Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

WNT signalling in prostate cancer

Key Points

  • Genetic changes in APC and CTNNB1, which activate canonical (β-catenin-dependent) WNT signalling, are observed in up to 22% of castration-resistant prostate cancers (CRPC)

  • Mutations in the ubiquitin ligases RNF43 and ZNRF3 and gene fusions that increase expression of RSPO2 have been detected in 6% of metastatic CRPC tumours

  • Activation of noncanonical (β-catenin-independent) WNT signalling is observed in advanced prostate cancer and in CRPC

  • Prostate cancer stroma secrete WNT proteins that activate WNT signalling in tumour cells and promote therapy resistance and disease progression

  • Agents that target WNT signalling are in early-stage clinical trials for some cancers, but not prostate cancer

Abstract

Genome sequencing and gene expression analyses of prostate tumours have highlighted the potential importance of genetic and epigenetic changes observed in WNT signalling pathway components in prostate tumours — particularly in the development of castration-resistant prostate cancer. WNT signalling is also important in the prostate tumour microenvironment, in which WNT proteins secreted by the tumour stroma promote resistance to therapy, and in prostate cancer stem or progenitor cells, in which WNT–β-catenin signals promote self-renewal or expansion. Preclinical studies have demonstrated the potential of inhibitors that target WNT receptor complexes at the cell membrane or that block the interaction of β-catenin with lymphoid enhancer-binding factor 1 and the androgen receptor, in preventing prostate cancer progression. Some WNT signalling inhibitors are in phase I trials, but they have yet to be tested in patients with prostate cancer.

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: WNT signalling pathways.
Figure 2: Crystal structure of wnt8–FZD8 CRD complex.
Figure 3: WNT signalling regulation by RNF43, ZNRF3, and R-spondin (RSPO).
Figure 4: Paracrine WNT signals from the tumour microenvironment.
Figure 5: Drugs that target WNT signalling.

References

  1. Siegel, R., Miller, K. & Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin. 66, 7–30 (2016).

    Google Scholar 

  2. Livermore, K. E., Munkley, J. & Elliott, D. J. Androgen receptor and prostate cancer. AIMS Mol. Sci. 3, 280–299 (2016).

    CAS  Google Scholar 

  3. Zhou, Y., Bolton, E. C. & Jones, J. O. Androgens and androgen receptor signaling in prostate tumorigenesis. J. Mol. Endocrinol. 54, R15–R29 (2015).

    CAS  PubMed  Google Scholar 

  4. Mottet, N. et al. Guidelines on prostate cancer. Eur. Assoc. Urol. http://dx.doi.org/10.1016/j.eururo.2016.08.003 (2016).

  5. Feldman, B. J. & Feldman, D. The development of androgen-independent prostate cancer. Nat. Rev. Cancer 1, 34–45 (2001).

    CAS  PubMed  Google Scholar 

  6. Hotte, S. J. & Saad, F. Current management of castrate-resistant prostate cancer. Curr. Oncol. 17, 72–79 (2010).

    Google Scholar 

  7. Chandrasekar, T., Yang, J. C., Gao, A. C. & Evans, C. P. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl. Urol. 4, 365–380 (2015).

    PubMed  PubMed Central  Google Scholar 

  8. Karantanos, T., Corn, P. G. & Thompson, T. C. Prostate cancer progression after androgen deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. Oncogene 32, 5501–5511 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Watson, P. A., Arora, V. K. & Sawyers, C. L. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat. Rev. Cancer 15, 701–711 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. 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. 2, 27–44 (2014).

    PubMed  PubMed Central  Google Scholar 

  11. Kypta, R. M. & Waxman, J. Wnt/β-catenin signalling in prostate cancer. Nat. Rev. Urol. 9, 418–428 (2012).

    CAS  PubMed  Google Scholar 

  12. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01351103 (2017).

  13. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02278133 (2017).

  14. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02521844 (2017).

  15. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01931046 (2015).

  16. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02482441 (2017).

  17. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02020291 (2016).

  18. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02655952 (2016).

  19. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01608867 (2016).

  20. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02092363 (2017).

  21. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02069145 (2017).

  22. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02050178 (2017).

  23. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01345201 (2016).

  24. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01957007 (2017).

  25. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01973309 (2017).

  26. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02005315 (2017).

  27. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01469975 (2017).

  28. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02222688 (2017).

  29. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02860676 (2017).

  30. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03088878 (2017).

  31. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02776917 (2017).

  32. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01302405 (2015).

  33. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01764477 (2015).

  34. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT01606579 (2017).

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

    CAS  PubMed  Google Scholar 

  36. Klaus, A. & Birchmeier, W. Wnt signalling and its impact on development and cancer. Nat. Rev. Cancer 8, 387–398 (2008).

