins, A.T.; Berney, D.M.; Maitland, N.J. Telomerase activity and telomere length in human benign prostatic hyperplasia stem-like cells and their progeny implies the existence of distinct basal and luminal cell lineages. European Urol. 2015. [CrossRef][PubMed]
51. Miki, J.; Furusato, B.; Li, H.; Gu, Y.; Takahashi, H.; Egawa, S.; Sesterhenn, I.A.; McLeod, D.G.; Srivastava, S.; Rhim, J.S. Identification of putative stem cell markers, CD133 and CXCR4, in htert-immortalized primary nonmalignant and malignant tumor-derived human prostate epithelial cell lines and in prostate cancer specimens. Cancer Res. 2007, 67, 3153–3161. [CrossRef][PubMed]
52. Gu, G.; Yuan, J.; Wills, M.; Kasper, S. Prostate cancer cells with stem cell characteristics reconstitute the original human tumor in vivo. Cancer Res. 2007, 67, 4807–4815. [CrossRef][PubMed]
53. Patrawala, L.; Calhoun, T.; Schneider-Broussard, R.; Li, H.; Bhatia, B.; Tang, S.; Reilly, J.G.; Chandra, D.; Zhou, J.; Claypool, K., et al. Highly purified CD44+ prostate cancer cells from xenograft human tumors are enriched in tumorigenic and metastatic progenitor cells. Oncogene 2006, 25, 1696–1708. [CrossRef][PubMed]
54. Huss, W.J.; Gray, D.R.; Greenberg, N.M.; Mohler, J.L.; Smith, G.J. Breast cancer resistance protein-mediated efflux of androgen in putative benign and malignant prostate stem cells. Cancer Res. 2005, 65, 6640–6650. [CrossRef][PubMed]
55. Wang, Z.A.; Mitrofanova, A.; Bergren, S.K.; Abate-Shen, C.; Cardiff, R.D.; Califano, A.; Shen, M.M. Lineage analysis of basal epithelial cells reveals their unexpected plasticity and supports a cell-of-origin model for prostate cancer heterogeneity. Nat. Cell Biol. 2013, 15, 274–283. [CrossRef][PubMed]
56. Chen, X.; Rycaj, K.; Liu, X.; Tang, D.G. New insights into prostate cancer stem cells. Cell Cycle 2013, 12, 579–586. [CrossRef][PubMed]
57. Li, H.; Zhou, J.; Miki, J.; Furusato, B.; Gu, Y.; Srivastava, S.; McLeod, D.G.; Vogel, J.C.; Rhim, J.S. Telomerase-immortalized non-malignant human prostate epithelial cells retain the properties of multipotent stem cells. Exp. Cell Res. 2008, 314, 92–102. [CrossRef][PubMed]
58. Qin, J.; Liu, X.; Laffin, B.; Chen, X.; Choy, G.; Jeter, C.R.; Calhoun-Davis, T.; Li, H.; Palapattu, G.S.; Pang, S., et al. The psa(-/lo) prostate cancer cell population harbors self-renewing long-term tumor-propagating cells that resist castration. Cell Stem Cell 2012, 10, 556–569. [CrossRef][PubMed]
59. Fidler, I.J.; Hart, I.R. Biological diversity in metastatic neoplasms: Origins and implications. Science 1982, 217, 998–1003. [CrossRef][PubMed]
60. Heppner, G.H.; Miller, B.E. Tumor heterogeneity: Biological implications and therapeutic consequences. Cancer Metastasis Rev. 1983, 2, 5–23. [CrossRef][PubMed]
61. Nowell, P.C. Mechanisms of tumor progression. Cancer Res. 1986, 46, 2203–2207. [PubMed]
62. Bonnet, D.; Dick, J.E. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat. Med. 1997, 3, 730–737. [CrossRef][PubMed]
63. Greaves, M. Cancer stem cells as “units of selection”. Evolut. Appl. 2013, 6, 102–108. [CrossRef][PubMed]
64. Visvader, J.E.; Lindeman, G.J. Cancer stem cells in solid tumours: Accumulating evidence and unresolved questions. Nat. Rev. Cancer 2008, 8, 755–768. [CrossRef][PubMed]
65. Dean, M.; Fojo, T.; Bates, S. Tumour stem cells and drug resistance. Nat. Rev. Cancer 2005, 5, 275–284. [CrossRef][PubMed]
