Since the rediscovery of the cancer stem cell hypothesis by Peter Dirks at the University of Toronto, researchers often use these cancer stem cells (or cancer initiating cells) as the scapegoat to explain why cancers are so hard to treat.

While scientists have yet to pinpoint the exact identity and origin of cancer stem cells, the general verdict in the cancer research community is that cancer stem cells are the guilty masterminds for the deadly progression of aggressive cancers. A well-accepted theory, coined the “cancer stem cell hypothesis” nearly 50 years ago, suggest that cancer stem cells are the “bad seeds” giving rise to cellular heterogeneity, aggressiveness and treatment resistance of most cancers. Indeed, many speakers in cancer research conferences are giving the impression that therapeutic strategies geared towards killing “cancer stem cells” would lead to more treatment outcomes in most aggressive cancers in the clinic.

However, as researchers unravel the complex cell biology of cancer, it is apparent that the cancer stem cell hypothesis is a working hypothesis that needs to be continually refined as research progresses.

The cancer stem cell hypothesis was originally based on studies in the late 1940s by Charles Phillipe Leblond, a professor of anatomy at McGill University, who first discovered the presence of stem-like cancer cells in leukemia that was dubbed the “leukemia stem cells”. With the new radiolabeling technique at the time, Dr. Leblond traced the small population stem-like cancer cells and found that they were capable of giving rise to differentiated cancer populations in leukemia.

This finding soon lead to a wave of studies in the last 50 years to look for these elusive stem-like cancer cells in various cancers including brain, breast and colon cancers (Reviewed in Ailles&Wiessman, 2007). Of particular interest is the 2004 study by Dr. Peter Dirks, who used advanced stem cell technology of this decade to “rediscover” cancer stem cells. Specifically, Dr. Dirks was the first to show direct evidence that cancer stem cells are capable of self-renewal and multi-lineage differentiation, generating tumors that strongly recapitulate the parental tumor from which they were derived. These results clearly supported the role of cancer stem cells as the initiator of tumor progression.

But as scientists recently begin to uncover the complex cell biology of cancers, many groups soon discovered that cancer stem cells are not the only ones that can give rise to the aggressive phenotypes in cancers (Soeda et al., 2009; Read et al., 2009). These discoveries began to sow doubt into the cancer stem cell hypothesis, causing much debate that questions the existence of cancer stem cells and their significance in tumor progression.

So, what exactly are cancer stem cells?

Pioneers have classified cancer stem cells generically as a small population of CD133 expressing cells that demonstrate stem-cell features such as their ability to grow as spheres in suspension culture. Importantly, these CD133-positive cells demonstrate robust tumor initiating abilities even with serial transplantation (Singh et al., 2004), and so are dubbed tumor-initiating cells. However, later studies revealed many other CD133 negative cell populations that make up the bulk of the tumor are also capable of tumor initiation.

Remarkably, a recent study by Robert Weschler-Reya at Duke University has identified a tumor-initiating cell population that strangely enough do not have the stem-like properties normally seen in cancer stem cells, namely the ability to grow spheres in suspension culture (Read et al., 2009). Clearly, tumor initiation is not a property exclusive to cancer stem cells, but rather applies to certain populations of non-stem cancer cells that make up the tumor mass.

These disparaging results have created much contention among tumor cell biologists, and caused considerable indecision about the validity of the cancer stem cell hypothesis. Over the years, accumulating evidence supporting or casting doubt to the cancer stem cell hypothesis has divided the scientific community into supporters and skeptics of this concept.

Supporters of the cancer stem cell hypothesis are generally those who continue use cancer stem cells as the scapegoat for the cancer initiation, aggressive progression and even tumor resistance and recurrence. In light of studies by Robert Weschler-Reya (Read et al., 2009), researchers have recognized that cancer stem cells does not comprise of only CD133+ population, but also a heterogeneous CD133- population expressing a wide range of markers (Soeda et al., 2009). A recent study published in Cell by Chen et al (2010) presented compelling evidence that cancer stem cells are organized in a 3-tiered hierarchy similar to endogenous stem cells, where “stem cells” higher up in the hierarchy could differentiate into a more lineage restricted progenitor populations at the bottom of the hierarchy.