    CAS  PubMed  Google Scholar 

  37. Logan, C. & Nusse, R. The Wnt signaling pathway in development and disease. Annu. Rev. Cell Dev. Biol. 20, 781–810 (2004).

    CAS  PubMed  Google Scholar 

  38. Niehrs, C. The complex world of WNT receptor signalling. Nat. Rev. Mol. Cell Biol. 13, 767–779 (2012).

    CAS  PubMed  Google Scholar 

  39. Komiya, Y. & Habas, R. Wnt signal transduction pathways. Organogenesis 4, 68–75 (2008).

    PubMed  PubMed Central  Google Scholar 

  40. Acebron, S. P., Karaulanov, E., Berger, B. S., Huang, Y. L. & Niehrs, C. Mitotic Wnt Signaling promotes protein stabilization and regulates cell size. Mol. Cell 54, 663–674 (2014).

    CAS  PubMed  Google Scholar 

  41. Acebron, S. P. & Niehrs, C. β-Catenin-independent roles of Wnt/LRP6 signaling. Trends Cell Biol. 26, 956–967 (2016).

    CAS  PubMed  Google Scholar 

  42. van Amerongen, R. Alternative Wnt pathways and receptors. Cold Spring Harb. Perspect. Biol. 2012, 4 (2012).

    Google Scholar 

  43. Veeman, M. T., Axelrod, J. D. & Moon, R. T. A second canon: functions and mechanisms of β-catenin-independent Wnt signaling. Dev. Cell 5, 367–377 (2003).

    CAS  Article  PubMed  Google Scholar 

  44. Eferl, R. & Wagner, E. F. AP-1: a double-edged sword in tumorigenesis. Nat. Rev. Cancer 3, 859–868 (2003).

    CAS  PubMed  Google Scholar 

  45. Kohn, A. D., M. R. Wnt and calcium signaling: beta-catenin-independent pathways. Cell Calcium 38, 439–446 (2005).

    CAS  PubMed  Google Scholar 

  46. Mancini, M. & Toker, A. NFAT proteins: emerging roles in cancer progression. Nat. Rev. Cancer 9, 810–820 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Varelas, X. et al. The Hippo pathway regulates Wnt/β-catenin signaling. Dev. Cell 18, 579–591 (2010).

    CAS  PubMed  Google Scholar 

  48. Piccolo, S., Dupont, S. & Cordenonsi, M. The biology of YAP/TAZ: Hippo signaling and beyond. Physiol. Rev. 94, 1287–1312 (2014).

    CAS  PubMed  Google Scholar 

  49. Azzolin, L. et al. YAP/TAZ incorporation in the β-catenin destruction complex orchestrates the Wnt response. Cell 158, 157–170 (2014).

    CAS  PubMed  Google Scholar 

  50. Park, H. W. et al. Alternative Wnt signaling activates YAP/TAZ. Cell 162, 780–794 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Anastas, J. N. & Moon, R. T. WNT signalling pathways as therapeutic targets in cancer. Nat. Rev. Cancer 13, 11–26 (2013).

    CAS  PubMed  Google Scholar 

  52. van Amerongen, R., Mikels, A. & Nusse, R. Alternative wnt signaling is initiated by distinct receptors. Sci. Signal. 1, re9 (2008).

    PubMed  Google Scholar 

  53. Schulte, G. International Union of Basic and Clinical Pharmacology. LXXX. The class Frizzled receptors. Pharmacol. Rev. 62, 632–667 (2010).[

    CAS  PubMed  Google Scholar 

  54. Dijksterhuis, J. P., Petersen, J. & Schulte, G. WNT/Frizzled signalling: receptor-ligand selectivity with focus on FZD-G protein signalling and its physiological relevance: IUPHAR Review 3. Br. J. Pharmacol. 171, 1195–1209 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. MacDonald, B. T. & He, X. Frizzled and LRP5/6 receptors for Wnt/β-Catenin signaling. Cold Spring Harb. Perspect. Biol. 4, a007880 (2012).

    PubMed  PubMed Central  Google Scholar 

  56. Janda, C. Y., Waghray, D., Levin, A. M., Thomas, C. & Garcia, K. C. Structural basis of Wnt recognition by Frizzled. Science 337, 59–64 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Nile, A. H., Mukund, S., Stanger, K., Wang, W. & Hannoush, R. N. Unsaturated fatty acyl recognition by Frizzled receptors mediates dimerization upon Wnt ligand binding. Proc. Natl Acad. Sci. USA 114, 4147–4152 (2017).

    CAS  PubMed  Google Scholar 

  58. Debruine, Z. J. et al. Wnt5a promotes Frizzled-4 signalosome assembly by stabilizing cysteine-rich domain dimerization. Genes Dev. 31, 916–926 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  59. Green, J. & Nusse, R. The role of Ryk and Ror receptor tyrosine kinases in Wnt signal transduction. Cold Spring Harb. Perspect. Biol. 6, a009175 (2014).

