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Cancer stem cells in solid tumours: accumulating evidence and unresolved questions

Key Points

  • The cancer stem cell (CSC) hypothesis is an attractive model to account for the functional heterogeneity that is commonly observed in solid tumours. It proposes a hierarchical organization of cells within the tumour, in which a subpopulation of stem-like cells is responsible for sustaining tumour growth.

  • The first evidence for CSCs came from acute myeloid leukaemia. There is now increasing evidence for CSCs in a variety of solid tumours (both mouse and human), provided through transplantation studies using prospectively isolated tumour cells.

  • The frequency of CSCs in solid tumours is highly variable, reflecting biological variation as well as technical issues. Technical issues include the purity of solid tumour cell fractionation, the requirement for more definitive markers and the challenges associated with xenotransplantation. Ultimately it will be necessary to study CSCs and potential heterogeneity within this population at a clonal level through 'cell tagging'.

  • Not all solid tumours will follow the CSC model of heterogeneity. Some may conform to the clonal evolution model, in which a dominant population of proliferating cells drives tumorigenesis.

  • Metastatic CSCs may exist, with properties distinct from primary CSCs.

  • The concept of CSCs has significant clinical implications: CSCs have been shown to be more resistant to chemotherapy and radiotherapy.

  • Recent reports, primarily for haematopoietic malignancies, suggest that CSCs can be selectively targeted without ablating normal stem cell function.

Abstract

Solid tumours are an enormous cancer burden and a major therapeutic challenge. The cancer stem cell (CSC) hypothesis provides an attractive cellular mechanism to account for the therapeutic refractoriness and dormant behaviour exhibited by many of these tumours. There is increasing evidence that diverse solid tumours are hierarchically organized and sustained by a distinct subpopulation of CSCs. Direct evidence for the CSC hypothesis has recently emerged from mouse models of epithelial tumorigenesis, although alternative models of heterogeneity also seem to apply. The clinical relevance of CSCs remains a fundamental issue but preliminary findings indicate that specific targeting may be possible.

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Figure 1: Two models for tumour heterogeneity and propagation.
Figure 2: Evolution of a metastatic cancer stem cell (CSC).
Figure 3: Ex vivo and in vivo assays for tumour cells.
Figure 4: Reciprocal interactions between the cancer stem cell (CSC) and its microenvironment or niche.

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Acknowledgements

We sincerely apologize to those authors whose papers we could not cite owing to space constraints. We are grateful to J. Adams for discussions and P. Maltezos for expert help with the figures. This work was supported by the Victorian Breast Cancer Research Consortium and the National Health and Medical Research Council (Australia). We also acknowledge support from the National Breast Cancer Foundation (Australia), the Susan G. Komen Breast Cancer Foundation, the US Department of Defense, the Australian Stem Cell Centre and the Australian Cancer Research Foundation.

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Correspondence to Jane E. Visvader.

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DATABASES

National Cancer Institute

breast cancer

colon cancer

ependymomas

glioblastoma multiforme

glioma

lung cancer

medulloblastoma

melanoma

ovarian cancer

pancreatic carcinoma

prostate cancer

teratoma

National Cancer Institute Drug Dictionary

bevacizumab

cisplatin

cyclophosphamide

doxorubicin

epirubicin

gemcitabine

rapamycin

temozolomide

verapamil

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Glossary

Tumour xenograft

Owing to the limited amount of tumour material it is necessary to establish xenografts. This involves limited passaging of the tumour, preferably in an orthotopic location, in immunocompromised mice such as NOD-SCID strains. The validity of using xenografts has been documented for many different tumour types. The engraftment rate can be variable, dependent on the tumour type.

Non-adherent sphere

Both normal and cancerous cells from numerous organs can be expanded as non-adherent sphere-like cellular aggregates in serum-free media containing EGF and FGF2.

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Visvader, J., Lindeman, G. Cancer stem cells in solid tumours: accumulating evidence and unresolved questions. Nat Rev Cancer 8, 755–768 (2008). https://doi.org/10.1038/nrc2499

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