Not all cancer cells are created equal. There are intrinsic differences among cancer cells from the same patient in terms of their ability to proliferate and form tumours in vivo.
A subset of cancer cells have the properties of cancer stem cells, which self-renew to generate additional cancer stem cells and differentiate to generate phenotypically diverse cancer cells with limited proliferative potential. Cancer stem cells are highly enriched for the ability to form tumours following transplantation relative to bulk tumour cells or non-tumorigenic cancer cells.
Cancer stem cells have been characterized in the context of human acute myeloid leukaemia, breast cancer and glioblastoma. In each case, surface markers have been identified that distinguish cancer stem cells from cancer cells with more limited proliferative potential, allowing the prospective identification of cancer stem cells.
In some cases, cancer stem cells might arise from the mutational transformation of normal stem cells, whereas in other cases mutations might cause restricted progenitors or differentiated cells to acquire properties of cancer stem cells such as self-renewal potential.
The neoplastic proliferation of cancer stem cells is likely to be driven by mutations that inappropriately activate pathways that promote the self-renewal of normal stem cells. Examples of these pathways include the WNT, and BMI1-dependent pathways that regulate the self-renewal of haematopoietic stem cells and neural stem cells.
Further characterization of cancer stem cells might lead to improved diagnostics and therapies by allowing us to better identify and target cancer stem cells. To cure cancer it is necessary to kill, differentiate or prevent the metastasis of cancer stem cells.
Why are tumours heterogeneous, in terms of cell phenotype and proliferative potential, even in cases in which all cells are derived from a single clone? Ongoing mutagenesis can partially explain this heterogeneity, but it also seems that some tumours arise from small populations of 'cancer stem cells' that give rise to phenotypically diverse cancer cells, with less proliferative potential. These cancer stem cells are likely to arise from mutations that dysregulate normal stem-cell self-renewal. Using this information, it might be possible to devise more effective therapies.
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We are grateful to N. Joseph, T. Ross, A. Dlugosz and E. Fearon for comments on the manuscript. R. P. was the recipient of a postdoctoral fellowship from the Spanish Ministry of Science and Technology and Sean Morrison is an assistant investigator of the Howard Hughes Medical Institute. We apologize to authors whose papers were not referenced due to space constraints.
Mike Clarke and Sean Morrison own stock in Cancer Stem Cell Genomics, a company that is developing products based on the use of cancer stem cells.
- STEM CELL
A self-renewing, typically multipotent, progenitor with the broadest developmental potential in a particular tissue at a particular time.
- CANCER STEM CELL
A cancer cell that has the potential to transfer disease or to form tumours following transplantation. Cancer stem cells have the potential to self-renew, forming additional tumorigenic cancer cells of similar phenotype, and to give rise to phenotypically diverse cancer cells with more limited proliferative potential.
The process by which a progenitor gives rise to daughter progenitors of equivalent developmental potential. For example, multipotent stem cells self-renew by dividing to generate one or two multipotent daughter cells.
Any cell that divides to give rise to other cells. Progenitors include both stem cells and restricted progenitors.
- PROSPECTIVE IDENTIFICATION
The ability to reliably predict which cells are stem cells and which are not in vivo or among freshly dissociated cells that have not yet been cultured. This is typically done based on surface-marker expression, such as by isolating highly purified populations of uncultured stem cells by flow cytometry.
- RESTRICTED PROGENITOR
A cell that divides to give rise to other cells, but which has a more limited developmental potential than the stem cells in the same tissue from which it arises.
- POLYCOMB FAMILY
Polycomb family members repress gene expression by assembling into multimeric protein complexes that alter chromatin structure. Polycomb family members regulate the expression of cell-cycle genes as well as HOX genes, and are known to regulate proliferation and patterning.
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