    PubMed  PubMed Central  Google Scholar 

  60. Peradziryi, H., Tolwinski, N. S. & Borchers, A. The many roles of PTK7: A versatile regulator of cell-cell communication. Arch. Biochem. Biophys. 524, 71–76 (2012).

    CAS  PubMed  Google Scholar 

  61. Martinez, S. et al. The PTK7 and ROR2 protein receptors interact in the vertebrate WNT/Planar cell polarity (PCP) pathway. J. Biol. Chem. 290, 30562–30572 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Debebe, Z. & Rathmell, W. K. Ror2 as a therapeutic target in cancer. Pharmacol. Ther. 150, 143–148 (2015).

    CAS  PubMed  Google Scholar 

  63. Kawano, Y. & Kypta, R. Secreted antagonists of the Wnt signalling pathway. J. Cell Sci. 116, 2627–2634 (2003).

    CAS  PubMed  Google Scholar 

  64. Malinauskas, T. & Jones, E. Y. Extracellular modulators of Wnt signalling. Curr. Opin. Struct. Biol. 29, 77–84 (2014).

    CAS  PubMed  Google Scholar 

  65. Cruciat, C. M. & Niehrs, C. Secreted and transmembrane Wnt inhibitors and activators. Cold Spring Harb. Perspect. Biol. 5, 1–26 (2013).

    Google Scholar 

  66. Bovolenta, P., Esteve, P., Ruiz, J. M., Cisneros, E. & Lopez-Rios, J. Beyond Wnt inhibition: new functions of secreted Frizzled-related proteins in development and disease. J. Cell Sci. 121, 737–746 (2008).

    CAS  PubMed  Google Scholar 

  67. Hao, H. X., Jiang, X. & Cong, F. Control of Wnt receptor turnover by R-spondin-ZNRF3/RNF43 signaling module and its dysregulation in cancer. Cancers (Basel). 8, 1–12 (2016).

    Google Scholar 

  68. Hao, H.-X. et al. ZNRF3 promotes Wnt receptor turnover in an R-spondin-sensitive manner. Nature 485, 195–200 (2012).

    CAS  PubMed  Google Scholar 

  69. Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000).

    CAS  PubMed  Google Scholar 

  70. Beltran, H. et al. Targeted next-generation sequencing of advanced prostate cancer identifies potential therapeutic targets and disease heterogeneity. Eur. Urol. 63, 920–926 (2013).

    CAS  PubMed  Google Scholar 

  71. Grasso, C. S. et al. The mutational landscape of lethal castrate resistant prostate cancer. Nature 487, 239–243 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Huang, S.-P. et al. Association analysis of Wnt pathway genes on prostate-specific antigen recurrence after radical prostatectomy. Ann. Surg. Oncol. 17, 312–322 (2010).

    PubMed  Google Scholar 

  74. Geng, J.-H. et al. Inherited variants in Wnt pathway genes influence outcomes of prostate cancer patients receiving androgen deprivation therapy. Int. J. Mol. Sci. 17, 1970 (2016).

    PubMed Central  Google Scholar 

  75. Valkenburg, K. C., Hostetter, G. & Williams, B. O. Concurrent hepsin overexpression and adenomatous polyposis coli deletion causes invasive prostate carcinoma in mice. Prostate 75, 1579–1585 (2015).

    CAS  PubMed  Google Scholar 

  76. Francis, J. C., Thomsen, M. K., Taketo, M. M. & Swain, A. β-Catenin is required for prostate development and cooperates with pten loss to drive invasive carcinoma. PLoS Genet. 9, e1003180 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Li, Y. et al. LEF1 in androgen-independent prostate cancer: regulation of androgen receptor expression, prostate cancer growth and invasion. Cancer Res. 69, 3332–3338 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Wu, L. et al. ERG is a critical regulator of Wnt/LEF1 signaling in prostate cancer. Cancer Res. 73, 6068–6079 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  79. Bauman, T. M. et al. Expression and colocalization of β-catenin and lymphoid enhancing factor-1 in prostate cancer progression. Hum. Pathol. 51, 124–133 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Terry, S., Yang, X., Chen, M. W., Vacherot, F. & Buttyan, R. Multifaceted interaction between the androgen and Wnt signaling pathways and the implication for prostate cancer. J. Cell. Biochem. 99, 402–410 (2006).

    CAS  PubMed  Google Scholar 

  81. Wang, G., Wang, J. & Sadar, M. D. Crosstalk between the androgen receptor and β-catenin in castrate resistant prostate cancer. Cancer 68, 9918–9927 (2009).

    Google Scholar 

  82. Jung, S. J. et al. Clinical significance of Wnt/β-Catenin signalling and androgen receptor expression in prostate cancer. World J. Mens Health 31, 36–46 (2013).

