Metastatic Prostate Cancer

Part of the Molecular Pathology Library book series (MPLB)


Prostate cancer is a localized disease for the majority of patients. However, local or distant relapse presents a major health burden for a number of men each year. Androgen deprivation therapy is the cornerstone of therapy, and new-generation hormonal treatment has been introduced in the past years. Recent large-scale genomic studies have been performed utilizing metastatic biopsies from heavily treated patients and elucidated upon alterations in this patient cohort. Much less is known about molecular alterations in untreated metastatic prostate cancer. This chapter aims to explore mechanism of metastatic spread to lymph node and bone and to highlight the molecular characteristics of hormone-naïve metastatic prostate cancer.


Lymph node metastasis Bone metastasis Visceral metastasis Hormone-naïve Untreated MYC Bisphosphonates Denosumab 


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29.PubMedCrossRefGoogle Scholar
  2. 2.
    Rucci N, Angelucci A. Prostate cancer and bone: the elective affinities. Biomed Res Int. 2014;2014:167035.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Bubendorf L, Schopfer A, Wagner U, Sauter G, Moch H, Willi N, et al. Metastatic patterns of prostate cancer: an autopsy study of 1,589 patients. Hum Pathol. 2000;31(5):578–83.PubMedCrossRefGoogle Scholar
  4. 4.
    Bitting RL, Schaeffer D, Somarelli JA, Garcia-Blanco MA, Armstrong AJ. The role of epithelial plasticity in prostate cancer dissemination and treatment resistance. Cancer Metastasis Rev. 2014;33(2–3):441–68.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Crawford ED, Stone NN, EY Y, Koo PJ, Freedland SJ, Slovin SF, et al. Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology. 2014;83(3):664–9.PubMedCrossRefGoogle Scholar
  6. 6.
    Crook J, Ots AF. Prognostic factors for newly diagnosed prostate cancer and their role in treatment selection. Semin Radiat Oncol. 2013;23(3):165–72.PubMedCrossRefGoogle Scholar
  7. 7.
    Roehl KA, Han M, Ramos CG, Antenor JA, Catalona WJ. Cancer progression and survival rates following anatomical radical retropubic prostatectomy in 3,478 consecutive patients: long-term results. J Urol. 2004;172(3):910–4.PubMedCrossRefGoogle Scholar
  8. 8.
    Nguyen HG, Welty CJ, Cooperberg MR. Diagnostic associations of gene expression signatures in prostate cancer tissue. Curr Opin Urol. 2015;25(1):65–70.PubMedCrossRefGoogle Scholar
  9. 9.
    Liu W, Laitinen S, Khan S, Vihinen M, Kowalski J, Yu G, et al. Copy number analysis indicates monoclonal origin of lethal metastatic prostate cancer. Nat Med. 2009;15(5):559–65.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 10.
    Lindberg J, Kristiansen A, Wiklund P, Gronberg H, Egevad L. Tracking the origin of metastatic prostate cancer. Eur Urol. 2015;67(5):819–22.PubMedCrossRefGoogle Scholar
  11. 11.
    Guo CC, Wang Y, Xiao L, Troncoso P, Czerniak BA. The relationship of TMPRSS2-ERG gene fusion between primary and metastatic prostate cancers. Hum Pathol. 2012;43(5):644–9.PubMedCrossRefGoogle Scholar
  12. 12.
    Boorjian SA, Thompson RH, Siddiqui S, Bagniewski S, Bergstralh EJ, Karnes RJ, et al. Long-term outcome after radical prostatectomy for patients with lymph node positive prostate cancer in the prostate specific antigen era. J Urol. 2007;178(3 Pt 1):864–70. discussion 70–1.PubMedCrossRefGoogle Scholar
  13. 13.
    Bader P, Burkhard FC, Markwalder R, Studer UE. Disease progression and survival of patients with positive lymph nodes after radical prostatectomy. Is there a chance of cure? J Urol. 2003;169(3):849–54.PubMedCrossRefGoogle Scholar
  14. 14.
    Harbin AC, Eun DD. The role of extended pelvic lymphadenectomy with radical prostatectomy for high-risk prostate cancer. Urol Oncol. 2015;33:208.PubMedCrossRefGoogle Scholar
  15. 15.
    Messing EM, Manola J, Sarosdy M, Wilding G, Crawford ED, Trump D. Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med. 1999;341(24):1781–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Datta K, Muders M, Zhang H, Tindall DJ. Mechanism of lymph node metastasis in prostate cancer. Future Oncol. 2010;6(5):823–36.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Alitalo K, Carmeliet P. Molecular mechanisms of lymphangiogenesis in health and disease. Cancer Cell. 2002;1(3):219–27.PubMedCrossRefGoogle Scholar
  18. 18.
    Alitalo K, Tammela T, Petrova TV. Lymphangiogenesis in development and human disease. Nature. 2005;438(7070):946–53.PubMedCrossRefGoogle Scholar
  19. 19.
