Cancer stem cells (CSCs) are cancer cells (found within tumors or hematological cancers) that possess characteristics associated with normal stem cells, specifically the ability to give rise to all cell types found in a particular cancer sample. CSCs are therefore tumorigenic (tumor-forming), perhaps in contrast to other non-tumorigenic cancer cells. CSCs may generate tumors through the stem cell processes of self-renewal and differentiation into multiple cell types. Such cells are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors. Therefore, development of specific therapies targeted at CSCs holds hope for improvement of survival and quality of life of cancer patients, especially for patients with metastatic disease.

Existing cancer treatments have mostly been developed based on animal models, where therapies able to promote tumor shrinkage were deemed effective. However, animals could not provide a complete model of human disease. In particular, in mice, whose life spans do not exceed two years, tumor relapse is exceptionally difficult to study.

The efficacy of cancer treatments is, in the initial stages of testing, often measured by the ablation fraction of tumor mass (fractional kill). As CSCs would form a very small proportion of the tumor, this may not necessarily select for drugs that act specifically on the stem cells. The theory suggests that conventional chemotherapies kill differentiated or differentiating cells, which form the bulk of the tumor but are unable to generate new cells. A population of CSCs, which gave rise to it, could remain untouched and cause a relapse of the disease.

Cancer stem cells were first identified by John Dick in acute myeloid leukemia in the late 1990s. As a stem cell biologist interested in blood stem cells, Dick was fortunate in his choice of cancer to study, picking one of the types where cancer stem cells have proved to have an especially important role. Since the early 2000s they have been an intense focus of cancer research[1]

In different tumor subtypes, cells within the tumor population exhibit functional heterogeneity, and tumors are formed from cells with various proliferative and differentiate capacities.[2] This functional tumour heterogeneity among cancer cells has led to the creation of at least two models, which have been put forward to account for heterogeneity and differences in tumor-regenerative capacity: the cancer stem cell (CSC) and clonal evolution models[3]

The cancer stem cell model refers to a subset of tumor cells that have the ability to self-renew and are able to generate the diverse tumor cells.[3] These cells have been termed cancer stem cells to reflect their stem-like properties. One implication of the CSC model and the existence of CSCs is that the tumor population is hierarchically arranged with CSCs lying at the apex of the hierarchy[4] (Fig. 3).

The clonal evolution model postulates that mutant tumor cells with a growth advantage are selected and expanded. Cells in the dominant population have a similar potential for initiating tumor growth[5] (Fig. 4).

[6] These two models are not mutually exclusive, as CSCs themselves undergo clonal evolution. Thus, the secondary more dominant CSCs may emerge, if a mutation confers more aggressive properties[7] (Fig. 5).

The existence of CSCs is a subject of debate within medical research, because many studies have not been successful in discovering the similarities and differences between normal tissue stem cells and cancer (stem) cells.[8] Cancer cells must be capable of continuous proliferation and self-renewal in order to retain the many mutations required for carcinogenesis, and to sustain the growth of a tumor since differentiated cells (constrained by the Hayflick Limit[9]) cannot divide indefinitely. However, it is debated whether such cells represent a minority. If most cells of the tumor are endowed with stem cell properties, there is no incentive to focus on a specific subpopulation. There is also debate on the cell of origin of CSCs - whether they originate from normal stem cells that have lost the ability to regulate proliferation, or from more differentiated population of progenitor cells that have acquired abilities to self-renew (which is related to the issue of stem cell plasticity).

The first conclusive evidence for CSCs was published in 1997 in Nature Medicine. Bonnet and Dick[10] isolated a subpopulation of leukaemic cells that expressed a specific surface marker CD34, but lacked the CD38 marker. The authors established that the CD34+/CD38- subpopulation is capable of initiating tumors in NOD/SCID mice that are histologically similar to the donor. The first evidence of a solid tumor cancer stem-like cell followed in 2002 with the discovery of a clonogenic, sphere-forming cell isolated and characterized from human brain gliomas [Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro [Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD, Steindler DA. Glia. 2002 Sep;39(3):193-206. PMID 12203386 [PubMed - indexed for MEDLINE].

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Authors Committee on the Biological and Biomedical Applications of Stem Cell Research; Commission on Life Sciences (CLS); Board on Neuroscience and Behavioral Health (NBH); Board on Life Sciences (BLS); Institute of Medicine (IOM); Division on Earth and Life Studies (DELS); National Research Council Description Recent scientific breakthroughs, celebrity patient advocates, and conflicting religious beliefs have come together to bring the state of stem cell research specifically embryonic stem cell research into the political crosshairs. President Bush s watershed policy statement allows federal funding for embryonic stem cell research but only on a limited number of stem cell lines. Millions of Americans could be affected by the continuing political debate among policymakers and the public.

Stem Cells and the Future of Regenerative Medicine provides a deeper exploration of the biological, ethical, and funding questions prompted by the therapeutic potential of undifferentiated human cells. In terms accessible to lay readers, the book summarizes what we know about adult and embryonic stem cells and discusses how to go about the transition from mouse studies to research that has therapeutic implications for people.

Perhaps most important, Stem Cells and the Future of Regenerative Medicine also provides an overview of the moral and ethical problems that arise from the use of embryonic stem cells. This timely book compares the impact of public and private research funding and discusses approaches to appropriate research oversight.

Based on the insights of leading scientists, ethicists, and other authorities, the book offers authoritative recommendations regarding the use of existing stem cell lines versus new lines in research, the important role of the federal government in this field of research, and other fundamental issues.

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Stem Cells and the Future of Regenerative Medicine