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Unravelling disparate roles of NOTCH in bladder cancer

Nature Reviews Urology volume 15, pages 345–357 (2018)Cite this article

Subjects

Abstract

The Notch pathway has been implicated in both oncogenic and tumour-suppressive roles in cancer depending on the tissue type and cellular context. However, until recently, little was known about the pathway in bladder cancer. Studies have revealed that NOTCH1 copy number and expression are decreased in bladder cancer and NOTCH1 activation in bladder cancer cell lines reduces proliferation, suggesting that NOTCH1 acts as a tumour suppressor. Furthermore, in transgenic models, bladder cancer is promoted by bladder-specific inactivation of a component of the γ-secretase complex, which liberates the intracellular domain of neurogenic locus Notch homologue protein (NOTCH) and starts the signalling cascade. By contrast, further work has demonstrated that NOTCH2 acts as an oncogene that promotes cell proliferation and metastasis through epithelial-to-mesenchymal transition, cell cycle progression, and maintenance of stemness. Studies indicating that NOTCH1 and NOTCH2 have opposite effects on the progression of bladder cancer could give rise to potential therapeutic approaches aimed at blocking or restoring the Notch pathway.

Key points

  • The Notch pathway has been shown to have both oncogenic and tumour-suppressive effects depending on the tissue and cellular context.

  • NOTCH1 copy number and expression are decreased in bladder cancer; activation of NOTCH1 in bladder cancer cell lines reduces cellular proliferation, suggesting a tumour-suppressive role.

  • Transgenic models have shown that bladder-specific inactivation of a component of the γ-secretase complex liberates the intracellular domain of Notch and starts the signalling cascade.

  • NOTCH2 has been shown to act as an oncogene in bladder cancer, promoting cellular proliferation and metastasis.

  • The Notch pathway could be harnessed for therapeutic benefit in patients with bladder cancer.

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Fig. 1: The core Notch pathway in bladder cancer.
Fig. 2: Copy number variations and mutations in Notch receptors in The Cancer Genome Atlas.
Fig. 3: Map of mutations found in NOTCH1 and NOTCH2 receptors.
Fig. 4: Notch pathway alterations do not correlate with survival.
Fig. 5: HES1 expression correlates with improved survival.
Fig. 6: HEY1 expression correlates with poorer survival.

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Acknowledgements

This work was funded by a grant from the Canadian Cancer Society Research Institute (P.C.B.).

Author information

Authors and Affiliations

  1. The Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada

    Akihiro Goriki, Alexander W. Wyatt, Alberto Contreras-Sanz, Akshay Bhat & Peter C. Black

  2. Department of Urology, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan

    Akihiro Goriki, Akio Matsubara & Tetsutaro Hayashi

  3. Department of Urology, Hiroshima Prefectural Hospital, Hiroshima, Japan

    Akihiro Goriki

  4. Department of Urology, Inselspital Bern, University of Bern, Bern, Switzerland

    Roland Seiler

Authors
  1. Akihiro Goriki
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  2. Roland Seiler
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  3. Alexander W. Wyatt
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  4. Alberto Contreras-Sanz
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  5. Akshay Bhat
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  6. Akio Matsubara
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  7. Tetsutaro Hayashi
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  8. Peter C. Black
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Contributions

P.C.B., A.G., R.S., A.W.W., and A.B. researched data for the article. P.C.B., A.G., R.S., and A.W.W. made substantial contributions to discussions of content. P.C.B., A.G., and A.W.W. wrote the manuscript. P.C.B., A.G., R.S., A.W.W., A.C.-S., A.M., and T.H. reviewed and edited the manuscript before submission.

Corresponding author

Correspondence to Peter C. Black.

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Goriki, A., Seiler, R., Wyatt, A.W. et al. Unravelling disparate roles of NOTCH in bladder cancer. Nat Rev Urol 15, 345–357 (2018). https://doi.org/10.1038/s41585-018-0005-1

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