The authors further observed that cancer stem cells higher up in the hierarchy are generally slow-dividing sphere forming cells, but gives rise to expansive infiltrative tumor growth in vivo that is well-correlated with high tumor grade. On the other hand, progenitor populations at the bottom of the hierarchy generally divide faster, but produce slower and less expansive tumor growth in vivo that is correlated with low tumor grade.

Based on this study, it was generally agreed that cancer stem cells is organized into a hierarchy consisting of cancer “stem cells” at the top of hierarchy capable of sphere formation such as those identified by Singh et al (2004), and cancer “progenitor cells” lower in the hierarchy similar to the CD15+ cells (Read et al., 2009) that are incapable of sphere formation but still retain the ability to initiate tumors.

Skeptics on the other hand responded to the above studies by presenting an alternative hypothesis called the clonal evolution hypothesis, which suggests that all cancer cells could initiate tumor formation, and that the cancer stem cells are only a product of the profound genomic instability of cancer cells. Triggers of genomic instability could arise from the dysfunctional DNA repair machinery and mitotic checkpoints in cancer cells, causing random mutations to emerge in the genome. In a recent study, Liang et al (2009) demonstrated for the first time that drug induced genomic instability in cancer cells can drive the emergence of CD133+ cancer stem cells. Along the same vein, studies by Sharma et al (2010) published this April’s issue of Cell revealed that these cancer stem cell populations are not a fixed population, but rather a volatile population arising from the profound epigenetic instability of cancer cells.

Specifically, they demonstrated that cancer cell stemness and concomitant resistance to chemotherapy can be turned on and off through DNA methylation, a process through which gene expression is regulated by chemical modification of the chromatin structure. This result suggests that the tumor stem cell phenotype is highly volatile, and can emerge from seemingly non-stem cancer cells. Overall, the inherent genomic instability of cancer cells enables them to change their phenotype in adaptive response to environmental pressures and/or anti-cancer treatments.
With strong evidence supporting both the cancer stem cell and clonal evolution hypotheses, it is apparent that both theories need not be disparate but could be merged together to paint a more concise role of cancer stem cells. So, what story does the current data present? First, true to the clonal evolution model, the emergence of cancer stem cells is the result of the inherent genomic and epigenetic instability of cancer cells in response to selective pressures in vivo. However, true to the cancer stem cell hypothesis, the CSCs (including cancer “progenitors”) can undergo continuous self-renewal and multi-lineage differentiation to produce heterogeneous cell populations that make up the tumor mass. Lastly, the common ground for both hypotheses is the undeniable role of CSCs not only in the malignant progression of tumors, but also in the development of tumor resistance to conventional therapy.

Overall, the current evidence suggest that cancer stem cells are probably not the guilty “masterminds” of cancer initiation and aggressive progression. Rather, they might be simply “accessories in crime” that enable most tumors to undergo malignant progression, and to resist conventional anti-cancer treatments.

It is apparent that the execution of cancer stem cells may not completely eliminate the tumor as the root of the problem may not be the presence of cancer stem cells per se, but the inherent genomic and epigenetic instability of cancer cells from which cancer stem cells arise.

Future studies should be focused on combating the genomic and epigenomic instability of cancer cells, rather than gearing towards specifically cancer stem cells.


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Ailles, L.E., Weissman, I.L. 2007. Curr Opin Biotechnol. 8, 460-6.
Read, T.A., et al., Cancer Cell, 2009. 15, 135-47.
Soeda, A., et al., Oncogene, 2009. 28, 3949-59
Liang, Y., et al., J Biol Chem. 285, 4931-40.
Sharma, S.V., et al., Cell. 2010. 141, 69-80.
Chen, R., et al. Cancer Cell. 2010. 17, 362-75.