66. Cojoc, M.; Mabert, K.; Muders, M.H.; Dubrovska, A. A role for cancer stem cells in therapy resistance: Cellular and molecular mechanisms. Semin. Cancer Biol. 2015, 31, 16–27. [CrossRef][PubMed]
67. Vlashi, E.; Pajonk, F. Cancer stem cells, cancer cell plasticity and radiation therapy. Semin. Cancer Biol. 2015, 31, 28–35. [CrossRef][PubMed]
68. Yan, J.; Tang, D. Prostate cancer stem-like cells proliferate slowly and resist etoposide-induced cytotoxicity via enhancing DNA damage response. Exp. Cell Res. 2014, 328, 132–142. [CrossRef][PubMed]
69. Frame, F.M.; Pellacani, D.; Collins, A.T.; Simms, M.S.; Mann, V.M.; Jones, G.D.; Meuth, M.; Bristow, R.G.; Maitland, N.J. HDAC inhibitor confers radiosensitivity to prostate stem-like cells. Br. J. Cancer 2013, 109, 3023–3033. [CrossRef][PubMed]
70. Nieto, M.A. Epithelial plasticity: A common theme in embryonic and cancer cells. Science 2013, 342, 1234850. [CrossRef][PubMed]
71. Blanpain, C.; Fuchs, E. Stem cell plasticity. Plasticity of epithelial stem cells in tissue regeneration. Science 2014, 344, 1242281. [CrossRef][PubMed]
72. Germann, M.; Wetterwald, A.; Guzman-Ramirez, N.; van der Pluijm, G.; Culig, Z.; Cecchini, M.G.; Williams, E.D.; Thalmann, G.N. Stem-like cells with luminal progenitor phenotype survive castration in human prostate cancer. Stem Cells 2012, 30, 1076–1086. [CrossRef][PubMed]
73. Colombel, M.; Eaton, C.L.; Hamdy, F.; Ricci, E.; van der Pluijm, G.; Cecchini, M.; Mege-Lechevallier, F.; Clezardin, P.; Thalmann, G. Increased expression of putative cancer stem cell markers in primary prostate cancer is associated with progression of bone metastases. Prostate 2012, 72, 713–720. [CrossRef][PubMed]
74. 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., et al. Suppression of acquired docetaxel resistance in prostate cancer through depletion of notch- and hedgehog-dependent tumor-initiating cells. Cancer Cell 2012, 22, 373–388. [CrossRef][PubMed]
75. Palapattu, G.S.; Wu, C.; Silvers, C.R.; Martin, H.B.; Williams, K.; Salamone, L.; Bushnell, T.; Huang, L.S.; Yang, Q.; Huang, J. Selective expression of CD44, a putative prostate cancer stem cell marker, in neuroendocrine tumor cells of human prostate cancer. Prostate 2009, 69, 787–798. [CrossRef][PubMed]
76. Bitting, R.L.; Schaeffer, D.; Somarelli, J.A.; Garcia-Blanco, M.A.; Armstrong, A.J. The role of epithelial plasticity in prostate cancer dissemination and treatment resistance. Cancer Metastasis Rev. 2014, 33, 441–468. [CrossRef][PubMed]
77. Burgio, S.L.; Conteduca, V.; Menna, C.; Carretta, E.; Rossi, L.; Bianchi, E.; Kopf, B.; Fabbri, F.; Amadori, D.; de Giorgi, U. Chromogranin a predicts outcome in prostate cancer patients treated with abiraterone. Endocr. Relat. Cancer 2014, 21, 487–493. [CrossRef][PubMed]
78. Conteduca, V.; Burgio, S.L.; Menna, C.; Carretta, E.; Rossi, L.; Bianchi, E.; Masini, C.; Amadori, D.; de Giorgi, U. Chromogranin a is a potential prognostic marker in prostate cancer patients treated with enzalutamide. Prostate 2014, 74, 1691–1696. [CrossRef][PubMed]
79. Berruti, A.; Mosca, A.; Tucci, M.; Terrone, C.; Torta, M.; Tarabuzzi, R.; Russo, L.; Cracco, C.; Bollito, E.; Scarpa, R.M., et al. Independent prognostic role of circulating chromogranin a in prostate cancer patients with hormone-refractory disease. Endocr. Relat. Cancer 2005, 12, 109–117. [CrossRef][PubMed]
80. Sarkar, D.; Singh, S.K.; Mandal, A.K.; Agarwal, M.M.; Mete, U.K.; Kumar, S.; Mavuduru, R.S.; Prasad, R. Plasma chromogranin A: Clinical implications in patients with castrate resistant prostate cancer receiving docetaxel chemotherapy. Cancer Biomark. 2010, 8, 81–87. [PubMed]
