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Mechanisms of Disease: cancer stem cells—targeting the evil twin

Nature Clinical Practice Oncology volume 5, pages 337–347 (2008)Cite this article

Abstract

Classical antineoplastic treatments such as chemotherapy or radiation can efficiently eradicate the majority of proliferating and genetically unstable malignant cells within neoplastic lesions. There is increasing evidence, however, that these regimens frequently fail to eliminate a minor subpopulation of resistant tumor cells that have distinct features of somatic stem cells. These serve as a reservoir for disease recurrence, and are the origin of metastatic growth. These so-called cancer stem cells (CSCs) or cancer-initiating cells represent often a rare, highly self-renewing population within the tumor mass, which is thought to be the only one required for both initiation and maintenance of disease. Tumor-cell populations enriched for CSC activity were originally identified in leukemias, but have now also been uncovered in a number of solid cancers. Their marked resistance towards classical antitumor regimens is mediated by the combination of several critical features, including relative dormancy, efficient DNA repair, high expression of multidrug-resistance-type membrane transporters and protection by a hypoxic niche environment. We review the concept of CSCs with particular emphasis on the mechanism of therapy resistance, and discuss potential future therapeutic interventions with the goal of specifically eliminating CSCs in a clinical setting.

Key Points

  • Many human neoplasms are likely to contain an often minor population of cancer cells within the tumor mass called cancer stem cells (CSCs), which are the only cells required for both initiation and maintenance of the disease

  • CSCs have unlimited self-renewal activity, and also can give rise to a large number of more-differentiated cells, which generate the bulk of the tumor

  • CSCs can either originate from normal stem cells or from more-differentiated progenitors

  • Long-lived CSCs seem to be resistant to radiation and classical chemotherapy and thus serve as an often small but highly malignant reservoir of cells

  • Due to their potential for migration and seeding in specific tissue niches, these CSCs might also drive disease recurrence and metastatic growth even after a significant latency period

  • The mechanisms that allow CSCs to escape current therapies remains to be elucidated, but are likely to be caused by several inherent features of CSCs, which include relative quiescence/dormancy, expression of multi-drug resistance transporters, localization in a protective and hypoxic niche and highly effective DNA repair mechanisms

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Figure 1: Model representing the cellular mechanisms responsible for CSC resistance towards radiation and antiproliferative chemotherapy and potential strategies to overcome such avoidance machinery.

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Acknowledgements

The authors would like to thank Dr Christelle Adolphe and Dr Anne Wilson for critical comments on the manuscript and members of the Trumpp laboratory for numerous discussions. This work was supported by grants to AT from the Swiss National Science Foundation, the Swiss Cancer League and the EU-FP6 Program “INTACT” as well as by funds from the Helmholtz association to ODW and to the DKFZ.

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Authors and Affiliations

  1. A Trumpp is Professor (PATT) and Head of the Genetics and Stem Cell Laboratory at the Ecole Polytechnique Fédérale de Lausanne, Swiss Institute for Experimental Cancer Research, School of Life Science, Epalinges, Switzerland,

    Andreas Trumpp

  2. O Wiestler is Professor and Chairman at the German Cancer Research Center, Heidelberg, Germany.,

    Otmar D Wiestler

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Correspondence to Andreas Trumpp.

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Trumpp, A., Wiestler, O. Mechanisms of Disease: cancer stem cells—targeting the evil twin. Nat Rev Clin Oncol 5, 337–347 (2008). https://doi.org/10.1038/ncponc1110

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