Are Cancer Stem Cells Ready for Prime Time?

By Suling Liu, Hasan Korkaya, and Max S. Wicha | April 1, 2012

Inthe 30-year battle waged since the initiation of the war on cancer, there have been substantial victories, with cures for childhood malignancies among the most important. Our ever-expanding understanding of cellular and molecular biology has provided substantial insights into the molecular underpinnings of the spectrum of diseases we call cancer. Yet, while researchers view this as tremendous progress, many patients have seen only limited improvement. In fact, the relatively modest gains achieved in treating the most common malignancies have caused some to say that we are actually losing the war on cancer.

Based on new intelligence, oncologists are making informed battle plans to attack a particularly pernicious enemythe cancer stem cell. Controversial though they are, cancer stem cells are an incredibly promising target. If treatment-resistant cancer, and the metastases that transplant the cancer throughout the body, could be attributed to the actions of a single cell type, it could explain many of the treatment failures and provide a novel way to attack the disease.

The idea that cancers are driven by cells with embryonic features is an old one. Many cancers regress to a less differentiated state, expressing proteins that are usually expressed only in the embryo or during early development. It is only in the past 20 years or so, however, that additional observations led to the hypothesis that these embryonic-like cells were a separate subpopulation that fueled tumor expansion, much the same way that stem cells churn out the cells that make up a particular organ.

A number of groups, including our own, have identified cancer stem cell markers enabling the isolation and characterization of these cells. In addition, the development of in vitro and mouse functional assays has led to a veritable explosion of research on cancer stem cells from both blood-derived malignancies and solid tumors., However, the limitations of these markers and assays have generated heated debate regarding which tumors follow a stem cell model, and which do not. New data from our lab and from others is helping to clarify some of these areas of debate with the goal of better understanding how these cells can be identified and characterized.

A cancer stem cell (CSC) is defined as a cell that has the ability to self-renew, dividing to give rise to another malignant stem cell, as well as to produce the phenotypically diverse, differentiated tumor cells that form the bulk of the tumor. Evidence for CSCs was first documented in leukemia, where it was clear that only a small subset of cancer cells was capable of perpetuating the cancer upon serial transplantation from one mouse to another. Extensive knowledge of normal blood stem cells facilitated our recognition and understanding of leukemia stem cells. Evidence for CSCs in solid tumors has been more controversial, because it is more technically challenging to divide a solid mass into individual cells without damage or alteration, and knowledge of the properties of normal-tissue stem cells in these organs is more limited. However, some of the areas of contention may be resolved by continuing research into the biology of these CSCs.

Relatively modest gains achieved in treating the most common malignancies have caused some to say that we are actually losing the war on cancer.

One of the points of confusion in CSC biology is the question of where these cells come from. Do they arise from normal stem cells that have become cancerous through mutation, or do they arise from partially differentiated tissue-progenitor cells that have acquired the ability to self-renew? Recent evidence suggests CSCs may arise from either source.

A second misconception is that the definition of CSCs precludes the possibility that cancers arise from sequential mutations that accumulate over many cell generations and are selected for through a Darwinian processthe so-called clonal evolution model. Some have proposed that the CSC model is a competing theory of carcinogenesis. In fact, both models may be correct. There is evidence that CSCs may also be genetically unstable, resulting in clonal evolution that generates several distinct CSC clones in a tumor.

While the identification of CSC markers and the development of in vitro and mouse models have led to important advances in the field, each of these markers and models has limitations that have fueled debate. Markers used to isolate cancer stem cells, such as CD44, CD24, CD133, aldehyde dehydrogenase (ALDH), and Hoechst dye exclusion, have proven useful for identifying these cell populations in tumor samples. However, expression of these markers is highly dependent on experimental conditions such as culture medium and oxygen concentration. Similarly, in vitro assays that rely on the ability to form spherical colonies in suspension can be useful, but are notoriously inaccurate. Since the definition of CSCs is ultimately an operational one, the most reliable assay for these cells has been their ability to initiate tumors when transplanted into mouse models. Because the immune system will reject any implanted foreign tissue, researchers have had to use immunosuppressed mice to test for human CSCs. In some tumor types, such as melanoma, the proportion of cells capable of initiating tumors is dependent on the degree of immunosuppression in the mouse models utilized. However, the more immunosuppressed mouse models may actually overestimate the true frequency of CSCs.

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Are Cancer Stem Cells Ready for Prime Time?