Cancer Stem Cells


Cancer stem cells (CSCs) are the pathological counterpart of normal somatic tissue stem cells. They possess the capacities to self‐renew and to generate a more differentiated, rapidly dividing and expanding tumour progeny. Although they constitute just a small percentage of the tumour mass, they are responsible for its maintenance and, therefore, they should be the target of anticancer treatments. The existence of CSCs is still a matter of controversy for certain tumour types – some of which are actually frequent and clinically relevant – but it is confirmed in many others. Moreover, CSCs are predictably genetically diverse, and their frequency and phenotype can vary in the course of the disease. However, CSCs have nowadays been identified in almost all the frequent types of tumours, and recent findings have shown that CSC gene expression signatures can be predictive of adverse clinical outcome, therefore maintaining the study of CSCs at the forefront of cancer research.

Key Concepts:

  • Not all the cells within the tumour are equally capable of regenerating the tumour, either in transplantation experiments or in patient's relapse after surgery and treatment.

  • Cancer stem cells (CSCs) are the only cells within the tumour with the capacity to maintain and regenerate the tumour, and are responsible for cancer relapse.

  • Tumours are therefore stem cell‐maintained tissues, like many other tissues in the organism.

  • Understanding the biology of CSCs, their origin, evolution and molecular characteristics, should help us to design CSC‐specific therapies that should complement current anticancer treatments, mainly aimed at the reduction of the tumour mass composed, for the most part, of nonself‐renewing cells.

Keywords: stem cells; cancer; solid tumours; leukaemia; mouse models

Figure 1.

Traditional cancer theories versus CSC theory. (a) Traditional view of cancer as a disease of abnormal proliferation where cells divide in an uncontrolled fashion. Divisions are symmetrical, daughter cells are identical. According to this model, each cell in the tumour mass should be equally capable of regenerating a new tumour in an empty host. However, upon injection of a single tumour cell, although potentially initial engraftment might happen, experimentally there is neither cancer formation nor capability of serial transplantation unless a certain minimum number of cells are injected. This required number would be dependent on the percentage of CSCs present in the tumour of origin. (b) CSC theory. Cancer as a hierarchically organised tissue originated and maintained by CSCs. These cells can divide asymmetrically, giving rise to a new CSC maintaining stem properties and another transit‐amplifying cell with no stem potential but with high proliferative capacity. These cells will expand, differentiate to a certain extent and constitute the majority of the tumour mass. Cells from the differentiated pool lack the capacity to regenerate cancer in a new host. One single cell from the CSC pool is able to recapitulate all the tumour features and give rise to a complete tumour upon transplantation (even serialy). Upon injection of a certain number of nonpurified, nondiscriminated tumour cells, the tumour will only be transplanted if CSCs are injected in this mixture. The cells in the CSC pool can also divide symmetrically, giving rise to two new CSCs without necessarily having to contribute to the main tumour population.

Figure 2.

Origin of the CSCs. Within a hierarchically organised normal tissue, the acquisition by a given cell of the properties of a cancer stem cell can happen mainly via two possible mechanisms. (1) If the cancer‐inducing genetic defect occurs in a differentiated cell without stem properties, there are two possible scenarios, depending on the interactions between the cell phenotype and the new properties that the oncogenic mutations are able to confer. If the genetic defect cannot confer stem cell properties to the target cell, then there is no long‐term self‐renewal of the clone and no tumour will arise. If the genetic defect can, however, endow stem cell properties to the target cell, then a new functional CSC is generated that will give rise to a new tumour composed by a population of proliferating cells unable to terminally differentiate that is maintained by the CSC. (2) If the cancer‐inducing genetic defect occurs in a stem cell, then no additional requirements are needed, since the cell already possesses all the necessary capabilities to function as the stem cell of the tumour.

Figure 3.

