Cancer Stem Cells

Cancer is a complex heterogeneous disease whose treatment presents unique challenges. Despite recent advances, the survival of patients with solid tumors remains low when their disease is no longer organ-confined, and advanced disease stages are rarely associated with a cure. Dawood and colleagues[1] have examined a potential explanation for the difficulties encountered when treating advanced stages of cancer: the presence of cancer stem cells. In their article, the authors explore the unique properties that make cancer stem cells a source of recurrence and metastasis, examine how they differ from normal stem cells, and emphasize how their features play a role in chemoresistance. In addition, they explore various ways of identifying and treating this population of cells, including targeting cancer stem cell signaling pathways, cell surface markers, quiescence, and epigenetic mechanisms.

One characteristic that all tumors and cancer types share is that the individual cancer cells within each tumor are heterogeneous. This variability leads to differences in size, morphology, antigen expression, and membrane composition, which in turn can lead to behavioral diversity. Characteristics such as proliferation rate, cell-cell interaction, metastatic potential, and sensitivity to chemotherapy can all vary among the individual cells in a tumor. Two hypotheses have been proposed to explain the establishment and maintenance of tumor heterogeneity: the “cancer stem cell hypothesis” and the “clonal evolution model”.[2] The cancer stem cell hypothesis states that a subset of cells within a tumor have stem cell–like properties; this is similar to the concept that in a normal bodily organ, the stem cells are the source of all cells that arise in that organ. The unique characteristics of stem cells are their capacity for unlimited self-renewal and their ability to differentiate into various lineages; as a result of these characteristics, stem cells are able to give rise to all daughter cells in the organ, and can repopulate the organ in response to damage. In the context of a tumor, then, the cancer stem cells give rise to daughter cells (accounting for tumor growth), as well as giving rise to intratumoral heterogeneity. In addition, cancer stem cells, like normal stem cells, have several important properties that ensure their survival. These include resistance to toxins, often in the form of ATP-binding cassette (ABC) transporters (eg, multidrug resistance protein MDR1), which may allow them to escape cell death from standard chemotherapy agents. In addition, the plasticity of stem cells, thought to be under epigenetic control, allows the cells to alter cell surface expression of various antigens that could be targets for therapy.

The clonal evolution model postulates that cancer cells acquire many mutations over time, and that genetic drift and natural selection for the cells with the most favorable phenotype drives tumor progression.[2] Over the lifetime of a tumor, multiple mutations will occur that can alter cells and prompt them to become invasive and/or metastatic, or to become resistant to treatment, leading to recurrence.

Dawood and colleagues highlight the different clinical implications of these two models. For example, an effective treatment, based on the cancer stem cell model, would be one that specifically selects and targets the cancer stem cell subpopulation. In contrast, treatment options predicated on the clonal evolution model must select and target multiple subpopulations that are responsible for tumor progression.

As Dawood and colleagues note, there is mounting evidence for the existence of cancer stem cells, with the attendant implications for cancer therapy. However, neither the clonal evolution model nor the cancer stem cell hypothesis seems to explain all the phenomena we see in solid tumors. First of all, each model uses a different mechanism to explain tumor heterogeneity: either a program of aberrant differentiation or a Darwinian selection process produces the multitude of cell types seen in a tumor. If cancer stem cell differentiation is the primary method by which tumors develop heterogeneity, it is difficult to explain the generalized failure of epigenetic therapy in solid tumors, which would theoretically reprogram the cancer stem cells’ ability to induce differentiation. Second, the cancer stem cell hypothesis states that only a small pool of cells has the potential to be involved in this process. While the hypothesis is attractive, studies vary greatly in the frequency of putative cancer stem cells in breast tumor populations, whether identified by CD44+/CD24− or ALDH1,[3,4] suggesting that the small population model is not appropriate.