    PubMed  PubMed Central  Google Scholar 

  83. Weischenfeldt, J. et al. Integrative genomic analyses reveal an androgen-driven somatic alteration landscape in early-onset prostate cancer. Cancer Cell 23, 159–170 (2013).

    CAS  PubMed  Google Scholar 

  84. Lee, S. H. et al. Androgen signaling is a confounding factor for β-catenin- mediated prostate tumorigenesis. Oncogene 35, 702–714 (2016).

    CAS  PubMed  Google Scholar 

  85. Lee, E., Ha, S. & Logan, S. K. Divergent androgen receptor and beta-catenin signaling in prostate cancer cells. PLoS ONE 10, 1–16 (2015).

    Google Scholar 

  86. Xie, Y. et al. Crosstalk between nuclear MET and SOX9/β-catenin correlates with castration-resistant prostate cancer. Mol. Endocrinol. 28, 1629–1639 (2014).

    PubMed  PubMed Central  Google Scholar 

  87. Yang, M. et al. Estrogen induces androgen-repressed sox4 expression to promote progression of prostate cancer cells. Prostate 75, 1363–1375 (2015).

    CAS  PubMed  Google Scholar 

  88. Bilir, B. et al. SOX4 is essential for prostate tumorigenesis initiated by PTEN ablation. Cancer Res. 76, 1112–1121 (2016).

    CAS  PubMed  Google Scholar 

  89. Zhu, H. et al. Analysis of Wnt gene expression in prostate cancer: mutual inhibition by wnt11 and the androgen receptor. Cancer Res. 64, 7918–7926 (2004).

    CAS  PubMed  Google Scholar 

  90. Thiele, S. et al. Expression profile of WNT molecules in prostate cancer and its regulation by aminobisphosphonates. J. Cell. Biochem. 112, 1593–1600 (2011).

    CAS  PubMed  Google Scholar 

  91. Chen, G. et al. Up-regulation of Wnt-1 and beta-catenin production in patients with advanced metastatic prostate carcinoma: potential pathogenetic and prognostic implications. Cancer 101, 1345–1356 (2004).

    CAS  PubMed  Google Scholar 

  92. Yamamoto, H. et al. Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase. Oncogene 29, 2036–2046 (2010).

    CAS  PubMed  Google Scholar 

  93. Takahashi, S. et al. Noncanonical Wnt signaling mediates androgen-dependent tumor growth in a mouse model of prostate cancer. Proc. Natl Acad. Sci. USA 108, 4938–4943 (2011).

    CAS  PubMed  Google Scholar 

  94. Khaja, A. S. et al. Elevated level of Wnt5a protein in localized prostate cancer tissue is associated with better outcome. PLoS ONE 6, e26539 (2011).

    Google Scholar 

  95. Thiele, S. et al. WNT5A has anti-prostate cancer effects in vitro and reduces tumor growth in the skeleton in vivo. J. Bone Miner. Res. 30, 471–480 (2015).

    PubMed  Google Scholar 

  96. Khaja, A. S. S. et al. Emphasizing the role of Wnt5a protein expression to predict favorable outcome after radical prostatectomy in patients with low-grade prostate cancer. Cancer Med. 1, 96–104 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Gujral, T. S. et al. A noncanonical Frizzled2 pathway regulates epithelial-mesenchymal transition and metastasis. Cell 159, 844–856 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Sandsmark, E. et al. A novel non-canonical Wnt signature for prostate cancer aggressiveness. Oncotarget 8, 9572–9586 (2017).

    PubMed  Google Scholar 

  99. Chen, C. L. et al. Single-cell analysis of circulating tumor cells identifies cumulative expression patterns of EMT-related genes in metastatic prostate cancer. Prostate 73, 813–826 (2013).

    PubMed  Google Scholar 

  100. Miyamoto, D. T. et al. RNA-Seq of single prostate CTCs implicates noncanonical Wnt signaling in antiandrogen resistance. Science 349, 1351–1356 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  101. Li, Z. G. et al. Low-density lipoprotein receptor-related protein 5 (LRP5) mediates the prostate cancer-induced formation of new bone. Oncogene 27, 596–603 (2008).

    CAS  PubMed  Google Scholar 

  102. Zheng, D. et al. Role of WNT7B-induced noncanonical pathway in advanced prostate cancer. Mol. Cancer Res. 11, 482–493 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Uysal-Onganer, P. & Kypta, R. M. Wnt11 in 2011 - the regulation and function of a non-canonical Wnt. Acta Physiol. 204, 52–64 (2012).

    CAS  Google Scholar 

  104. Volante, M. et al. Androgen deprivation modulates gene expression profile along prostate cancer progression. Hum. Pathol. 56, 81–88 (2016).

