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  • Review Article
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Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways

Nature Reviews Clinical Oncology volume 8, pages 97–106 (2011)Cite this article

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Abstract

Tumor relapse and metastasis remain major obstacles for improving overall cancer survival, which may be due at least in part to the existence of cancer stem cells (CSCs). CSCs are characterized by tumorigenic properties and the ability to self-renew, form differentiated progeny, and develop resistance to therapy. CSCs use many of the same signaling pathways that are found in normal stem cells, such as Wnt, Notch, and Hedgehog (Hh). The origin of CSCs is not fully understood, but data suggest that they originate from normal stem or progenitor cells, or possibly other cancer cells. Therapeutic targeting of both CSCs and bulk tumor populations may provide a strategy to suppress tumor regrowth. Development of agents that target critical steps in the Wnt, Notch, and Hh pathways will be complicated by signaling cross-talk. The role that embryonic signaling pathways play in the function of CSCs, the development of new anti-CSC therapeutic agents, and the complexity of potential CSC signaling cross-talk are described in this Review.

Key Points

  • The stochastic model and cancer stem cell (CSC) model of tumorigenesis could be combined to help explain tumor relapse and metastasis

  • DNA mutations, microenvironmental factors, and/or epithelial-to-mesenchymal transition may drive CSCs towards a metastatic phenotype

  • Tumors composed of small populations of CSCs plus large numbers of bulk tumor cells may be particularly susceptible to combination drug regimens that target each cell population

  • The potential for cross-talk among signaling pathways by CSCs opens new opportunities for designing combination drug regimens

  • New experimental agents are being developed to block Wnt, Notch, and Hedgehog signaling by CSCs, some of which are being tested in early clinical trials

  • Measurement of biologic effects of anti-CSC therapeutic regimens will remain a challenge until more-effective methods to identify CSCs in vivo or in vitro surrogate assays are improved

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Figure 1: Notch signaling pathway inhibition.
Figure 2: Hedgehog signaling pathway inhibition.
Figure 3: Wnt/β-catenin signaling pathway inhibition.

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Authors and Affiliations

  1. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Cancer Therapy Evaluation Program, Investigational Drug Branch, EPN7131, 6130 Executive Boulevard, Rockville, Bethesda, 20852, MD, USA

    Naoko Takebe, Pamela J. Harris & S. Percy Ivy

  2. PSI International, Inc., 6500 Rock Spring Drive, Suite 650, Bethesda, 20817, MD, USA

    Ronald Q. Warren

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  1. Naoko Takebe
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  2. Pamela J. Harris
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  3. Ronald Q. Warren
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  4. S. Percy Ivy
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N. Takebe, P. J. Harris, R. Q. Warren and S. P. Ivy contributed equally to the literature review, discussions of the content, writing and reviewing and editing of this manuscript before submission.

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Correspondence to S. Percy Ivy.

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J. Cortés is a consultant for Roche. The other authors declare no competing interests.

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Takebe, N., Harris, P., Warren, R. et al. Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways. Nat Rev Clin Oncol 8, 97–106 (2011). https://doi.org/10.1038/nrclinonc.2010.196

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