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Targeting signalling pathways and the immune microenvironment of cancer stem cells — a clinical update

Nature Reviews Clinical Oncology volume 17, pages 204–232 (2020)Cite this article

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Abstract

Cancer stem cells (CSCs) have important roles in tumour development, relapse and metastasis; the intrinsic self-renewal characteristics and tumorigenic properties of these cells provide them with unique capabilities to resist diverse forms of anticancer therapy, seed recurrent tumours, and disseminate to and colonize distant tissues. The findings of several studies indicate that CSCs originate from non-malignant stem or progenitor cells. Accordingly, inhibition of developmental signalling pathways that are crucial for stem and progenitor cell homeostasis and function, such as the Notch, WNT, Hedgehog and Hippo signalling cascades, continues to be pursued across multiple cancer types as a strategy for targeting the CSCs hypothesized to drive cancer progression — with some success in certain malignancies. In addition, with the renaissance of anticancer immunotherapy, a better understanding of the interplay between CSCs and the tumour immune microenvironment might be the key to unlocking a new era of oncological treatments associated with a reduced propensity for the development of resistance and with enhanced antimetastatic activity, thus ultimately resulting in improved patient outcomes. Herein, we provide an update on the progress to date in the clinical development of therapeutics targeting the Notch, WNT, Hedgehog and Hippo pathways. We also discuss the interactions between CSCs and the immune system, including the potential immunological effects of agents targeting CSC-associated developmental signalling pathways, and provide an overview of the emerging approaches to CSC-targeted immunotherapy.

Key points

  • The results of laboratory-based research have demonstrated the fundamental roles of cancer stem cells (CSCs) in mediating the resistance of cancers to therapy, tumour recurrence and metastasis.

  • CSCs harbour important alterations affecting developmental signalling pathways that control cell renewal and differentiation, including the Notch, WNT and Hedgehog pathways.

  • Crosstalk with the WNT pathways has led to the molecular characterization of abnormalities in the core components of the Hippo pathway in multiple malignancies; transcriptional co-activation or co-repression by the Hippo pathway effectors YAP1 and TAZ serves as an important regulatory hub for multiple pathways and has potential context-dependent oncogene or tumour suppressor activity.

  • Multiple clinical trials using single agents and combination therapies have been performed to study the safety and efficacy of targeting CSCs via the inhibition of these development pathways.

  • Various interactions of CSCs with the tumour immune microenvironment result in evasion of CSC detection by the immune system and are therefore key candidates for novel approaches to immunotherapy.

  • Further improvements in targeting CSCs as a specific population are fundamental to improving the efficacy of new anticancer therapies.

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Fig. 1: The canonical Notch signalling pathway and related pharmacological inhibitors that are under development in oncology.
Fig. 2: The canonical and non-canonical WNT signalling pathway and related pharmacological inhibitors that are under investigation in oncology.
Fig. 3: The canonical Hedgehog signalling pathway and related pharmacological inhibitors that are under development as anticancer treatments.
Fig. 4: The Hippo signalling pathway and associated therapeutic targets.
Fig. 5: Novel immune-based approaches to targeting CSCs.

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Author notes

  1. These authors contributed equally: Joseph A. Clara, Cecilia Monge

Authors and Affiliations

  1. National Heart Lung and Blood Institute, NIH, Bethesda, MD, USA

    Joseph A. Clara

  2. Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH, Bethesda, MD, USA

    Cecilia Monge & Naoko Takebe

  3. Department of Developmental Biology, Harvard School of Dental Medicine, Dana-Farber/Harvard Cancer Center, Boston, MA, USA

    Yingzi Yang

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All authors contributed substantially to researching the data for the article, discussions of content, writing the article and review/editing of the manuscript before submission.

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Clara, J.A., Monge, C., Yang, Y. et al. Targeting signalling pathways and the immune microenvironment of cancer stem cells — a clinical update. Nat Rev Clin Oncol 17, 204–232 (2020). https://doi.org/10.1038/s41571-019-0293-2

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