    Muders MH, Zhang H, Wang E, Tindall DJ, Datta K. Vascular endothelial growth factor-C protects prostate cancer cells from oxidative stress by the activation of mammalian target of rapamycin complex-2 and AKT-1. Cancer Res. 2009;69(15):6042–8.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Li R, Younes M, Wheeler TM, Scardino P, Ohori M, Frolov A, et al. Expression of vascular endothelial growth factor receptor-3 (VEGFR-3) in human prostate. Prostate. 2004;58(2):193–9.PubMedCrossRefGoogle Scholar
  21. 21.
    Jennbacken K, Vallbo C, Wang W, Damber JE. Expression of vascular endothelial growth factor C (VEGF-C) and VEGF receptor-3 in human prostate cancer is associated with regional lymph node metastasis. Prostate. 2005;65(2):110–6.PubMedCrossRefGoogle Scholar
  22. 22.
    Tsurusaki T, Kanda S, Sakai H, Kanetake H, Saito Y, Alitalo K, et al. Vascular endothelial growth factor-C expression in human prostatic carcinoma and its relationship to lymph node metastasis. Br J Cancer. 1999;80(1–2):309–13.PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Burton JB, Priceman SJ, Sung JL, Brakenhielm E, An DS, Pytowski B, et al. Suppression of prostate cancer nodal and systemic metastasis by blockade of the lymphangiogenic axis. Cancer Res. 2008;68(19):7828–37.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Brakenhielm E, Burton JB, Johnson M, Chavarria N, Morizono K, Chen I, et al. Modulating metastasis by a lymphangiogenic switch in prostate cancer. Int J Cancer. 2007;121(10):2153–61.PubMedPubMedCentralCrossRefGoogle Scholar
  25. 25.
    Bladou F, Gleave ME, Penault-Llorca F, Serment G, Lange PH, Vessella RL. In vitro and in vivo models developed from human prostatic cancer. Prog Urol. 1997;7(3):384–96.PubMedGoogle Scholar
  26. 26.
    Horoszewicz JS, Leong SS, Chu TM, Wajsman ZL, Friedman M, Papsidero L, et al. The LNCaP cell line—a new model for studies on human prostatic carcinoma. Prog Clin Biol Res. 1980;37:115–32.PubMedGoogle Scholar
  27. 27.
    Horoszewicz JS, Leong SS, Kawinski E, Karr JP, Rosenthal H, Chu TM, et al. LNCaP model of human prostatic carcinoma. Cancer Res. 1983;43(4):1809–18.PubMedGoogle Scholar
  28. 28.
    Phin S, Moore MW, Cotter PD. Genomic rearrangements of PTEN in prostate cancer. Front Oncol. 2013;3:240.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Dong JT. Chromosomal deletions and tumor suppressor genes in prostate cancer. Cancer Metastasis Rev. 2001;20(3–4):173–93.PubMedCrossRefGoogle Scholar
  30. 30.
    Yoshimoto M, Ding K, Sweet JM, Ludkovski O, Trottier G, Song KS, et al. PTEN losses exhibit heterogeneity in multifocal prostatic adenocarcinoma and are associated with higher Gleason grade. Mod Pathol. 2013;26(3):435–47.PubMedCrossRefGoogle Scholar
  31. 31.
    Lapointe J, Li C, Giacomini CP, Salari K, Huang S, Wang P, et al. Genomic profiling reveals alternative genetic pathways of prostate tumorigenesis. Cancer Res. 2007;67(18):8504–10.PubMedCrossRefGoogle Scholar
  32. 32.
    Schmitz M, Grignard G, Margue C, Dippel W, Capesius C, Mossong J, et al. Complete loss of PTEN expression as a possible early prognostic marker for prostate cancer metastasis. Int J Cancer. 2007;120(6):1284–92.PubMedCrossRefGoogle Scholar
  33. 33.
    Abate-Shen C, Banach-Petrosky WA, Sun X, Economides KD, Desai N, Gregg JP, et al. Nkx3.1; Pten mutant mice develop invasive prostate adenocarcinoma and lymph node metastases. Cancer Res. 2003;63(14):3886–90.PubMedGoogle Scholar
  34. 34.
    Kibel AS, Faith DA, Bova GS, Isaacs WB. Loss of heterozygosity at 12P12–13 in primary and metastatic prostate adenocarcinoma. J Urol. 2000;164(1):192–6.PubMedCrossRefGoogle Scholar
  35. 35.
    Lee JT, Lehmann BD, Terrian DM, Chappell WH, Stivala F, Libra M, et al. Targeting prostate cancer based on signal transduction and cell cycle pathways. Cell Cycle. 2008;7(12):1745–62.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Perner S, Mosquera JM, Demichelis F, Hofer MD, Paris PL, Simko J, et al. TMPRSS2-ERG fusion prostate cancer: an early molecular event associated with invasion. Am J Surg Pathol. 2007;31(6):882–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Perner S, Demichelis F, Beroukhim R, Schmidt FH, Mosquera JM, Setlur S, et al. TMPRSS2:ERG fusion-associated deletions provide insight into the heterogeneity of prostate cancer. Cancer Res. 2006;66(17):8337–41.PubMedCrossRefGoogle Scholar
  38. 38.
