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Tumour-initiating cells: challenges and opportunities for anticancer drug discovery

Key Points

  • The experimental demonstration of tumour-initiating cells (popularly known as cancer stem cells) in several human tumours in recent years supports tumour hierarchy as a fundamental concept in tumour biology.

  • Many patients with cancer, particularly those with solid tumours, either do not respond to existing cancer therapies or relapse quickly after initial remission. Key possible reasons for this failure include the inherent drug resistance of tumour-initiating cells, the inefficiency of the treatment and/or the genetic instability of cancer cells.

  • The cancer stem cell hypothesis provides a rationale for several therapeutic strategies beyond traditional antiproliferative agents. Potential approaches to kill tumour-initiating cells include inhibiting the survival mechanisms of these cells, blocking essential self-renewal signalling, or targeting tumour-initiating cell surface markers through antibody-based cytotoxic approaches.

  • Another strategy is to induce tumour cell differentiation, which can potentially be achieved by inhibiting developmental pathways or epigenetic programmes. As many tumour-initiating cells might be dependent on a niche for their identities, targeting the niche could be a strategy to indirectly inhibit or differentiate tumour-initiating cells.

  • The conventional approach for anticancer drug discovery is to target cell proliferation rather than self-renewal and/or differentiation, and so is often biased to select targets with homogeneous expression patterns and potent compounds that kill the cells of the bulk tumour. In addition, some traditional preclinical models may not reflect clinical complexities such as tumour hierarchy.

  • The large body of evidence in support of the cancer stem cell hypothesis and the related therapeutic strategies suggest that adjustments to anticancer drug discovery platforms are required to make them more clinically relevant, which are discussed in this article.

  • Although the paths for developing agents that target tumour-initiating cells are not straightforward, the cancer stem cell hypothesis provides an important framework for drug discovery and cancer treatment, with the potential to find novel antitumour activities, to have an impact on cancers with undifferentiated phenotypes and to yield long-term benefits for many patients with cancer.

Abstract

The hypothesis that cancer is driven by tumour-initiating cells (popularly known as cancer stem cells) has recently attracted a great deal of attention, owing to the promise of a novel cellular target for the treatment of haematopoietic and solid malignancies. Furthermore, it seems that tumour-initiating cells might be resistant to many conventional cancer therapies, which might explain the limitations of these agents in curing human malignancies. Although much work is still needed to identify and characterize tumour-initiating cells, efforts are now being directed towards identifying therapeutic strategies that could target these cells. This Review considers recent advances in the cancer stem cell field, focusing on the challenges and opportunities for anticancer drug discovery.

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Figure 1: The cancer stem cell hypothesis and therapeutic strategies to target tumour-initiating cells.
Figure 2: Signalling pathways that regulate self renewal during normal stem cell development and cancer transformation.
Figure 3: Anticancer drug discovery platforms to target tumour-initiating cells.

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Acknowledgements

We thank J. Dick, L. Li, K. Arndt, R. Abraham, J. Rosen and F. Behbod for discussions and comments on the manuscript.

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Correspondence to Bin-Bing S. Zhou or Justin C. Grindley.

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B.-B.S.Z., M.D., K.G.G. and J.C.G. are employees of Wyeth Pharmaceuticals. H.Z. is an employee of Abbott Laboratories. P.B.D declares no conflict of interest.

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Glossary

Self-renewal

The ability of a cell to reproduce itself without losing developmental potential, characterized by cell divisions in which differentiation is blocked in at least one daughter cell.

Anoikis

A form of programmed cell death that is induced in anchorage-dependent cells when they become detached from the surrounding extracellular matrix.

Niche

Cells and/or extracellular matrix components in specific anatomical locations that regulate the participation of the normal stem cells in tissue generation, maintenance and repair. In some cases, the behaviour of tumour-initiating cells might also be influenced by interactions with surrounding cells and matrix.

Asymmetrical division

A form of cellular replication in which a cell renews itself and generates a more differentiated progeny.

Symmetrical division

A form of cellular replication in which a single cell gives rise to two identical cells.

Epithelial–mesenchymal transition

A cellular program in normal development and in cancer whereby cells of an epithelial origin acquire the properties of mesenchymal cells, typically characterized by loss of cell adhesion, repression of E-cadherin expression, and increased cell motility.

Oncomir

MicroRNA known to be involved in cancer and tumorigenesis.

Orthotopic model

A system in which tumour cells are implanted at the site of the organ of origin.

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Zhou, BB., Zhang, H., Damelin, M. et al. Tumour-initiating cells: challenges and opportunities for anticancer drug discovery. Nat Rev Drug Discov 8, 806–823 (2009). https://doi.org/10.1038/nrd2137

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