    CAS  PubMed  Google Scholar 

  105. Uysal-Onganer, P. et al. Wnt-11 promotes neuroendocrine-like differentiation, survival and migration of prostate cancer cells. Mol. Cancer 9, 55 (2010).

    PubMed  PubMed Central  Google Scholar 

  106. Rajan, P. et al. Next-generation sequencing of advanced prostate cancer treated with androgen-deprivation therapy. Eur. Urol. 66, 32–39 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  107. Tomlins, S. A. et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 310, 644–648 (2005).

    CAS  PubMed  Google Scholar 

  108. Perner, S. et al. TMPRSS2-ERG fusion prostate cancer: an early molecular event associated with invasion. Am. J. Surg. Pathol. 31, 882–888 (2007).

    PubMed  Google Scholar 

  109. Brase, J. C. et al. TMPRSS2-ERG-specific transcriptional modulation is associated with prostate cancer biomarkers and TGF-β signaling. BMC Cancer 11, 507 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  110. Gupta, S. et al. FZD4 as a mediator of ERG oncogene-induced WNT signaling and epithelial-to-mesenchymal transition in human prostate cancer cells. Cancer Res. 70, 6735–6745 (2010).

    CAS  PubMed  Google Scholar 

  111. Pascal, L. E. et al. Gene expression relationship between prostate cancer cells of Gleason 3, 4 and normal epithelial cells as revealed by cell type-specific transcriptomes. BMC Cancer 9, 452 (2009).

    PubMed  PubMed Central  Google Scholar 

  112. Ma, F. et al. SOX9 drives WNT pathway activation in prostate cancer. J. Clin. Invest. 126, 525–530 (2016).

    Google Scholar 

  113. Zhang, S. et al. The onco-embryonic antigen ROR1 is expressed by a variety of human cancers. Am. J. Pathol. 181, 1903–1910 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Yee, D. S. et al. 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. Mol. Cancer 9, 162 (2010).

    PubMed  PubMed Central  Google Scholar 

  115. Zheng, L. et al. Diagnostic value of SFRP1 as a favorable predictive and prognostic biomarker in patients with prostate cancer. PLoS ONE 10, 1–16 (2015).

    Google Scholar 

  116. García-Tobilla, P. et al. SFRP1 repression in prostate cancer is triggered by two different epigenetic mechanisms. Gene 593, 292–301 (2016).

    PubMed  Google Scholar 

  117. O'Hurley, G. et al. The role of secreted frizzled-related protein 2 expression in prostate cancer. Histopathology 59, 1240–1248 (2011).

    PubMed  Google Scholar 

  118. Perry, A. S. et al. Gene expression and epigenetic discovery screen reveal methylation of SFRP2 in prostate cancer. Int. J. Cancer 132, 1771–1780 (2013).

    CAS  PubMed  Google Scholar 

  119. Sun, Y. et al. SFRP2 augments WNT16B signaling to promote therapeutic resistance in the damaged tumor microenvironment. Oncogene 35, 4321–4334 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Rachner, T. D. et al. High serum levels of Dickkopf-1 are associated with a poor prognosis in prostate cancer patients. BMC Cancer 14, 649 (2014).

    PubMed  PubMed Central  Google Scholar 

  121. Thudi, N. K. et al. Dickkopf-1 (DKK-1) stimulated prostate cancer growth and metastasis and inhibited bone formation in osteoblastic bone metastases. Prostate 71, 615–625 (2011).

    CAS  PubMed  Google Scholar 

  122. Mazon, M., Masi, D. & Carreau, M. Modulating Dickkopf-1: a strategy to monitor or treat cancer? Cancers (Basel). 8, 1–9 (2016).

    Google Scholar 

  123. Kimura, H. et al. CKAP4 is a Dickkopf1 receptor and is involved in tumor progression. J. Clin. Invest. 126, 2689–2705 (2016).

    PubMed  PubMed Central  Google Scholar 

  124. Josson, S., Matsuoka, Y., Chung, L. W. K. & Zhau, H. E. Tumor stroma co-evolution in prostate cancer progression and metastasis. Semin. Cell Dev. Biol. 21, 26–32 (2010).

    CAS  PubMed  Google Scholar 

  125. Li, X. et al. Prostate tumor progression is mediated by a paracrine TGF-β/Wnt3a signaling axis. Oncogene 27, 7118–7130 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Zong, Y. et al. Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling. Proc. Natl Acad. Sci. USA 109, 3395–3404 (2012).

    Google Scholar 

  127. Dakhova, O., Rowley, D. & Ittmann, M. Genes upregulated in prostate cancer reactive stroma promote prostate cancer progression in vivo. Clin. Cancer Res. 20, 100–109 (2014).