    Lapointe J, Kim YH, Miller MA, Li C, Kaygusuz G, van de Rijn M, et al. A variant TMPRSS2 isoform and ERG fusion product in prostate cancer with implications for molecular diagnosis. Mod Pathol. 2007;20(4):467–73.PubMedCrossRefGoogle Scholar
  39. 39.
    Perner S, Svensson MA, Hossain RR, Day JR, Groskopf J, Slaughter RC, et al. ERG rearrangement metastasis patterns in locally advanced prostate cancer. Urology. 2010;75(4):762–7.PubMedPubMedCentralCrossRefGoogle Scholar
  40. 40.
    Prochownik EV. c-Myc: linking transformation and genomic instability. Curr Mol Med. 2008;8(6):446–58.PubMedCrossRefGoogle Scholar
  41. 41.
    Hughes C, Murphy A, Martin C, Sheils O, O’Leary J. Molecular pathology of prostate cancer. J Clin Pathol. 2005;58(7):673–84.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Jenkins RB, Qian J, Lieber MM, Bostwick DG. Detection of c-myc oncogene amplification and chromosomal anomalies in metastatic prostatic carcinoma by fluorescence in situ hybridization. Cancer Res. 1997;57(3):524–31.PubMedGoogle Scholar
  43. 43.
    Gurel B, Iwata T, Koh CM, Jenkins RB, Lan F, Van Dang C, et al. Nuclear MYC protein overexpression is an early alteration in human prostate carcinogenesis. Mod Pathol. 2008;21(9):1156–67.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253(5015):49–53.PubMedCrossRefGoogle Scholar
  45. 45.
    MacGrogan D, Bookstein R. Tumor suppressor genes in prostate cancer. Semin Cancer Biol. 1997;8(1):11–9.PubMedCrossRefGoogle Scholar
  46. 46.
    Heidenberg HB, Bauer JJ, McLeod DG, Moul JW, Srivastava S. The role of the p53 tumor suppressor gene in prostate cancer: a possible biomarker? Urology. 1996;48(6):971–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Mu P, Zhang Z, Benelli M, Karthaus WR, Hoover E, Chen CC, et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science. 2017;355(6320):84–8.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Thompson TC, Park SH, Timme TL, Ren C, Eastham JA, Donehower LA, et al. Loss of p53 function leads to metastasis in ras+myc-initiated mouse prostate cancer. Oncogene. 1995;10(5):869–79.PubMedGoogle Scholar
  49. 49.
    Eastham JA, Stapleton AM, Gousse AE, Timme TL, Yang G, Slawin KM, et al. Association of p53 mutations with metastatic prostate cancer. Clin Cancer Res. 1995;1(10):1111–8.PubMedGoogle Scholar
  50. 50.
    Myers RB, Oelschlager D, Srivastava S, Grizzle WE. Accumulation of the p53 protein occurs more frequently in metastatic than in localized prostatic adenocarcinomas. Prostate. 1994;25(5):243–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Cheng L, Leibovich BC, Bergstralh EJ, Scherer BG, Pacelli A, Ramnani DM, et al. p53 alteration in regional lymph node metastases from prostate carcinoma: a marker for progression? Cancer. 1999;85(11):2455–9.PubMedCrossRefGoogle Scholar
  52. 52.
    Schlomm T, Iwers L, Kirstein P, Jessen B, Kollermann J, Minner S, et al. Clinical significance of p53 alterations in surgically treated prostate cancers. Mod Pathol. 2008;21(11):1371–8.PubMedCrossRefGoogle Scholar
  53. 53.
    Chen M, Pratt CP, Zeeman ME, Schultz N, Taylor BS, O’Neill A, et al. Identification of PHLPP1 as a tumor suppressor reveals the role of feedback activation in PTEN-mutant prostate cancer progression. Cancer Cell. 2011;20(2):173–86.PubMedPubMedCentralCrossRefGoogle Scholar
  54. 54.
    Cho H, Herzka T, Zheng W, Qi J, Wilkinson JE, Bradner JE, et al. RapidCaP, a novel GEM model for metastatic prostate cancer analysis and therapy, reveals myc as a driver of Pten-mutant metastasis. Cancer Discov. 2014;4(3):318–33.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Fleischmann A, Rocha C, Schobinger S, Seiler R, Wiese B, Thalmann GN. Androgen receptors are differentially expressed in Gleason patterns of prostate cancer and down-regulated in matched lymph node metastases. Prostate. 2011;71(5):453–60.PubMedCrossRefGoogle Scholar
  56. 56.
    Li R, Wheeler T, Dai H, Frolov A, Thompson T, Ayala G. High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence-free survival in prostate: cancer patients treated with radical prostatectomy. Am J Surg Pathol. 2004;28(7):928–34.PubMedCrossRefGoogle Scholar
  57. 57.