81. Marin-Aguilera, M.; Codony-Servat, J.; Reig, O.; Lozano, J.J.; Fernandez, P.L.; Pereira, M.V.; Jimenez, N.; Donovan, M.; Puig, P.; Mengual, L., et al. Epithelial-to-mesenchymal transition mediates docetaxel resistance and high risk of relapse in prostate cancer. Mol. Cancer Ther. 2014, 13, 1270–1284. [CrossRef][PubMed]
82. Puhr, M.; Hoefer, J.; Schafer, G.; Erb, H.H.; Oh, S.J.; Klocker, H.; Heidegger, I.; Neuwirt, H.; Culig, Z. Epithelial-to-mesenchymal transition leads to docetaxel resistance in prostate cancer and is mediated by reduced expression of miR-200c and miR-205. Am. J. Pathol. 2012, 181, 2188–2201. [CrossRef][PubMed]
83. Seiler, D.; Zheng, J.; Liu, G.; Wang, S.; Yamashiro, J.; Reiter, R.E.; Huang, J.; Zeng, G. Enrichment of putative prostate cancer stem cells after androgen deprivation: Upregulation of pluripotency transactivators concurs with resistance to androgen deprivation in lncap cell lines. Prostate 2013, 73, 1378–1390. [CrossRef][PubMed]
84. Rybak, A.P.; He, L.; Kapoor, A.; Cutz, J.C.; Tang, D. Characterization of sphere-propagating cells with stem-like properties from DU145 prostate cancer cells. Biochim. Biophys. Acta 2011, 1813, 683–694. [CrossRef][PubMed]
85. Tang, Y.; Hamburger, A.W.; Wang, L.; Khan, M.A.; Hussain, A. Androgen deprivation and stem cell markers in prostate cancers. Int. J. Clin. Exp. Pathol. 2009, 3, 128–138. [PubMed]
86. Shang, Z.; Cai, Q.; Zhang, M.; Zhu, S.; Ma, Y.; Sun, L.; Jiang, N.; Tian, J.; Niu, X.; Chen, J., et al. A switch from CD44(+) cell to emt cell drives the metastasis of prostate cancer. Oncotarget 2015, 6, 1202–1216. [CrossRef][PubMed]
87. Roudier, M.P.; True, L.D.; Higano, C.S.; Vesselle, H.; Ellis, W.; Lange, P.; Vessella, R.L. Phenotypic heterogeneity of end-stage prostate carcinoma metastatic to bone. Hum. Pathol. 2003, 34, 646–653. [CrossRef]
88. Shah, R.B.; Mehra, R.; Chinnaiyan, A.M.; Shen, R.; Ghosh, D.; Zhou, M.; Macvicar, G.R.; Varambally, S.; Harwood, J.; Bismar, T.A., et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: Lessons from a rapid autopsy program. Cancer Res. 2004, 64, 9209–9216. [CrossRef][PubMed]
89. Klarmann, G.J.; Hurt, E.M.; Mathews, L.A.; Zhang, X.; Duhagon, M.A.; Mistree, T.; Thomas, S.B.; Farrar, W.L. Invasive prostate cancer cells are tumor initiating cells that have a stem cell-like genomic signature. Clin. Exp. Metastasis 2009, 26, 433–446. [CrossRef][PubMed]
90. Sun, Y.; Wang, B.E.; Leong, K.G.; Yue, P.; Li, L.; Jhunjhunwala, S.; Chen, D.; Seo, K.; Modrusan, Z.; Gao, W.Q., et al. Androgen deprivation causes epithelial-mesenchymal transition in the prostate: Implications for androgen-deprivation therapy. Cancer Res. 2012, 72, 527–536. [CrossRef][PubMed]
91. Kahn, B.; Collazo, J.; Kyprianou, N. Androgen receptor as a driver of therapeutic resistance in advanced prostate cancer. Int. J. Biol. Sci. 2014, 10, 588–595. [CrossRef][PubMed]
92. Tanaka, H.; Kono, E.; Tran, C.P.; Miyazaki, H.; Yamashiro, J.; Shimomura, T.; Fazli, L.; Wada, R.; Huang, J.; Vessella, R.L., et al. Monoclonal antibody targeting of N-cadherin inhibits prostate cancer growth, metastasis and castration resistance. Nat. Med. 2010, 16, 1414–1420. [CrossRef][PubMed]
93. Nouri, M.; Ratther, E.; Stylianou, N.; Nelson, C.C.; Hollier, B.G.; Williams, E.D. Androgen-targeted therapy-induced epithelial mesenchymal plasticity and neuroendocrine transdifferentiation in prostate cancer: An opportunity for intervention. Front. Oncol. 2014, 4, 370. [CrossRef][PubMed]