    CAS  PubMed  Google Scholar 

  128. Sun, Y. et al. Treatment-induced damage to the tumor microenvironment promotes prostate cancer therapy resistance through WNT16B. Nat. Med. 18, 1359–1368 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Lee, G. T. et al. Prostate cancer bone metastases acquire resistance to androgen deprivation via WNT5A-mediated BMP-6 induction. Br. J. Cancer 110, 1634–1644 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  130. Packer, J. R. & Maitland, N. J. The molecular and cellular origin of human prostate cancer. Biochim. Biophys. Acta 1863, 1238–1260 (2016).

    CAS  PubMed  Google Scholar 

  131. Chen, X., Rycaj, K., Liu, X. & Tang, D. G. New insights into prostate cancer stem cells. Cell Cycle 12, 579–586 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Bisson, I. & Prowse, D. M. WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics. Cell Res. 19, 683–697 (2009).

    CAS  PubMed  Google Scholar 

  133. Eun-Jin, Y. et al. Targeting cancer stem cell in castration resistant prostate cancer. Clin. Cancer Res. 22, 670–679 (2016).

    Google Scholar 

  134. Cojoc, M. et al. Aldehyde dehydrogenase is regulated by β-Catenin/TCF and promotes radioresistance in prostate cancer progenitor cells. Cancer Res. 75, 1482–1494 (2015).

    CAS  PubMed  Google Scholar 

  135. Takebe, N. et al. Targeting Notch, Hedgehog, and Wnt Pathways in cancer stem cells: clinical update. Nat. Rev. Clin. Oncol. 12, 445–464 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  136. Kahn, M. Can we safely target the WNT pathway? Nat. Rev. Drug Discov. 13, 513–532 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  137. Ahmed, K., Shaw, H. V., Koval, A. & Katanaev, V. L. A second WNT for old drugs: Drug repositioning against WNT-dependent cancers. Cancers (Basel). 8, 1–27 (2016).

    Google Scholar 

  138. Vidal, A. C. et al. Aspirin, NSAID and risk of prostate cancer: results from the REDUCE study. Clin. Cancer Res. 21, 756–762 (2015).

    CAS  PubMed  Google Scholar 

  139. Mikels, A. & Nusse, R. Wnts as ligands: processing, secretion and reception. Oncogene 25, 7461–7468 (2006).

    CAS  PubMed  Google Scholar 

  140. Chen, B. et al. Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer. Nat. Chem. Biol. 5, 100–107 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Proffitt, K. D. et al. Pharmacological inhibition of the Wnt acyltransferase PORCN prevents growth of WNT-driven mammary cancer. Cancer Res. 73, 502–507 (2013).

    CAS  PubMed  Google Scholar 

  142. Liu, J. et al. Targeting Wnt-driven cancer through the inhibition of Porcupine by LGK974. Proc. Natl Acad. Sci. USA 110, 20224–20229 (2013).

    CAS  PubMed  Google Scholar 

  143. Jiang, X. et al. Inactivating mutations of RNF43 confer Wnt dependency in pancreatic ductal adenocarcinoma. Proc. Natl Acad. Sci. USA 110, 12649–12654 (2013).

    CAS  PubMed  Google Scholar 

  144. Madan, B. et al. Wnt addiction of genetically defined cancers reversed by PORCN inhibition. Oncogene 35, 2197–2207 (2016).

    CAS  PubMed  Google Scholar 

  145. Janku, F. et al. Phase I study of WNT974, a first-in-class Porcupine inhibitor, in advanced solid tumors [abstract]. Mol. Cancer Ther. 14 (Suppl. 2), C45 (2015).

    Google Scholar 

  146. Teneggi, V. et al. A phase 1, first-in-human dose escalation study of ETC-159 in advanced or metastatic solid tumours [abstract]. Ann. Oncol. 27 (Suppl. 9), 1520 (2016).

    Google Scholar 

  147. Cooper, S. J. et al. Reexpression of tumor suppressor, sFRP1, leads to antitumor synergy of combined hdac and methyltransferase inhibitors in chemoresistant cancers. Mol. Cancer Ther. 11, 2105–2115 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  148. Ghoshal, A., Goswami, U., Sahoo, A. K., Chattopadhyay, A. & Ghosh, S. S. Targeting Wnt canonical signaling by recombinant sFRP1 bound luminescent au-nanocluster embedded nanoparticles in cancer theranostics. ACS Biomater. Sci. Eng. 1, 1256–1266 (2015).

    CAS  Google Scholar 

  149. Veeck, J. & Dahl, E. Targeting the Wnt pathway in cancer: the emerging role of Dickkopf-3. Biochim. Biophys. Acta Rev. Cancer 1825, 18–28 (2012).

