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The complex roles of Wnt antagonists in RCC

Nature Reviews Urology volume 8, pages 690–699 (2011)Cite this article

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Abstract

Renal cell carcinoma (RCC) is the most lethal of all the genitourinary cancers, as it is generally refractory to current treatment regimens, including chemotherapy and radiation therapy. Targeted therapies against critical signaling pathways associated with RCC pathogenesis, such as vascular endothelial growth factor, von Hippel–Lindau tumor suppressor and mammalian target of rapamycin, have shown limited efficacy so far. Thus, Wnt signaling, which is known to be intricately involved in the pathogenesis of RCC, has attracted much interest. Several Wnt signaling components have been examined in RCC, and, while studies suggest that Wnt signaling is constitutively active in RCC, the molecular mechanisms differ considerably from other human carcinomas. Increasing evidence indicates that secreted Wnt antagonists have important roles in RCC pathogenesis. Considering these vital roles, it has been postulated—and supported by experimental evidence—that the functional loss of Wnt antagonists, for example by promoter hypermethylation, can contribute to constitutive activation of the Wnt pathway, resulting in carcinogenesis through dysregulation of cell proliferation and differentiation. However, subsequent functional studies of these Wnt antagonists have demonstrated the inherent complexities underlying their role in RCC pathogenesis.

Key Points

  • Constitutive Wnt signaling is intricately involved in the pathogenesis of renal cell carcinoma (RCC); inactivation and attenuation of Wnt signaling is affected by a class of molecules called Wnt antagonists

  • The functional loss of Wnt antagonists, usually by promoter hypermethylation, has been shown to contribute to the activation or amplification of aberrant Wnt–β-catenin signaling in RCC, supporting a tumor suppressor role for these molecules

  • These soluble factors are now increasingly recognized as having complex roles in RCC, as some of these proteins have been reported to exhibit oncogenic activities in this malignancy

  • Some Wnt antagonists show biphasic effects in primary versus metastatic RCC

  • Further studies are warranted to understand the detailed role of these proteins in RCC and exploit their potential as therapeutic targets in RCC

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Figure 1: Wnt signaling pathway and its regulation by Wnt antagonists.
Figure 2: Antagonists that bind Wnt.
Figure 3: Antagonists that bind LRP5/LRP6.

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Acknowledgements

We thank Dr Roger Erickson for his support and assistance with the preparation of the manuscript. The work in Dr Dahiya's lab is supported by Grant RO1CA130860 from the NIH.

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Authors and Affiliations

  1. Department of Urology, Veterans Affairs Medical Center, San Francisco and University of California San Francisco, 4150 Clement Street, 94121, CA, USA

    Sharanjot Saini, Shahana Majid & Rajvir Dahiya

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  1. Sharanjot Saini
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  2. Shahana Majid
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  3. Rajvir Dahiya
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All authors contributed equally to researching data for the article and discussing its content. S. Saini wrote the article. S. Saini and R. Dahiya performed review/editing of the manuscript before submission.

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Correspondence to Rajvir Dahiya.

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Saini, S., Majid, S. & Dahiya, R. The complex roles of Wnt antagonists in RCC. Nat Rev Urol 8, 690–699 (2011). https://doi.org/10.1038/nrurol.2011.146

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