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WNT signalling in prostate cancer

Nature Reviews Urology volume 14, pages 683–696 (2017)Cite this article

Subjects

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.

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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.

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Authors and Affiliations

  1. Cell Biology and Stem Cells Unit, CIC bioGUNE, Building 801A, Bizkaia Technology Park, Derio, 48160, Spain

    Virginia Murillo-Garzón & Robert Kypta

  2. Department of Surgery and Cancer, Imperial College London, Du Cane Road, London, W12 0NN, UK

    Robert Kypta

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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

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