94. Dethlefsen, C.; Hojfeldt, G.; Hojman, P. The role of intratumoral and systemic IL-6 in breast cancer. Breast Cancer Res. Treat. 2013, 138, 657–664. [CrossRef][PubMed]
95. Heinrich, P.C.; Behrmann, I.; Haan, S.; Hermanns, H.M.; Muller-Newen, G.; Schaper, F. Principles of interleukin (IL)-6-type cytokine signalling and its regulation. Biochem. J. 2003, 374, 1–20. [CrossRef][PubMed]
96. Wang, H.; Lathia, J.D.; Wu, Q.; Wang, J.; Li, Z.; Heddleston, J.M.; Eyler, C.E.; Elderbroom, J.; Gallagher, J.; Schuschu, J., et al. Targeting interleukin 6 signaling suppresses glioma stem cell survival and tumor growth. Stem Cells 2009, 27, 2393–2404. [CrossRef][PubMed]
97. Nilsson, C.L.; Dillon, R.; Devakumar, A.; Shi, S.D.; Greig, M.; Rogers, J.C.; Krastins, B.; Rosenblatt, M.; Kilmer, G.; Major, M., et al. Quantitative phosphoproteomic analysis of the STAT3/IL-6/hif1alpha signaling network: An initial study in GSC11 glioblastoma stem cells. J. Proteome Res. 2010, 9, 430–443. [CrossRef][PubMed]
98. Yi, H.; Cho, H.J.; Cho, S.M.; Jo, K.; Park, J.A.; Kim, N.H.; Amidon, G.L.; Kim, J.S.; Shin, H.C. Blockade of interleukin-6 receptor suppresses the proliferation of H460 lung cancer stem cells. Int. J. Oncol. 2012, 41, 310–316. [PubMed]
99. Lin, L.; Liu, A.; Peng, Z.; Lin, H.J.; Li, P.K.; Li, C.; Lin, J. STAT3 is necessary for proliferation and survival in colon cancer-initiating cells. Cancer Res. 2011, 71, 7226–7237. [CrossRef][PubMed]
100. Iliopoulos, D.; Hirsch, H.A.; Struhl, K. An epigenetic switch involving nf-kappab, LIN28, LET-7 microrna, and il6 links inflammation to cell transformation. Cell 2009, 139, 693–706. [CrossRef][PubMed]
101. Iliopoulos, D.; Hirsch, H.A.; Wang, G.; Struhl, K. Inducible formation of breast cancer stem cells and their dynamic equilibrium with non-stem cancer cells via IL6 secretion. Proc. Natl. Acad. Sci. USA 2011, 108, 1397–1402. [CrossRef][PubMed]
102. Marotta, L.L.; Almendro, V.; Marusyk, A.; Shipitsin, M.; Schemme, J.; Walker, S.R.; Bloushtain-Qimron, N.; Kim, J.J.; Choudhury, S.A.; Maruyama, R., et al. The JAK2/STAT3 signaling pathway is required for growth of CD44(+)CD24(_) stem cell-like breast cancer cells in human tumors. J. Clin. Investig. 2011, 121, 2723–2735. [CrossRef][PubMed]
103. Lin, J.T.; Wang, J.Y.; Chen, M.K.; Chen, H.C.; Chang, T.H.; Su, B.W.; Chang, P.J. Colon cancer mesenchymal stem cells modulate the tumorigenicity of colon cancer through interleukin 6. Exp. Cell Res. 2013, 319, 2216–2229. [CrossRef][PubMed]
104. De Luca, A.; Lamura, L.; Gallo, M.; Maffia, V.; Normanno, N. Mesenchymal stem cell-derived interleukin-6 and vascular endothelial growth factor promote breast cancer cell migration. J. Cell. Biochem. 2012, 113, 3363–3370. [CrossRef][PubMed]
105. Korkaya, H.; Kim, G.I.; Davis, A.; Malik, F.; Henry, N.L.; Ithimakin, S.; Quraishi, A.A.; Tawakkol, N.; D’Angelo, R.; Paulson, A.K., et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol. Cell 2012, 47, 570–584. [CrossRef][PubMed]
106. Tam, L.; McGlynn, L.M.; Traynor, P.; Mukherjee, R.; Bartlett, J.M.; Edwards, J. Expression levels of the JAK/STAT pathway in the transition from hormone-sensitive to hormone-refractory prostate cancer. Br. J. Cancer 2007, 97, 378–383. [CrossRef][PubMed]
107. Kwon, E.M.; Holt, S.K.; Fu, R.; Kolb, S.; Williams, G.; Stanford, J.L.; Ostrander, E.A. Androgen metabolism and JAK/STAT pathway genes and prostate cancer risk. Cancer Epidemiol. 2012, 36, 347–353. [CrossRef][PubMed]