The clonal evolution model is supported by findings that various drug-resistant clones are observed after some cancer therapies, such as treatment with the alkylating agent temozolomide or the tyrosine kinase inhibitor imatinib.[5,6] In addition, several studies of various cancers have shown that the patterns of genetic alterations seen between primary tumors, metastases, and recurrences match what is expected from the process of clonal evolution. Within individual patients, most mutations in primary tumors and metastases are identical, but some are unique to each. An increasing degree of chromosomal aberration occurs during tumor progression, and recurrences contain the mutations seen in the primary tumors, along with additional ones.[7-9]

Therapeutic Implications

Distinct therapeutic strategies are suggested by the cancer stem cell hypothesis and the clonal evolution model. According to the cancer stem cell hypothesis, killing the rare cancer stem cells that fuel tumor growth will cause tumors to be unable to propagate and will cure disease. Yet standard chemotherapy agents are able to eliminate widespread micrometastasis in early-stage breast cancer, and this would not be expected if a drug-resistant population of cancer stem cells was responsible for future tumor growth. This observation is more supportive of the clonal evolution model than of the proposition that a small drug-resistant subpopulation generates metastases as time passes.

Conclusions

As suggested by Polyak, it is likely that tumor heterogeneity and drug resistance are governed by a clonal evolution model that incorporates some features of the cancer stem cell hypothesis.[2] Tumor initiation may take place in a normal stem or progenitor cell, and the resulting cancer cell may self-renew and undergo a combination of differentiation and clonal selection, driven by the microenvironment and mutations, and producing a variety of genetically and developmentally distinct tumor cells. Some differentiated cells may have less proliferative potential, while some mutated cells may acquire self-renewal capacity, a higher proliferation rate, and other cancer-promoting traits. Perhaps a better framework for this joint process is suggested by Donnenburg et al,[9] whereby cancer stem cells are not a unique population but a “state” that is fluid within the tumor environment. This approach incorporates both the clonal evolution and the cancer stem cell models in a dynamic process that involves both.

The cancer stem cell hypothesis has generated much enthusiasm recently and is therefore the focus of study; however, there are still questions concerning its actual role in cancer. Treatments that target cancer stem cells have been proposed as alternatives to current cancer therapies. However, the clonal evolution model suggests that multiple tumor cell populations may need to be targeted for these treatments to be successful. It is likely that both are required. For instance, in breast cancer, a combination of drugs directed against cancer CD44+/ALDH1 and CD24+ cells may be most effective. Treatments that target only cancer CD44+ cells and that do not eradicate cancer CD24+ cells are less likely to work. Since mutations that lead to drug resistance may occur partway through tumor progression in the clonal evolution model, early intervention may be an especially important facet of treatment if this idea is correct. Because of the great interest in understanding more aspects of cancer stem cell biology, these challenges are being addressed-in the hope that doing so will help in the fight against the devastating disease that we face.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

References:

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2. Campbell LL, Polyak K. Breast tumor heterogeneity: cancer stem cells or clonal evolution? Cell Cycle. 2007;6: 2332-8.

3. Al-Hajj M, Wicha MS, Benito-Hernandez A, et al. Prospective identification of tumorigenic breast cancer cells. Cell Biol. 2003;100: 3983-8.

4. Ginestier C, Hur MH, Charaffe-Jauffret E, et al. ALDH1 is a marker of normal and malignant human mammary stem cells and predictor of poor clinical outcome. Cell Stem Cell. 2008;1: 555-67.

5. Swords R, Quinn J, Fay M, et al. CML clonal evolution with resistance to single agent imatinib therapy. Clin Lab Haematol. 2005; 27:347-9.

6. Hunter C, Smith R, Cahill DP, et al. A hypermutation phenotype and somatic MSH6 mutations in recurrent human malignant gliomas after alkylator chemotherapy. Cancer Res. 2006; 66:3987-91.

7. Wang E, Voiculescu S, Le Poole IC, et al. Clonal persistence and evolution during a decade of recurrent melanoma. J Invest Dermatol. 2006;126:1372-7.

8. Takahashi K, Kohno T, Matsumoto S, et al. Clonal and parallel evolution of primary lung cancers and their metastases revealed by molecular dissection of cancer cells. Clin Cancer Res. 2007;13:111-20.

9. Navin N, Kendall J, Troge J, et al. Tumour evolution inferred by single-cell sequencing. Nature. 2011;472:90-4.

10. Donnenberg AD, Hicks JB, Wigler M, Donnenberg VS. The cancer stem cell: cell type or cell state? Cytometry A. 2013;83:5-7.