Searching for CSC‐specific targets. To specifically destroy CSCs without having harmful side‐effects it is necessary to find molecular targets than can distinguish them from normal somatic tissue stem cells. One possible way to do this is to purify normal stem and CSC populations, both from human tumours or from CSC‐based animal models of cancer and to compare them at all the levels (genetic, epigenetic, transcriptional and translational profiles) and study the differences between them in order to find targets that can potentially serve for diagnosis, prognosis and/or treatment.



Al‐Hajj M, Wicha MS, Benito‐Hernandez A, Morrison SJ and Clarke MF (2003) Prospective identification of tumorigenic breast cancer cells. Proceedings of the National Academy of Sciences of the USA 100: 3983–3988.

Ben‐Porath I, Thomson MW, Carey VJ et al. (2008) An embryonic stem cell‐like gene expression signature in poorly differentiated aggressive human tumors. Nature Genetics 40(5): 499–507.

Bonnet D and Dick JE (1997) Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nature Medicine 3: 730–737.

Cairns J (1975) Mutation selection and the natural history of cancer. Nature (London) 255: 197–200.

Chabner BA and Roberts TG Jr (2005) Timeline: chemotherapy and the war on cancer. Nature Reviews Cancer 5: 65–72.

Clevers H (2005) Stem cells, asymmetric division and cancer. Nature Genetics 37: 1027–1028.

Cobaleda C, Gutierrez‐Cianca N, Perez‐Losada J et al. (2000) A primitive hematopoietic cell is the target for the leukemic transformation in human Philadelphia‐positive acute lymphoblastic leukemia. Blood 95: 1007–1013.

Cobaleda C and Sánchez‐García I (2009) B‐cell acute lymphoblastic leukaemia: towards understanding its cellular origin. Bioessays 31(6): 600–609.

Corbin AS, Agarwal A, Loriaux M et al. (2011) Human chronic myeloid leukemia stem cells are insensitive to imatinib despite inhibition of BCR‐ABL activity. Journal of Clinical Investigation 121(1): 396–409.

Dick JE (2009) Looking ahead in cancer stem cell research. Nature Biotechnology 27: 44–46.

Eppert K, Takenaka K, Lechman ER et al. (2011) Stem cell gene expression programs influence clinical outcome in human leukemia. Nature Medicine 17(9): 1086–1893.

Etzioni R, Urban N, Ramsey S et al. (2003) The case for early detection. Nature Reviews Cancer 3: 243–252.

Fialkow PJ, Jacobson RJ and Papayannopoulou T (1977) Chronic myelocytic leukemia: clonal origin in a stem cell common to the granulocyte, erythrocyte, platelet and monocyte/macrophage. American Journal of Medicine 63: 125–130.

Graham SM, Jorgensen HG, Allan E et al. (2002) Primitive, quiescent, Philadelphia‐positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 99: 319–325.

Hamburger A and Salmon SE (1977) Primary bioassay of human myeloma stem cells. Journal of Clinical Investigation 60: 846–854.

Huntly BJ, Shigematsu H, Deguchi K et al. (2004) MOZ‐TIF2, but not BCR‐ABL, confers properties of leukemic stem cells to committed murine hematopoietic progenitors. Cancer Cell 6: 587–596.

Jamieson CH, Ailles LE, Dylla SJ et al. (2004) Granulocyte‐macrophage progenitors as candidate leukemic stem cells in blast‐crisis CML. New England Journal of Medicine 351: 657–667.

Kikushige Y, Ishikawa F, Miyamoto T et al. (2011) Self‐renewing hematopoietic stem cell is the primary target in pathogenesis of human chronic lymphocytic leukemia. Cancer Cell 20: 246–259.

Knoblich JA (2010) Asymmetric cell division: recent developments and their implications for tumour biology. Nature Reviews Molecular Cell Biology 11: 849–860.

Merlos‐Suárez A, Barriga FM, Jung P et al. (2011) The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell 8(5): 511–524.

Morrison SJ and Kimble J (2006) Asymmetric and symmetric stem‐cell divisions in development and cancer. Nature 441: 1068–1074.