108. Akimoto, S.; Okumura, A.; Fuse, H. Relationship between serum levels of interleukin-6, tumor necrosis factor-alpha and bone turnover markers in prostate cancer patients. Endocr. J. 1998, 45, 183–189. [CrossRef][PubMed]
109. Adler, H.L.; McCurdy, M.A.; Kattan, M.W.; Timme, T.L.; Scardino, P.T.; Thompson, T.C. Elevated levels of circulating interleukin-6 and transforming growth factor-beta1 in patients with metastatic prostatic carcinoma. J. Urol. 1999, 161, 182–187. [CrossRef]
110. Drachenberg, D.E.; Elgamal, A.A.; Rowbotham, R.; Peterson, M.; Murphy, G.P. Circulating levels of interleukin-6 in patients with hormone refractory prostate cancer. Prostate 1999, 41, 127–133. [CrossRef]
111. Nakashima, J.; Tachibana, M.; Horiguchi, Y.; Oya, M.; Ohigashi, T.; Asakura, H.; Murai, M. Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin. Cancer Res. 2000, 6, 2702–2706. [PubMed]
112. Qu, Y.; Oyan, A.M.; Liu, R.; Hua, Y.; Zhang, J.; Hovland, R.; Popa, M.; Liu, X.; Brokstad, K.A.; Simon, R., et al. Generation of prostate tumor-initiating cells is associated with elevation of reactive oxygen species and IL-6/STAT3 signaling. Cancer Res. 2013, 73, 7090–7100. [CrossRef][PubMed]
113. Liu, C.; Zhu, Y.; Lou, W.; Cui, Y.; Evans, C.P.; Gao, A.C. Inhibition of constitutively active STAT3 reverses enzalutamide resistance in lncap derivative prostate cancer cells. Prostate 2014, 74, 201–209. [CrossRef][PubMed]
114. Kroon, P.; Berry, P.A.; Stower, M.J.; Rodrigues, G.; Mann, V.M.; Simms, M.; Bhasin, D.; Chettiar, S.; Li, C.; Li, P.K., et al. JAK-STAT blockade inhibits tumor initiation and clonogenic recovery of prostate cancer stem-like cells. Cancer Res. 2013, 73, 5288–5298. [CrossRef][PubMed]
115. Schroeder, A.; Herrmann, A.; Cherryholmes, G.; Kowolik, C.; Buettner, R.; Pal, S.; Yu, H.; Muller-Newen, G.; Jove, R. Loss of androgen receptor expression promotes a stem-like cell phenotype in prostate cancer through STAT3 signaling. Cancer Res. 2014, 74, 1227–1237. [CrossRef][PubMed]
116. Kregel, S.; Kiriluk, K.J.; Rosen, A.M.; Cai, Y.; Reyes, E.E.; Otto, K.B.; Tom, W.; Paner, G.P.; Szmulewitz, R.Z.; Vander Griend, D.J. SOX2 is an androgen receptor-repressed gene that promotes castration-resistant prostate cancer. PLoS ONE 2013, 8, e53701. [CrossRef][PubMed]
117. Lin, T.H.; Izumi, K.; Lee, S.O.; Lin, W.J.; Yeh, S.; Chang, C. Anti-androgen receptor ASC-J9 vs. anti-androgens MDV3100 (Enzalutamide) or Casodex (Bicalutamide) leads to opposite effects on prostate cancer metastasis via differential modulation of macrophage infiltration and STAT3-CCL2 signaling. Cell Death Dis. 2013, 4, e764. [CrossRef][PubMed]
118. Lin, T.H.; Lee, S.O.; Niu, Y.; Xu, D.; Liang, L.; Li, L.; Yeh, S.D.; Fujimoto, N.; Yeh, S.; Chang, C. Differential androgen deprivation therapies with anti-androgens casodex/bicalutamide or MDV3100/enzalutamide versus anti-androgen receptor ASC-J9(r) lead to promotion versus suppression of prostate cancer metastasis. J. Biol. Chem. 2013, 288, 19359–19369. [CrossRef][PubMed]
119. Fang, L.Y.; Izumi, K.; Lai, K.P.; Liang, L.; Li, L.; Miyamoto, H.; Lin, W.J.; Chang, C. Infiltrating macrophages promote prostate tumorigenesis via modulating androgen receptor-mediated CCL4-STAT3 signaling. Cancer Res. 2013, 73, 5633–5646. [CrossRef][PubMed]
120. Jia, S.; Gao, X.; Lee, S.H.; Maira, S.M.; Wu, X.; Stack, E.C.; Signoretti, S.; Loda, M.; Zhao, J.J.; Roberts, T.M. Opposing effects of androgen deprivation and targeted therapy on prostate cancer prevention. Cancer Discov. 2013, 3, 44–51. [CrossRef][PubMed]
121. Kahn, M. Can we safely target the wnt pathway? Nat. Rev. Drug Discov. 2014, 13, 513–532. [CrossRef][PubMed]
122. Krausova, M.; Korinek, V. Wnt signaling in adult intestinal stem cells and cancer. Cell. Signal. 2014, 26, 570–579. [CrossRef][PubMed]
123. Boman, B.M.; Fields, J.Z. An APC:Wnt counter-current-like mechanism regulates cell division along the human colonic crypt axis: A mechanism that explains how APC mutations induce proliferative abnormalities that drive colon cancer development. Front. Oncol. 2013, 3, 244. [CrossRef][PubMed]
124. Atlasi, Y.; Looijenga, L.; Fodde, R. Cancer stem cells, pluripotency, and cellular heterogeneity: A wnter perspective. Curr. Top. Dev. Biol. 2014, 107, 373–404. [PubMed]
125. Rajan, P.; Sudbery, I.M.; Villasevil, M.E.; Mui, E.; Fleming, J.; Davis, M.; Ahmad, I.; Edwards, J.; Sansom, O.J.; Sims, D., et al. Next-generation sequencing of advanced prostate cancer treated with androgen-deprivation therapy. Eur. Urol. 2014, 66, 32–39. [CrossRef][PubMed]
126. Kumar, A.; White, T.A.; MacKenzie, A.P.; Clegg, N.; Lee, C.; Dumpit, R.F.; Coleman, I.; Ng, S.B.; Salipante, S.J.; Rieder, M.J., et al. Exome sequencing identifies a spectrum of mutation frequencies in advanced and lethal prostate cancers. Proc. Natl. Acad. Sci. USA 2011, 108, 17087–17092. [CrossRef][PubMed]
127. Grasso, C.S.; Wu, Y.M.; Robinson, D.R.; Cao, X.; Dhanasekaran, S.M.; Khan, A.P.; Quist, M.J.; Jing, X.; Lonigro, R.J.; Brenner, J.C., et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature 2012, 487, 239–243. [CrossRef][PubMed]
128. Jiang, Y.; Dai, J.; Zhang, H.; Sottnik, J.L.; Keller, J.M.; Escott, K.J.; Sanganee, H.J.; Yao, Z.; McCauley, L.K.; Keller, E.T. Activation of the wnt pathway through AR79, a GSK3beta inhibitor, promotes prostate cancer growth in soft tissue and bone. Mol. Cancer Res. 2013, 11, 1597–1610. [CrossRef][PubMed]
129. Bisson, I.; Prowse, D.M. Wnt signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res. 2009, 19, 683–697. [CrossRef][PubMed]
130. Hsieh, I.S.; Chang, K.C.; Tsai, Y.T.; Ke, J.Y.; Lu, P.J.; Lee, K.H.; Yeh, S.D.; Hong, T.M.; Chen, Y.L. Microrna-320 suppresses the stem cell-like characteristics of prostate cancer cells by downregulating the wnt/beta-catenin signaling pathway. Carcinogenesis 2013, 34, 530–538. [CrossRef][PubMed]
131. Arnold, K.; Sarkar, A.; Yram, M.A.; Polo, J.M.; Bronson, R.; Sengupta, S.; Seandel, M.; Geijsen, N.; Hochedlinger, K. SOX2(+) adult stem and progenitor cells are important for tissue regeneration and survival of mice. Cell Stem Cell 2011, 9, 317–329. [CrossRef][PubMed]
132. Takahashi, K.; Tanabe, K.; Ohnuki, M.; Narita, M.; Ichisaka, T.; Tomoda, K.; Yamanaka, S. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 2007, 131, 861–872. [CrossRef][PubMed]
133. Kawamura, T.; Suzuki, J.; Wang, Y.V.; Menendez, S.; Morera, L.B.; Raya, A.; Wahl, G.M.; Izpisua Belmonte, J.C. Linking the p53 tumour suppressor pathway to somatic cell reprogramming. Nature 2009, 460, 1140–1144. [CrossRef][PubMed]
134. Li, H.; Collado, M.; Villasante, A.; Strati, K.; Ortega, S.; Canamero, M.; Blasco, M.A.; Serrano, M. The INK4/Arf locus is a barrier for ips cell reprogramming. Nature 2009, 460, 1136–1139. [CrossRef][PubMed]
135. Marion, R.M.; Strati, K.; Li, H.; Murga, M.; Blanco, R.; Ortega, S.; Fernandez-Capetillo, O.; Serrano, M.; Blasco, M.A. A p53-mediated DNA damage response limits reprogramming to ensure ips cell genomic integrity. Nature 2009, 460, 1149–1153. [CrossRef][PubMed]