    Habib FK, Ross M, Bayne CW, Bollina P, Grigor K, Chapman K. The loss of 5alpha-reductase type I and type II mRNA expression in metastatic prostate cancer to bone and lymph node metastasis. Clin Cancer Res. 2003;9(5):1815–9.PubMedGoogle Scholar
  58. 58.
    Hsieh CL, Xie Z, Yu J, Martin WD, Datta MW, GJ W, et al. Non-invasive bioluminescent detection of prostate cancer growth and metastasis in a bigenic transgenic mouse model. Prostate. 2007;67(7):685–91.PubMedCrossRefGoogle Scholar
  59. 59.
    Fendler A, Stephan C, Yousef GM, Jung K. MicroRNAs as regulators of signal transduction in urological tumors. Clin Chem. 2011;57(7):954–68.PubMedCrossRefGoogle Scholar
  60. 60.
    Hagman Z, Haflidadottir BS, Ceder JA, Larne O, Bjartell A, Lilja H, et al. miR-205 negatively regulates the androgen receptor and is associated with adverse outcome of prostate cancer patients. Br J Cancer. 2013;108(8):1668–76.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Majid S, Dar AA, Saini S, Yamamura S, Hirata H, Tanaka Y, et al. MicroRNA-205-directed transcriptional activation of tumor suppressor genes in prostate cancer. Cancer. 2010;116(24):5637–49.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Shi XB, Tepper CG, White RW. MicroRNAs and prostate cancer. J Cell Mol Med. 2008;12(5A):1456–65.PubMedPubMedCentralCrossRefGoogle Scholar
  63. 63.
    Saini S, Majid S, Yamamura S, Tabatabai L, Suh SO, Shahryari V, et al. Regulatory role of mir-203 in prostate cancer progression and metastasis. Clin Cancer Res. 2011;17(16):5287–98.PubMedCrossRefGoogle Scholar
  64. 64.
    Viticchie G, Lena AM, Latina A, Formosa A, Gregersen LH, Lund AH, et al. MiR-203 controls proliferation, migration and invasive potential of prostate cancer cell lines. Cell Cycle. 2011;10(7):1121–31.PubMedCrossRefGoogle Scholar
  65. 65.
    Kalogirou C, Spahn M, Krebs M, Joniau S, Lerut E, Burger M, et al. MiR-205 is progressively down-regulated in lymph node metastasis but fails as a prognostic biomarker in high-risk prostate cancer. Int J Mol Sci. 2013;14(11):21414–34.PubMedPubMedCentralCrossRefGoogle Scholar
  66. 66.
    Hailer A, Grunewald TG, Orth M, Reiss C, Kneitz B, Spahn M, et al. Loss of tumor suppressor mir-203 mediates overexpression of LIM and SH3 Protein 1 (LASP1) in high-risk prostate cancer thereby increasing cell proliferation and migration. Oncotarget. 2014;5(12):4144–53.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Ribas J, Ni X, Haffner M, Wentzel EA, Salmasi AH, Chowdhury WH, et al. miR-21: an androgen receptor-regulated microRNA that promotes hormone-dependent and hormone-independent prostate cancer growth. Cancer Res. 2009;69(18):7165–9.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Ribas J, Lupold SE. The transcriptional regulation of miR-21, its multiple transcripts, and their implication in prostate cancer. Cell Cycle. 2010;9(5):923–9.PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Hart M, Nolte E, Wach S, Szczyrba J, Taubert H, Rau TT, et al. Comparative microRNA profiling of prostate carcinomas with increasing tumor stage by deep sequencing. Mol Cancer Res. 2014;12(2):250–63.PubMedCrossRefGoogle Scholar
  70. 70.
    Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, et al. Targeting the STAT3 signaling pathway in cancer: role of synthetic and natural inhibitors. Biochim Biophys Acta. 2014;1845(2):136–54.PubMedGoogle Scholar
  71. 71.
    Lavecchia A, Di Giovanni C, Novellino E. STAT-3 inhibitors: state of the art and new horizons for cancer treatment. Curr Med Chem. 2011;18(16):2359–75.PubMedCrossRefGoogle Scholar
  72. 72.
    Abdulghani J, Gu L, Dagvadorj A, Lutz J, Leiby B, Bonuccelli G, et al. Stat3 promotes metastatic progression of prostate cancer. Am J Pathol. 2008;172(6):1717–28.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Gu L, Vogiatzi P, Puhr M, Dagvadorj A, Lutz J, Ryder A, et al. Stat5 promotes metastatic behavior of human prostate cancer cells in vitro and in vivo. Endocr Relat Cancer. 2010;17(2):481–93.PubMedCrossRefGoogle Scholar
  74. 74.
    Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012;44(6):685–9.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    Blattner M, Lee DJ, O’Reilly C, Park K, MacDonald TY, Khani F, et al. SPOP mutations in prostate cancer across demographically diverse patient cohorts. Neoplasia. 2014;16(1):14–20.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Haffner MC, Mosbruger T, Esopi DM, Fedor H, Heaphy CM, Walker DA, et al. Tracking the clonal origin of lethal prostate cancer. J Clin Invest. 2013;123(11):4918–22.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Thobe MN, Clark RJ, Bainer RO, Prasad SM, Rinker-Schaeffer CW. From prostate to bone: key players in prostate cancer bone metastasis. Cancer. 2011;3(1):478–93.CrossRefGoogle Scholar
  78. 78.
    Robinson VL, Kauffman EC, Sokoloff MH, Rinker-Schaeffer CW. The basic biology of metastasis. Cancer Treat Res. 2004;118:1–21.PubMedCrossRefGoogle Scholar
  79. 79.
    Patel LR, Camacho DF, Shiozawa Y, Pienta KJ, Taichman RS. Mechanisms of cancer cell metastasis to the bone: a multistep process. Future Oncol. 2011;7(11):1285–97.PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Ganguly SS, Li X, Miranti CK. The host microenvironment influences prostate cancer invasion, systemic spread, bone colonization, and osteoblastic metastasis. Front Oncol. 2014;4:364.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Klezovitch O, Chevillet J, Mirosevich J, Roberts RL, Matusik RJ, Vasioukhin V. Hepsin promotes prostate cancer progression and metastasis. Cancer Cell. 2004;6(2):185–95.PubMedCrossRefGoogle Scholar
  82. 82.
    Shou J, Ross S, Koeppen H, de Sauvage FJ, Gao WQ. Dynamics of notch expression during murine prostate development and tumorigenesis. Cancer Res. 2001;61(19):7291–7.PubMedGoogle Scholar
  83. 83.
    Bin Hafeez B, Adhami VM, Asim M, Siddiqui IA, Bhat KM, Zhong W, et al. Targeted knockdown of Notch1 inhibits invasion of human prostate cancer cells concomitant with inhibition of matrix metalloproteinase-9 and urokinase plasminogen activator. Clin Cancer Res. 2009;15(2):452–9.PubMedCrossRefGoogle Scholar
  84. 84.
    Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96.PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Murali AK, Norris JS. Differential expression of epithelial and mesenchymal proteins in a panel of prostate cancer cell lines. J Urol. 2012;188(2):632–8.PubMedCrossRefGoogle Scholar
  86. 86.
    Fan L, Wang H, Xia X, Rao Y, Ma X, Ma D, et al. Loss of E-cadherin promotes prostate cancer metastasis via upregulation of metastasis-associated gene 1 expression. Oncol Lett. 2012;4(6):1225–33.PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Machado JC, Oliveira C, Carvalho R, Soares P, Berx G, Caldas C, et al. E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma. Oncogene. 2001;20(12):1525–8.PubMedCrossRefGoogle Scholar
  88. 88.
    Yates C. Prostate tumor cell plasticity: a consequence of the microenvironment. Adv Exp Med Biol. 2011;720:81–90.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Nalla AK, Estes N, Patel J, Rao JS. N-cadherin mediates angiogenesis by regulating monocyte chemoattractant protein-1 expression via PI3K/Akt signaling in prostate cancer cells. Exp Cell Res. 2011;317(17):2512–21.PubMedCrossRefGoogle Scholar
  90. 90.
    Labelle M, Begum S, Hynes RO. Direct signaling between platelets and cancer cells induces an epithelial-mesenchymal-like transition and promotes metastasis. Cancer Cell. 2011;20(5):576–90.PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Boggon TJ, Eck MJ. Structure and regulation of Src family kinases. Oncogene. 2004;23(48):7918–27.PubMedCrossRefGoogle Scholar
  92. 92.
    Avizienyte E, Frame MC. Src and FAK signalling controls adhesion fate and the epithelial-to-mesenchymal transition. Curr Opin Cell Biol. 2005;17(5):542–7.PubMedCrossRefGoogle Scholar
  93. 93.
    Cai H, Babic I, Wei X, Huang J, Witte ON. Invasive prostate carcinoma driven by c-Src and androgen receptor synergy. Cancer Res. 2011;71(3):862–72.PubMedCrossRefGoogle Scholar
  94. 94.
    Park SI, Zhang J, Phillips KA, Araujo JC, Najjar AM, Volgin AY, et al. Targeting SRC family kinases inhibits growth and lymph node metastases of prostate cancer in an orthotopic nude mouse model. Cancer Res. 2008;68(9):3323–33.PubMedCrossRefGoogle Scholar
  95. 95.
    Paget S. The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 1989;8(2):98–101.PubMedGoogle Scholar
  96. 96.
    Rahim F, Hajizamani S, Mortaz E, Ahmadzadeh A, Shahjahani M, Shahrabi S, et al. Molecular regulation of bone marrow metastasis in prostate and breast cancer. Bone Marrow Res. 2014;2014:405920.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Shiozawa Y, Pedersen EA, Havens AM, Jung Y, Mishra A, Joseph J, et al. Human prostate cancer metastases target the hematopoietic stem cell niche to establish footholds in mouse bone marrow. J Clin Invest. 2011;121(4):1298–312.PubMedPubMedCentralCrossRefGoogle Scholar
  98. 98.
    Kalikin LM, Schneider A, Thakur MA, Fridman Y, Griffin LB, Dunn RL, et al. vivo visualization of metastatic prostate cancer and quantitation of disease progression in immunocompromised mice. Cancer Biol Ther. 2003;2(6):656–60.PubMedCrossRefGoogle Scholar
  99. 99.
    Tokuda Y, Satoh Y, Fujiyama C, Toda S, Sugihara H, Masaki Z. Prostate cancer cell growth is modulated by adipocyte-cancer cell interaction. BJU Int. 2003;91(7):716–20.PubMedCrossRefGoogle Scholar
  100. 100.
    Gazi E, Gardner P, Lockyer NP, Hart CA, Brown MD, Clarke NW. Direct evidence of lipid translocation between adipocytes and prostate cancer cells with imaging FTIR microspectroscopy. J Lipid Res. 2007;48(8):1846–56.PubMedCrossRefGoogle Scholar
  101. 101.
    Hardaway AL, Herroon MK, Rajagurubandara E, Podgorski I. Bone marrow fat: linking adipocyte-induced inflammation with skeletal metastases. Cancer Metastasis Rev. 2014;33(2–3):527–43.PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Clarke NW, McClure J, George NJ. Disodium pamidronate identifies differential osteoclastic bone resorption in metastatic prostate cancer. Br J Urol. 1992;69(1):64–70.PubMedCrossRefGoogle Scholar
  103. 103.
    Charhon SA, Chapuy MC, Delvin EE, Valentin-Opran A, Edouard CM, Meunier PJ. Histomorphometric analysis of sclerotic bone metastases from prostatic carcinoma special reference to osteomalacia. Cancer. 1983;51(5):918–24.PubMedCrossRefGoogle Scholar
  104. 104.
    Koeneman KS, Yeung F, Chung LW. Osteomimetic properties of prostate cancer cells: a hypothesis supporting the predilection of prostate cancer metastasis and growth in the bone environment. Prostate. 1999;39(4):246–61.PubMedCrossRefGoogle Scholar
  105. 105.
    Khosla S. Minireview: the OPG/RANKL/RANK system. Endocrinology. 2001;142(12):5050–5.PubMedCrossRefGoogle Scholar
  106. 106.
    Dushyanthen S, Cossigny DA, Quan GM. The osteoblastic and osteoclastic interactions in spinal metastases secondary to prostate cancer. Cancer Growth Metast. 2013;6:61–80.CrossRefGoogle Scholar
  107. 107.
    Chen G, Sircar K, Aprikian A, Potti A, Goltzman D, Rabbani SA. Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation. Cancer. 2006;107(2):289–98.PubMedCrossRefGoogle Scholar
  108. 108.
    Lynch CC, Hikosaka A, Acuff HB, Martin MD, Kawai N, Singh RK, et al. MMP-7 promotes prostate cancer-induced osteolysis via the solubilization of RANKL. Cancer Cell. 2005;7(5):485–96.PubMedCrossRefGoogle Scholar
  109. 109.
    Miyazaki T, Sanjay A, Neff L, Tanaka S, Horne WC, Baron R. Src kinase activity is essential for osteoclast function. J Biol Chem. 2004;279(17):17660–6.PubMedCrossRefGoogle Scholar
  110. 110.
    Boyce BF, Xing L, Shakespeare W, Wang Y, Dalgarno D, Iuliucci J, et al. Regulation of bone remodeling and emerging breakthrough drugs for osteoporosis and osteolytic bone metastases. Kidney Int Suppl. 2003;85:S2–5.CrossRefGoogle Scholar
  111. 111.
    Xing L, Venegas AM, Chen A, Garrett-Beal L, Boyce BF, Varmus HE, et al. Genetic evidence for a role for Src family kinases in TNF family receptor signaling and cell survival. Genes Dev. 2001;15(2):241–53.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Araujo JC, Poblenz A, Corn P, Parikh NU, Starbuck MW, Thompson JT, et al. Dasatinib inhibits both osteoclast activation and prostate cancer PC-3-cell-induced osteoclast formation. Cancer Biol Ther. 2009;8(22):2153–9.PubMedPubMedCentralCrossRefGoogle Scholar
  113. 113.
    Liu YN, Yin J, Barrett B, Sheppard-Tillman H, Li D, Casey OM, et al. Loss of Androgen-Regulated MicroRNA 1 Activates SRC and Promotes Prostate Cancer Bone Metastasis. Mol Cell Biol. 2015;35(11):1940–51.PubMedPubMedCentralCrossRefGoogle Scholar
  114. 114.
    Zhang J, Dai J, Yao Z, Lu Y, Dougall W, Keller ET. Soluble receptor activator of nuclear factor kappaB Fc diminishes prostate cancer progression in bone. Cancer Res. 2003;63(22):7883–90.PubMedGoogle Scholar
  115. 115.
    Chu GC, Zhau HE, Wang R, Rogatko A, Feng X, Zayzafoon M, et al. RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization. Endocr Relat Cancer. 2014;21(2):311–26.PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Bagnato A, Loizidou M, Pflug BR, Curwen J, Growcott J. Role of the endothelin axis and its antagonists in the treatment of cancer. Br J Pharmacol. 2011;163(2):220–33.PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Godara G, Cannon GW, Cannon GM Jr, Bies RR, Nelson JB, Pflug BR. Role of endothelin axis in progression to aggressive phenotype of prostate adenocarcinoma. Prostate. 2005;65(1):27–34.PubMedCrossRefGoogle Scholar
  118. 118.
    Nelson JB, Hedican SP, George DJ, Reddi AH, Piantadosi S, Eisenberger MA, et al. Identification of endothelin-1 in the pathophysiology of metastatic adenocarcinoma of the prostate. Nat Med. 1995;1(9):944–9.PubMedCrossRefGoogle Scholar
  119. 119.
    Chiao JW, Moonga BS, Yang YM, Kancherla R, Mittelman A, Wu-Wong JR, et al. Endothelin-1 from prostate cancer cells is enhanced by bone contact which blocks osteoclastic bone resorption. Br J Cancer. 2000;83(3):360–5.PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Nelson JB, Nguyen SH, Wu-Wong JR, Opgenorth TJ, Dixon DB, Chung LW, et al. New bone formation in an osteoblastic tumor model is increased by endothelin-1 overexpression and decreased by endothelin A receptor blockade. Urology. 1999;53(5):1063–9.PubMedCrossRefGoogle Scholar
  121. 121.
    Clines GA, Mohammad KS, Bao Y, Stephens OW, Suva LJ, Shaughnessy JD Jr, et al. Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. Mol Endocrinol. 2007;21(2):486–98.PubMedCrossRefGoogle Scholar
  122. 122.
    Thudi NK, Martin CK, Murahari S, Shu ST, Lanigan LG, Werbeck JL, et al. Dickkopf-1 (DKK-1) stimulated prostate cancer growth and metastasis and inhibited bone formation in osteoblastic bone metastases. Prostate. 2011;71(6):615–25.PubMedCrossRefGoogle Scholar
  123. 123.
    Drake JM, Danke JR, Henry MD. Bone-specific growth inhibition of prostate cancer metastasis by atrasentan. Cancer Biol Ther. 2010;9(8):607–14.PubMedCrossRefGoogle Scholar
  124. 124.
    Sun YX, Wang J, Shelburne CE, Lopatin DE, Chinnaiyan AM, Rubin MA, et al. Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo. J Cell Biochem. 2003;89(3):462–73.PubMedCrossRefGoogle Scholar
  125. 125.
    Lee JY, Kang DH, Chung DY, Kwon JK, Lee H, Cho NH, et al. Meta-Analysis of the Relationship between CXCR4 Expression and Metastasis in Prostate Cancer. World J Men Health. 2014;32(3):167–75.CrossRefGoogle Scholar
  126. 126.
    Sun YX, Schneider A, Jung Y, Wang J, Dai J, Wang J, et al. Skeletal localization and neutralization of the SDF-1(CXCL12)/CXCR4 axis blocks prostate cancer metastasis and growth in osseous sites in vivo. J Bone Miner Res. 2005;20(2):318–29.PubMedCrossRefGoogle Scholar
  127. 127.
    Singareddy R, Semaan L, Conley-Lacomb MK, St John J, Powell K, Iyer M, et al. Transcriptional regulation of CXCR4 in prostate cancer: significance of TMPRSS2-ERG fusions. Mol Cancer Res. 2013;11(11):1349–61.PubMedPubMedCentralCrossRefGoogle Scholar
  128. 128.
    Abou-Kheir W, Hynes PG, Martin P, Yin JJ, Liu YN, Seng V, et al. Self-renewing Pten-/- TP53-/- protospheres produce metastatic adenocarcinoma cell lines with multipotent progenitor activity. PLoS One. 2011;6(10):e26112.PubMedPubMedCentralCrossRefGoogle Scholar
  129. 129.
    Peng X, Guo W, Liu T, Wang X, Tu X, Xiong D, et al. Identification of miRs-143 and -145 that is associated with bone metastasis of prostate cancer and involved in the regulation of EMT. PLoS One. 2011;6(5):e20341.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Jernberg E, Thysell E, Bovinder Ylitalo E, Rudolfsson S, Crnalic S, Widmark A, et al. Characterization of prostate cancer bone metastases according to expression levels of steroidogenic enzymes and androgen receptor splice variants. PLoS One. 2013;8(11):e77407.PubMedPubMedCentralCrossRefGoogle Scholar
  131. 131.
    Coleman R, Gnant M, Morgan G, Clezardin P. Effects of bone-targeted agents on cancer progression and mortality. J Natl Cancer Inst. 2012;104(14):1059–67.PubMedCrossRefGoogle Scholar
  132. 132.
    Morgans AK, Smith MR. Bone-targeted agents: preventing skeletal complications in prostate cancer. Urol Clin North Am. 2012;39(4):533–46.PubMedPubMedCentralCrossRefGoogle Scholar
  133. 133.
    Yee AJ, Raje NS. Denosumab, a RANK ligand inhibitor, for the management of bone loss in cancer patients. Clin Interv Aging. 2012;7:331–8.PubMedPubMedCentralGoogle Scholar
  134. 134.
    Fizazi K, Carducci M, Smith M, Damiao R, Brown J, Karsh L, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813–22.PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Smith MR, Saad F, Coleman R, Shore N, Fizazi K, Tombal B, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. 2012;379(9810):39–46.PubMedCrossRefGoogle Scholar
  136. 136.
    Todenhofer T, Stenzl A, Hofbauer LC, Rachner TD. Targeting bone metabolism in patients with advanced prostate cancer: current options and controversies. Int J Endocrinol. 2015;2015:838202.PubMedPubMedCentralCrossRefGoogle Scholar
  137. 137.
    Ju X, Ertel A, Casimiro MC, Yu Z, Meng H, McCue PA, et al. Novel oncogene-induced metastatic prostate cancer cell lines define human prostate cancer progression signatures. Cancer Res. 2013;73(2):978–89.PubMedCrossRefGoogle Scholar
  138. 138.
    Sehgal I, Baley PA, Thompson TC. Transforming growth factor beta1 stimulates contrasting responses in metastatic versus primary mouse prostate cancer-derived cell lines in vitro. Cancer Res. 1996;56(14):3359–65.PubMedGoogle Scholar
  139. 139.
    Keller ET, Fu Z, Yeung K, Brennan M. Raf kinase inhibitor protein: a prostate cancer metastasis suppressor gene. Cancer Lett. 2004;207(2):131–7.PubMedCrossRefGoogle Scholar
  140. 140.
    Tucci P, Agostini M, Grespi F, Markert EK, Terrinoni A, Vousden KH, et al. Loss of p63 and its microRNA-205 target results in enhanced cell migration and metastasis in prostate cancer. Proc Natl Acad Sci U S A. 2012;109(38):15312–7.PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Shacter E, Weitzman SA. Chronic inflammation and cancer. Oncology. 2002;16(2):217–26. 29. discussion 30–2.PubMedGoogle Scholar
  142. 142.
    Burcham GN, Cresswell GM, Snyder PW, Chen L, Liu X, Crist SA, et al. Impact of prostate inflammation on lesion development in the POET3(+)Pten(+/-) mouse model of prostate carcinogenesis. Am J Pathol. 2014;184(12):3176–91.PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    Nickel JC, Roehrborn CG, O’Leary MP, Bostwick DG, Somerville MC, Rittmaster RS. The relationship between prostate inflammation and lower urinary tract symptoms: examination of baseline data from the REDUCE trial. Eur Urol. 2008;54(6):1379–84.PubMedCrossRefGoogle Scholar
  144. 144.
    Hirano T. The biology of interleukin-6. Chem Immunol. 1992;51:153–80.PubMedGoogle Scholar
  145. 145.
    Sfanos KS, De Marzo AM. Prostate cancer and inflammation: the evidence. Histopathology. 2012;60(1):199–215.PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Shukla S, Maclennan GT, Hartman DJ, Fu P, Resnick MI, Gupta S. Activation of PI3K-Akt signaling pathway promotes prostate cancer cell invasion. Int J Cancer. 2007;121(7):1424–32.PubMedCrossRefGoogle Scholar
  147. 147.
    Lu Y, Zhang J, Dai J, Dehne LA, Mizokami A, Yao Z, et al. Osteoblasts induce prostate cancer proliferation and PSA expression through interleukin-6-mediated activation of the androgen receptor. Clin Exp Metastasis. 2004;21(5):399–408.PubMedCrossRefGoogle Scholar
  148. 148.
    Nguyen DP, Li J, Tewari AK. Inflammation and prostate cancer: the role of interleukin 6 (IL-6). BJU Int. 2014;113(6):986–92.PubMedCrossRefGoogle Scholar
  149. 149.
    De Marzo AM, Platz EA, Sutcliffe S, Xu J, Gronberg H, Drake CG, et al. Inflammation in prostate carcinogenesis. Nat Rev Cancer. 2007;7(4):256–69.PubMedPubMedCentralCrossRefGoogle Scholar
  150. 150.
    Sutherland SI, Pe Benito R, Henshall SM, Horvath LG, Kench JG. Expression of phosphorylated-mTOR during the development of prostate cancer. Prostate. 2014;74(12):1231–9.PubMedCrossRefGoogle Scholar
  151. 151.
    Nakai Y, Nonomura N. Inflammation and prostate carcinogenesis. Int J Urol. 2013;20(2):150–60.PubMedCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Pathology and Laboratory MedicineWeill Cornell MedicineNew YorkUSA
  2. 2.Englander Institute for Precision MedicineNew York-Presbyterian, Weill Cornell MedicineNew YorkUSA

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