Pérez‐Caro M, Cobaleda C, González‐Herrero I et al. (2009) Cancer induction by restriction of oncogene expression to the stem cell compartment. EMBO Journal 28: 8–20.

Quintana E, Shackleton M, Foster HR et al. (2008) Efficient tumour formation by single human melanoma cells. Nature 456: 593–598.

Rosen JM and Jordan CT (2009) The increasing complexity of the cancer stem cell paradigm. Science 324: 1670–1673.

Saito Y, Uchida N, Tanaka S et al. (2010) Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nature Biotechnology 28: 275–280.

Sánchez‐García I, Vicente‐Dueñas C and Cobaleda C (2007) The theoretical basis of cancer‐stem‐cell‐based therapeutics of cancer: can it be put into practice? BioEssays 29: 1269–1280.

Sánchez‐García I (2009) The crossroads of oncogenesis and metastasis. New England Journal of Medicine 360: 297–299.

Shackleton M, Quintana E, Fearon ER and Morrison SJ (2009) Heterogeneity in cancer: cancer stem cells versus clonal evolution. Cell 138(5): 822–829.

Shats I, Gatza ML, Chang JT et al. (2011) Using a stem cell‐based signature to guide therapeutic selection in cancer. Cancer Research 71(5): 1772–1780.

Singh SK, Hawkins C, Clarke ID et al. (2004) Identification of human brain tumour initiating cells. Nature 432: 396–401.

Somervaille TC, Matheny CJ, Spencer GJ et al. (2009) Hierarchical maintenance of MLL myeloid leukemia stem cells employs a transcriptional program shared with embryonic rather than adult stem cells. Cell Stem Cell 4(2): 129–140.

Vicente‐Dueñas C, Cobaleda C, Pérez‐Losada J and Sánchez‐García I (2010) The evolution of cancer modeling: the shadow of stem cells. Disease Models & Mechanisms 3(3–4): 149–155.

Yilmaz OH, Valdez R, Theisen BK et al. (2006) Pten dependence distinguishes haematopoietic stem cells from leukaemia‐initiating cells. Nature 441: 475–482.

Further Reading

Castellanos A, Vicente‐Dueñas C, Campos‐Sánchez E et al. (2010) Cancer as a reprogramming‐like disease: implications in tumor development and treatment. Seminars in Cancer Biology 20(2): 93–97.

Clevers H (2011) The cancer stem cell: premises, promises and challenges. Nature Medicine 17: 313–319.

Dalerba P, Cho RW and Clarke MF (2007) Cancer stem cells: models and concepts. Annual Review of Medicine 58: 267–284.

Dick JE (2008) Stem cell concepts renew cancer research. Blood 112: 4793–4807.

Fuchs E, Tumbar T and Guasch G (2004) Socializing with the neighbours: stem cells and their niche. Cell 116: 769–778.

Huff CA, Matsui W, Smith BD and Jones RJ (2006) The paradox of response and survival in cancer therapeutics. Blood 107: 431–434.

Li F, Tiede B, Massague J and Kang Y (2007) Beyond tumorigenesis: cancer stem cells in metastasis. Cell Research 17: 3–14.

Perez‐Caro M and Sanchez‐Garcia I (2006) Killing time for cancer stem cells (CSC): discovery and development of selective CSC inhibitors. Current Medicinal Chemistry 13: 1719–1725.

Rangarajan A and Weinberg RA (2003) Opinion: comparative biology of mouse versus human cells: modelling human cancer in mice. Nature Reviews Cancer 3: 952–959.

Reya T, Morrison SJ, Clarke MF and Weissman IL (2001) Stem cells, cancer, and cancer stem cells. Nature 414: 105–111.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Cobaleda, C, Vicente‐Dueñas, C, Romero‐Camarero, I, and Sánchez‐García, I(Jan 2012) Cancer Stem Cells. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0020860.pub2]