136. Utikal, J.; Polo, J.M.; Stadtfeld, M.; Maherali, N.; Kulalert, W.; Walsh, R.M.; Khalil, A.; Rheinwald, J.G.; Hochedlinger, K. Immortalization eliminates a roadblock during cellular reprogramming into iPS cells. Nature 2009, 460, 1145–1148. [CrossRef][PubMed]
137. Weina, K.; Utikal, J. SOX2 and cancer: Current research and its implications in the clinic. Clin. Transl. Med. 2014, 3, 19. [CrossRef][PubMed]
138. Leis, O.; Eguiara, A.; Lopez-Arribillaga, E.; Alberdi, M.J.; Hernandez-Garcia, S.; Elorriaga, K.; Pandiella, A.; Rezola, R.; Martin, A.G. SOX2 expression in breast tumours and activation in breast cancer stem cells. Oncogene 2012, 31, 1354–1365. [CrossRef][PubMed]
139. Rybak, A.P.; Tang, D. SOX2 plays a critical role in egfr-mediated self-renewal of human prostate cancer stem-like cells. Cell. Signal. 2013, 25, 2734–2742. [CrossRef][PubMed]
140. Wang, J.; Zhu, H.H.; Chu, M.; Liu, Y.; Zhang, C.; Liu, G.; Yang, X.; Yang, R.; Gao, W.Q. Symmetrical and asymmetrical division analysis provides evidence for a hierarchy of prostate epithelial cell lineages. Nat. Commun. 2014, 5, 4758. [CrossRef][PubMed]
141. Jeter, C.R.; Liu, B.; Liu, X.; Chen, X.; Liu, C.; Calhoun-Davis, T.; Repass, J.; Zaehres, H.; Shen, J.J.; Tang, D.G. Nanog promotes cancer stem cell characteristics and prostate cancer resistance to androgen deprivation. Oncogene 2011, 30, 3833–3845. [CrossRef][PubMed]
142. Lin, Y.C.; Murayama, Y.; Hashimoto, K.; Nakamura, Y.; Lin, C.S.; Yokoyama, K.K.; Saito, S. Role of tumor suppressor genes in the cancer-associated reprogramming of human induced pluripotent stem cells. Stem Cell Res. Ther. 2014, 5. [CrossRef][PubMed]
143. Miyazawa, K.; Tanaka, T.; Nakai, D.; Morita, N.; Suzuki, K. Immunohistochemical expression of four different stem cell markers in prostate cancer: High expression of nanog in conjunction with hypoxia-inducible factor-1alpha expression is involved in prostate epithelial malignancy. Oncol. Lett. 2014, 8, 985–992. [CrossRef][PubMed]
144. Mathieu, J.; Zhang, Z.; Zhou, W.; Wang, A.J.; Heddleston, J.M.; Pinna, C.M.; Hubaud, A.; Stadler, B.; Choi, M.; Bar, M., et al. Hif induces human embryonic stem cell markers in cancer cells. Cancer Res. 2011, 71, 4640–4652. [CrossRef][PubMed]
145. Mimeault, M.; Batra, S.K. Hypoxia-inducing factors as master regulators of stemness properties and altered metabolism of cancer- and metastasis-initiating cells. J. Cell. Mol. Med. 2013, 17, 30–54. [CrossRef][PubMed]
146. Kawamura, N.; Nimura, K.; Nagano, H.; Yamaguchi, S.; Nonomura, N.; Kaneda, Y. CRISPR/Cas9-mediated gene knockout of NANOG and NANOGP8 decreases the malignant potential of prostate cancer cells. Oncotarget 2015, 6, 22361–22374. [CrossRef][PubMed]
147. Nyquist, M.D.; Dehm, S.M. Interplay between genomic alterations and androgen receptor signaling during prostate cancer development and progression. Horm. Cancer 2013, 4, 61–69. [CrossRef][PubMed]
148. Haffner, M.C.; Aryee, M.J.; Toubaji, A.; Esopi, D.M.; Albadine, R.; Gurel, B.; Isaacs, W.B.; Bova, G.S.; Liu, W.; Xu, J., et al. Androgen-induced TOP2B-mediated double-strand breaks and prostate cancer gene rearrangements. Nat. Genet. 2010, 42, 668–675. [CrossRef][PubMed]
149. Mani, R.S.; Tomlins, S.A.; Callahan, K.; Ghosh, A.; Nyati, M.K.; Varambally, S.; Palanisamy, N.; Chinnaiyan, A.M. Induced chromosomal proximity and gene fusions in prostate cancer. Science 2009, 326, 1230. [CrossRef][PubMed]
150. Berger, M.F.; Lawrence, M.S.; Demichelis, F.; Drier, Y.; Cibulskis, K.; Sivachenko, A.Y.; Sboner, A.; Esgueva, R.; Pflueger, D.; Sougnez, C., et al. The genomic complexity of primary human prostate cancer. Nature 2011, 470, 214–220. [CrossRef][PubMed]
151. Kreso, A.; Dick, J.E. Evolution of the cancer stem cell model. Cell Stem Cell 2014, 14, 275–291. [CrossRef][PubMed]
152. Ruizeveld de Winter, J.A.; Janssen, P.J.; Sleddens, H.M.; Verleun-Mooijman, M.C.; Trapman, J.; Brinkmann, A.O.; Santerse, A.B.; Schroder, F.H.; van der Kwast, T.H. Androgen receptor status in localized and locally progressive hormone refractory human prostate cancer. Am. J. Pathol. 1994, 144, 735–746. [PubMed]
153. Masai, M.; Sumiya, H.; Akimoto, S.; Yatani, R.; Chang, C.S.; Liao, S.S.; Shimazaki, J. Immunohistochemical study of androgen receptor in benign hyperplastic and cancerous human prostates. Prostate 1990, 17, 293–300. [CrossRef][PubMed]
154. Van der Kwast, T.H.; Schalken, J.; Ruizeveld deWinter, J.A.; van Vroonhoven, C.C.; Mulder, E.; Boersma, W.; Trapman, J. Androgen receptors in endocrine-therapy-resistant human prostate cancer. Int. J. Cancer 1991, 48, 189–193. [CrossRef][PubMed]
155. Nakayama, T.; Watanabe, M.; Suzuki, H.; Toyota, M.; Sekita, N.; Hirokawa, Y.; Mizokami, A.; Ito, H.; Yatani, R.; Shiraishi, T. Epigenetic regulation of androgen receptor gene expression in human prostate cancers. Lab. Investig. 2000, 80, 1789–1796. [CrossRef][PubMed]
156. Liu, X.; Chen, X.; Rycaj, K.; Chao, H.P.; Deng, Q.; Jeter, C.; Liu, C.; Honorio, S.; Li, H.; Davis, T., et al. Systematic dissection of phenotypic, functional, and tumorigenic heterogeneity of human prostate cancer cells. Oncotarget 2015, 6, 23959–23986. [CrossRef][PubMed]
157. Castagnetta, L.A.; Miceli, M.D.; Sorci, C.M.; Pfeffer, U.; Farruggio, R.; Oliveri, G.; Calabro, M.; Carruba, G. Growth of LNCaP human prostate cancer cells is stimulated by estradiol via its own receptor. Endocrinology 1995, 136, 2309–2319. [PubMed]
158. Marcelli, M.; Haidacher, S.J.; Plymate, S.R.; Birnbaum, R.S. Altered growth and insulin-like growth factor-binding protein-3 production in PC3 prostate carcinoma cells stably transfected with a constitutively active androgen receptor complementary deoxyribonucleic acid. Endocrinology 1995, 136, 1040–1048. [CrossRef][PubMed]
159. Sadi, M.V.; Barrack, E.R. Image analysis of androgen receptor immunostaining in metastatic prostate cancer. Heterogeneity as a predictor of response to hormonal therapy. Cancer 1993, 71, 2574–2580. [CrossRef]
160. Wang, G.; Wang, J.; Sadar, M.D. Crosstalk between the androgen receptor and beta-catenin in castrate-resistant prostate cancer. Cancer Res. 2008, 68, 9918–9927. [CrossRef][PubMed]
161. Yokoyama, N.N.; Shao, S.; Hoang, B.H.; Mercola, D.; Zi, X. Wnt signaling in castration-resistant prostate cancer: Implications for therapy. Am. J. Clin. Exp. Urol. 2014, 2, 27–44. [PubMed]
162. Kregel, S.; Szmulewitz, R.Z.; Vander Griend, D.J. The pluripotency factor nanog is directly upregulated by the androgen receptor in prostate cancer cells. Prostate 2014, 74, 1530–1543. [CrossRef][PubMed]
163. Kong, D.; Sethi, S.; Li, Y.; Chen, W.; Sakr, W.A.; Heath, E.; Sarkar, F.H. Androgen receptor splice variants contribute to prostate cancer aggressiveness through induction of emt and expression of stem cell marker genes. Prostate 2015, 75, 161–174. [CrossRef][PubMed]