Cancer Stem Cells: Fact or Fiction?

December 26, 2008 by Caroline Brandon

In the 1960s there was an unethical experiment where physicians took cancer cells from various types of malignancies and re-injected these cells back into the original cancer patient or another non-cancerous terminally ill patient.i  The results from this experiment suggested that those with cancer lacked immunity to the disease while “healthy” individuals carried some immunity to the cancer cells. However, another interesting observation was made throughout the experiments: that it requires millions of cancer cells to initiate the growth of a tumor. It is this observation from which two theories emerged in the decades to come regarding tumor initiation and maintenance.


Traditionally, it was thought that every cell within a tumor had an equal potential to cause the disease by incurring random genetic mutations that render them cancerous. This model, termed the stochastic model of cancer, explained that though these events were rare, cells were equally susceptible to these alterations through extrinsic factors and no tumor-initiating enrichment is possible. However, in the last 15 years there is accumulating support for the cancer stem cell model, which argues that tumors exhibit a hierarchical functional organization of its cellular components where only a rare population (~0.0001-1% of bulk) of immature cells that can self-renew and differentiate, known as cancer stem cells, are responsible for initiating and maintaining the tumor. It is believed that new therapies need to target these tumor-initiating cells in order to fully eradicate the cancer. John Dick’s group at the Hospital for Sick Children in Toronto (SickKids) was the first to identify cancer stem cells in Acute Myeloid Leukemia (AML) in 1997ii.  Since then, many groups followed in solid cancers including the brain (also identified at Sickkids)iii, breastiv, and the list keeps growing.

One of the malignancies on this list is melanoma, an aggressive form of skin cancer. In January of 2008 in the top-tiered scientific journal Nature, Schatton et alv.  published the identification of melanoma initiating cells based on the presence of the protein ABCB5. Through a series of experiments involving serial transplantation of these human melanoma cancer cells into partially immunodeficient (NOD/SCID) mice, they were able to determine that only 1 in 1 million (0.0001%) human melanoma cells had tumor-initiating properties in these mice, a frequency that is consistent with the frequencies of tumor initiating cells in other tumor types transplanted into NOD/SCID mice. Recently, however, Quintana et alvi.  published an article in the same journal that questioned the assays used to identify the cancer stem cells. What they found is that by altering the transplant assay conditions by injecting cells into a more severely immunodeficient mice and adding matrigel (extracellular matrix components), the number of cells capable of tumor initiation dramatically increased to as many as 1 in 4 of the total tumor cells, suggesting it may not be a rare cancer stem cell. This is highlighted by the fact that they could inject unsorted single melanoma cells into the mice that could initiate tumors within 20 weeks and found that no specific cell surface marker combination could increase tumor-initiating frequency.

The results from this study suggest several things. First, it will be necessary to optimize the transplant assays to ensure we are studying the full array of cancer cells contributing to the progression of the disease since our previous assays using NOD/SCID mice may be underestimating the number of tumor initiating cells. Second, their findings suggest that the cancer stem cell theory might not apply to all cancers. The cancer stem cell model implies a functional hierarchy in the tumor whereby a rare subpopulation has the potential to self-renew and gives rise to the rest of the mixed cellular population found in the tumor. However, this study shows that no hierarchy could be identified as no external marker combination tested could enrich for cells with tumor initiating capacity, although they did not test for the surface marker ABCB5 that was used to identify melanoma stem cells in Schatton et al. Quintana et al. are quick to point out that this is only one specific type of aggressive cancer and that the stem cell model may still hold true for other malignancies such as leukemias. In any event, this paper will provoke many groups within the cancer stem cell field to apply this study to their own system to ensure their previous findings hold true. It is very realistic that the majority of our findings that support the cancer stem cell theory are artifacts of the NOD/SCID mouse model and that we may have to reconsider the cardinal properties that define this theory entirely. I am hopeful that from studies like this that challenge the current cancer stem cell dogma, new creative approaches will be used to uncover the true culprits behind cancer, be it a rare population of stem cells or a more common population yet to be defined.
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i Lerner, B.H. (2004) “Sins of omission—cancer research without informed consent.” New England Journal of Medicine, 351(7):628-630.

ii Bonnet, D. & Dick, J.E. (1997) “Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell.” Nature Medicine, 3(7):730-737.

iii Singh, S.K., et al. (2004) “Identification of brain tumour initiating cells.” Nature, 432(7015):396-401.

iv Al-Hajj, M., et al. (2003) “Prospective identification of tumorigenic breast cancer cells.” PNAS USA, 100(7):3983-3988.

v Schatton, T., et al. (2008) “Identification of cells initiating human melanomas.” Nature, 451(7176):345-349.

vi Quintana, E., et al. (2008) “Efficient tumour formation by single human melanoma cells.” Nature, 456(7222):593-598.

 

 

Written by Caroline Brandon · Filed Under Home Blog 1, Research 

Comments

One Response to “Cancer Stem Cells: Fact or Fiction?”

  1. american cancer research on January 4th, 2009 6:37 am

    american cancer research…

    Every year in the……

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