    CAS  Google Scholar 

  150. Kumon, H. et al. Adenovirus vector carrying REIC/DKK-3 gene: neoadjuvant intraprostatic injection for high-risk localized prostate cancer undergoing radical prostatectomy. Cancer Gene Ther. 23, 400–409 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Kumon, H. et al. Ad-REIC gene therapy: promising results in a patient with metastatic CRPC following chemotherapy. Clin. Med. Insights Oncol. 9, 31–38 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  152. Storm, E. E. et al. Targeting PTPRK-RSPO3 colon tumours promotes differentiation and loss of stem-cell function. Nature 529, 97–100 (2015).

    PubMed  Google Scholar 

  153. Madan, B. & Virshup, D. M. Targeting Wnts at the source—new mechanisms, new biomarkers, new drugs. Mol. Cancer Ther. 14, 1087–1095 (2015).

    CAS  PubMed  Google Scholar 

  154. Hanaki, H. et al. An anti-Wnt5a antibody suppresses metastasis of gastric cancer cells in vivo by inhibiting receptor-mediated endocytosis. Mol. Cancer Ther. 11, 298–307 (2012).

    CAS  PubMed  Google Scholar 

  155. Shojima, K. et al. Wnt5a promotes cancer cell invasion and proliferation by receptor-mediated endocytosis-dependent and -independent mechanisms, respectively. Sci. Rep. 5, 8042 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  156. Säfholm, A. et al. A formylated hexapeptide ligand mimics the ability of Wnt-5a to impair migration of human breast epithelial cells. J. Biol. Chem. 281, 2740–2749 (2006).

    PubMed  Google Scholar 

  157. Säfholm, A. et al. The Wnt-5a-derived hexapeptide Foxy-5 inhibits breast cancer metastasis in vivo by targeting cell motility. Clin. Cancer Res. 14, 6556–6563 (2008).

    PubMed  Google Scholar 

  158. Le, P., McDermott, J. D. & Jimeno, A. Targeting the Wnt pathway in human cancers: therapeutic targeting with a focus on OMP-54F28. Pharmacol. Ther. 146, 1–11 (2015).

    CAS  PubMed  Google Scholar 

  159. Jimeno, A. et al. A first-in-human phase 1 study of anticancer stem cell agent OMP-54F28 (FZD8-Fc), decoy receptor for WNT ligands, in patients with advanced solid tumors [abstract]. J. Clin. Oncol. 32 (Suppl.), 2505 (2014).

    Google Scholar 

  160. O'Cearbhaill, R. E. et al. Phase 1b of WNT inhibitor ipafricept (IPA, decoy receptor for WNT ligands) with carboplatin (C) and paclitaxel (P) in recurrent platinum-sensitive ovarian cancer (OC) [abstract]. J. Clin. Oncol. 34 (Suppl.), 2515 (2016).

    Google Scholar 

  161. Phesse, T., Flanagan, D. & Vincan, E. Frizzled7: a promising achilles´ heel for targeting the Wnt receptor complex to treat cancer. Cancers (Basel). 8, 1–33 (2016).

    Google Scholar 

  162. Gurney, A. et al. Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc. Natl Acad. Sci. USA 109, 11717–11722 (2012).

    CAS  PubMed  Google Scholar 

  163. Fischer, M. M. et al. WNT antagonists exhibit unique combinatorial antitumor activity with taxanes by potentiating mitotic cell death. 3, e1700090 (2017).

  164. Fukukawa, C. et al. Radioimmunotherapy of human synovial sarcoma using a monoclonal antibody against FZD10. Cancer Sci. 99, 432–440 (2008).

    CAS  PubMed  Google Scholar 

  165. Giraudet, A. L. et al. SYNFRIZZ-a phase Ia/Ib of a radiolabelled monoclonal AB for the treatment of relapsing synovial sarcoma. J. Nucl. Med. 55 (Suppl. 1), 223 (2014).

    Google Scholar 

  166. Steinhart, Z. et al. Genome-wide CRISPR screens reveal a Wnt – FZD5 signaling circuit as a druggable vulnerability of RNF43 -mutant pancreatic tumors. Nat. Med. 23, 60–68 (2016).

    PubMed  Google Scholar 

  167. Lu, W. et al. Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/β-catenin pathway. PLoS ONE 6, 1–8 (2011).

    CAS  Google Scholar 

  168. Liu, C. et al. Niclosamide inhibits androgen receptor variants expression and overcomes enzalutamide resistance in castration resistant prostate cancer. Clin. Cancer Res. 20, 3198–3210 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  169. Liu, C., Armstrong, C., Zhu, Y., Lou, W. & Gao, A. C. Niclosamide enhances abiraterone treatment via inhibition of androgen receptor variants in castration resistant prostate cancer. Oncotarget 7, 32210–32220 (2016).

