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Tumour stem cells and drug resistance

Key Points

  • Stem-cell populations have been identified in a range of haematopoietic and solid tumours, and might represent the cell of origin of these tumours.

  • Normal and cancer stem cells express high levels of ATP-binding cassette (ABC) transporters, such as ABCB1, which encodes P-glycoprotein, and the half-transporter ABCG2, which was originally identified in mitoxantrone-resistant cells.

  • The drug-transporting property of stem cells conferred by ABC transporters is the basis for the 'side-population' phenotype that arises from the exclusion of the fluorescent dye Hoechst 33342.

  • Cancer stem cells are likely to share many of the properties of normal stem cells that provide for a long lifespan, including relative quiescence, resistance to drugs and toxins through the expression of several ABC transporters, an active DNA-repair capacity and a resistance to apoptosis. Therefore, tumours might have a built-in population of drug-resistant pluripotent cells that can survive chemotherapy and repopulate the tumour.

Abstract

The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters have been shown to protect cancer stem cells from chemotherapeutic agents. Gaining a better insight into the mechanisms of stem-cell resistance to chemotherapy might therefore lead to new therapeutic targets and better anticancer strategies.

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Figure 1: Cancer stem cells and tumour progression.
Figure 2: Models of tumour drug resistance.
Figure 3: Mouse models for testing tumour-stem-cell therapies.

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Correspondence to Michael Dean.

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DATABASES

Entrez Gene

ABCB1

ABCC1

ABCG2

ABL

BCR

CD133

HH

PTCH

National Cancer Institute

breast cancer

chronic myelogenous leukaemia

renal-cell cancer

OMIM

nevoid basal-cell carcinoma syndrome

FURTHER INFORMATION

ABC transporters

Glossary

TERATOCARCINOMAS

Malignant germ-cell tumours that exhibit cell phenotypes that are derived from more than one of the three primary germ-cell layers (endoderm, mesoderm, ectoderm).

BLAST CRISIS

In patients with chronic myelogenous leukaemia, this term describes the progression of the disease to an acute advanced phase, evidenced by an increased number of immature white blood cells in the circulating blood.

MULTIDRUG RESISTANCE

Simultaneous resistance to several structurally unrelated drugs that do not necessarily have a common mechanism of action.

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Dean, M., Fojo, T. & Bates, S. Tumour stem cells and drug resistance. Nat Rev Cancer 5, 275–284 (2005). https://doi.org/10.1038/nrc1590

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  • DOI: https://doi.org/10.1038/nrc1590

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