    PubMed  PubMed Central  Google Scholar 

  170. Lu, W. & Li, Y. Salinomycin suppresses LRP6 expression and inhibits both Wnt/β-catenin and mTORC1 signaling in breast and prostate cancer cells. J. Cell. Biochem. 115, 1799–1807 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Lin, C. et al. Mesd is a general inhibitor of different Wnt ligands in Wnt/LRP signaling and inhibits PC-3 tumor growth in vivo. FEBS Lett. 585, 3120–3125 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Borcherding, N., Kusner, D., Liu, G. H. & Zhang, W. ROR1, an embryonic protein with an emerging role in cancer biology. Protein Cell 5, 496–502 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Kolb, R., Kluz, P. & Zhang, W. ROR1 is an intriguing target for cancer therapy ROR1-based targeted therapies ROR1-mediated oncogenic signalling. Mol. Enzymol. Drug Targets 2, 1–3 (2016).

    Google Scholar 

  174. Yang, Y. et al. Dishevelled-2 silencing reduces androgen-dependent prostate tumor cell proliferation and migration and expression of Wnt-3a and matrix metalloproteinases. Mol. Biol. Rep. 40, 4241–4250 (2013).

    CAS  PubMed  Google Scholar 

  175. Grandy, D. et al. Discovery and characterization of a small molecule inhibitor of the PDZ domain of dishevelled. J. Biol. Chem. 284, 16256–16263 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  176. Haikarainen, T., Krauss, S. & Lehtio, L. Tankyrases: structure, function and therapeutic implications in cancer. Curr. Pharm. Des. 20, 6472–6488 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Shultz, M. D. et al. Identification of NVP-TNKS656: the use of structure−efficiency relationships to generate a highly potent, selective, and orally active tankyrase inhibitor. J. Med. Chem. 56, 6495–6511 (2013).

    CAS  PubMed  Google Scholar 

  178. de la Roche, M., Ibrahim, A. E. K., Mieszczanek, J. & Bienz, M. LEF1 and B9L shield β-catenin from inactivation by axin, desensitizing colorectal cancer cells to tankyrase inhibitors. Cancer Res. 74, 1495–1505 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  179. Wang, W. et al. Tankyrase inhibitors target YAP by stabilizing angiomotin family proteins. Cell Rep. 13, 524–532 (2015).

    PubMed  PubMed Central  Google Scholar 

  180. Li, N. et al. Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth. Genes Dev. 29, 157–170 (2015).

    PubMed  PubMed Central  Google Scholar 

  181. Gonsalves, F. C. et al. An RNAi-based chemical genetic screen identifies three small-molecule inhibitors of the Wnt / wingless signaling pathway. Proc. Natl Acad. Sci. USA 108, 5954–5963 (2011).

    CAS  PubMed  Google Scholar 

  182. Tian, W. et al. Structure-based discovery of a novel inhibitor targeting the β-catenin/Tcf4 interaction. Biochemistry 51, 724–731 (2012).

    CAS  PubMed  Google Scholar 

  183. Fang, L. et al. A small-molecule antagonist of the β-catenin/TCF4 interaction blocks the self-renewal of cancer stem cells and suppresses tumorigenesis. Cancer Res. 76, 891–901 (2016).

    CAS  PubMed  Google Scholar 

  184. Emami, K. H. et al. A small molecule inhibitor of β-catenin/CREB-binding protein transcription. Proc. Natl Acad. Sci. USA 101, 12682–12687 (2004).

    CAS  PubMed  Google Scholar 

  185. El-Khoueiry, A. B. et al. A phase I first-in-human study of PRI-724 in patients (pts) with advanced solid tumors [abstract]. J. Clin. Oncol. 31 (Suppl.), 2501 (2013).

    Google Scholar 

  186. Hao, J. et al. Selective small molecule targeting β -Catenin function discovered by in vivo chemical genetic screen. Cell Rep. 4, 898–904 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  187. Bordonaro, M. & Lazarova, D. L. CREB-binding protein, p300, butyrate, and Wnt signaling in colorectal cancer. World J. Gastroenterol. 21, 8238–8248 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  188. Chinison, J. et al. Triptonide effectively inhibits Wnt/β-Catenin signaling via C-terminal transactivation domain of β-catenin. Sci. Rep. 6, 32779 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  189. Mallinger, A. et al. Discovery of potent, orally bioavailable, small-molecule inhibitors of WNT signaling from a cell-based pathway screen. J. Med. Chem. 58, 1717–1735 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Lee, E. et al. Inhibition of androgen receptor and β-catenin activity in prostate cancer. Proc. Natl Acad. Sci. USA 110, 15710–15715 (2013).

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Robert Kypta.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Murillo-Garzón, V., Kypta, R. WNT signalling in prostate cancer. Nat Rev Urol 14, 683–696 (2017). https://doi.org/10.1038/nrurol.2017.144

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrurol.2017.144

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing