The Stem Cells That Promise No Miracles

Author:  Jiang Dennis
Date:  March 2008

Stem cells have recently been heralded as being the key to ending a great number of the world's maladies. Stem cells' functions range from tissue repair to the formation of the entire human body. Most stem cell research presently focuses on harnessing the powers of stem cells and using their plasticity to create new cells to replace damaged ones. Once this is realized, many degenerative diseases as we know them will probably be history. However, the pessimists amongst us have long suspected that this was all too good to be true. What happens when these miracle cells stop working properly? Cancer.

Cancer stem cells (top) looks and behaves almost exactly like normal stem cells (above). Image Courtesy of Union-Tribune

Cancer stem cells (top) looks and behaves almost exactly like normal stem cells (above). Image Courtesy of Union-Tribune

The Hypothesis

Most people think that when cells go bad, they become cancerous. For years, the general public and the medical community have held three beliefs. Firstly, all cancer cells divide without control, secondly, tumors will get larger if untreated and finally, the only way towards complete recovery is to obliterate as many cancer cells as possible. Very often, cancer destruction has come in the form of chemotherapy. More often than not, cancer treated in this way cannot be fully cured and will resurface through time.

The discovery that cancers recur after chemotherapy has baffled scientists for quite some time. Only as recently as 1997 were scientists able to first isolate a special subpopulation of cancer cells that seem to function differently from most other cancer cells. These cells may form the tiny pool of chemically-resistant cancer cells that continuously rejuvenates the supply of cancer cells after the completion of chemotherapy.

The hypothesis is that within a solid tumor exist a heterogeneous collection of different types of cancer cells. However, not all of these cells are tumorigenic, or have the ability to form new tumors. A special group of cancer cells seems to have unique powers in that they can form two daughter cells every cell cycle creating a new non-tumorigenic cancer cell as well as a new tumorigenic cancer cell. The ability of these special cancer cells to self-renew is a hallmark of regular stem cells. Hence, scientists have designated these cells to be cancer stem cells.

The Debate

Since John Dick and colleagues at the University of Toronto first managed to identify cancer stem cells in certain types of leukemia in 1997, the field has exploded with new findings in all sorts of different cancer types providing support for the stem cell hypothesis. In 2003, Dr. Michael Clarke, now of Stanford, succeeded in finding cancer stem cells in breast tumors. After transplanting numerous populations of cells from human breast tumors into immunodeficient mice, Dr. Clarke found that not all human breast cancer cells have the same capacity to generate new tumor tissue. In fact, only one subpopulation of the cells studied had the capacity to re-create the original tumor in the mice. In 2004, Dr. Peter Dirks of the University of Toronto identified cells with stemlike properties in human brain tumors, and in 2005, Dr. C. Parker Gibbs of the University of Florida reported stemlike cells in bone cancer.

"I think this is one of the most interesting developments in cancer research in the last five years," says Robert Weinberg, a cancer geneticist at the Whitehead Institute in Cambridge, Massachussets. "I think more and more people are accepting it and evidence is accumulating that cancer stem cells exist in a variety of tumors."

Gary Gilliland of Harvard agrees with Weinberg, "It's a very challenging population of cells to identify, but thus far in every cancer in which cells have been carefully screened they have been found."

Despite some strong evidence in support of the existence of cancer stem cells, some researchers are still reluctant to parallel cancer stem cells with true tissue stem cells.

"It's difficult to prove that there is a cancer stem cell because theoretically a single stem cell can reproduce an entire organ," says Dr. Benjamin Alman, a researcher of stem cell biology at the University of Toronto. "People have not shown definitively that one (cancer stem) cell can make a whole cancer. We have only seen that a population of cells has an enhanced ability to form a whole cancer."

However, the major debate isn't on whether cancer stem cells exist, but on what their significance is in terms of cancer treatment.

"It's not the idea that tumors have stem cells that is new," comments Doug Brash, a radiology and genetics researcher at Yale University. "What's really new is the idea that the tumor is . that tumors contain non-stem cells. The stem cells could be a minority of the tumor's cells, with our treatments just killing the non-stem cells."

Whether or not these cancer stem cells do form only a minority of a tumor's cells is what most researchers are concerned about and are unsure about. If they really are a minority population, then that explains how traditional chemotherapy might miss them and why new drugs may be needed to specifically target this minor group of cells. However, if further research finds that these cancer stem cells already represent the majority of a tumor's cells, then current chemotherapy methods are actually killing most of these cells and the excitement thus far would be for naught. Until results show the latter case to be true, most researchers are clinging onto the belief that cancer stem cells are in fact a minority population and that finding ways to destroy them would essentially remove cancers by their roots.

Cancer stem cells can arise from a variety of different sources. At any stage of development, mutations (lightning bolts) may accumulate enough to turn stem cells bad, or give non-stem cells stemlike abilities. Cancer stem cells may also form from the fusion of a stem cell and a mutated normal cell (not shown) Image Courtesy of Nature

Cancer stem cells can arise from a variety of different sources. At any stage of development, mutations (lightning bolts) may accumulate enough to turn stem cells bad, or give non-stem cells stemlike abilities. Cancer stem cells may also form from the fusion of a stem cell and a mutated normal cell (not shown) Image Courtesy of Nature

The Origin

Now that scientists can conclusively say that they have found a subset of cancer stem cells that seem to be responsible for the creation of new cancer cells, can they explain where these stem cells come from? Many different hypotheses have been thrown around and it seems every one of them may be valid depending on what tissue one is dealing with.

In any tissue, normal or not, there is a hierarchy of cells. Usually, a stem cell is capable of turning into any type of differentiated mature cell. They do this via a progenitor cell that is partially differentiated. With proper signals from the body, the progenitor cells will then divide to an extent and develop into terminally differentiated mature cells that are no longer capable of further division or changes. Stem cells are the only cells in this hierarchy that are capable of unlimited self-renewal and division.

A cancer stem cell may not necessarily arise from a normal stem cell, although logic would lead one to think so. Cases where normal stem cells may give rise to cancer stem cells are in tissues where the progenitor cells and the mature cells have too short of a lifespan to become cancerous, such as the skin. Otherwise, a cancer stem cell can form from the de-differentiation of progenitor cells or mature cells to regain stemlike properties. A cancer stem cell can even form when a normal stem cell fuses with a badly mutated mature cell. Regardless of the route that cells take to become stemlike, the underlying cause is always genetic mutation.

Since the origin of certain newly discovered cancer stem cells is difficult to determine, researchers would simply be better off targeting the resulting stem cells rather than trying to prevent cancer stem cells from developing in the first place.

The Detection

The reason why it took scientists until the 1990s to actually isolate cancer stem cells is because the flow cytometer, a crucial instrument that has the ability to sort different cells, was not commercially available until the 1970s. Through persistent trials and observations, researchers have realized that some cancer stem cells show unique arrays of cell surface proteins (aka cell markers) that could be labeled with fluorescent antibodies and sorted with a flow cytometer.

As useful as flow cytometers are, they do have technical limitations that do not quite permit the purification of cancer stem cells. For example, even when advanced sorting techniques are applied, doublets (cells sticking to one another) can still sort together from time to time.

Of course, there isn't presently a method that can be used to sort all cancer stem cells. Sometimes, certain cancer stem cells do not have cell markers. For these cells, flow cytometry may be effective only if the stem cells efflux certain chemical dyes differently from non-stem cells. If they don't, then new methods must be devised to separate and study these cells.

The feverfew plant contains a compound that has been shown to effectively and selectively induce cellular suicide in AML stem cells. Image Courtesy of

The feverfew plant contains a compound that has been shown to effectively and selectively induce cellular suicide in AML stem cells. Image Courtesy of

The Therapeutic Implications

It has been a decade since the first cancer stem cells were isolated and studied, what steps have researchers taken to actually kill these trouble makers? Well, it is one thing to be able to locate the source of the problem; it is another thing to be able to do something about it.

"Even if we know some cells are cancer stem cells, we don't know what makes them different from regular cells so it's hard to target them," remarks Dr. Alman. "A drug must not target normal stem cells of a similar tissue type."

What we do know is that traditional chemotherapy doesn't seem to be able to get the job done. Dr. Alman mentions that current drugs target fast growing cancer cells while cancer stem cells are slow growing cells. This may be the reason why the cancer stem cells would appear to be resistant to the drugs being used.

Once again, a plethora of hypotheses are laid out by opinionated researchers who are quick to offer cellular theories but not so quick to provide any tangible evidence. Amongst the popular routes of exploration are: training immune cells to go after cancer stem cells, using drugs to alter the microenvironment of the cancer stem cells in order to deprive them of the chemical cues required for survival, and finally using drugs to cause cancer stem cells to completely differentiate into mature cells, which would cause them to lose their ability to self-renew, and thus eventually die.

So far the only good news has come from treating acute myeloid leukemia (AML). A few different agents, one of which is a compound derived from the feverfew plant, have been identified to effectively kill these stem cells while leaving normal stem cells unaffected.

The Final Word

As thousands of researchers toil over the mysterious stem cells that hold so much promise in creating medical breakthroughs, just as many researchers are scratching their heads and pondering how to eradicate the elusive cancer stem cells that are causing havoc and nightmares in the medical community. In many ways, both types of stem cell research are intimately linked as new knowledge discovered in either field may be immensely useful in the other. The thought of having cells that are capable of forming the entire human body go astray and undeterred may be a scary one. However, the paradigm in cancer research has now shifted, and the necessary groundwork has been laid in this field in preparation for an exponential growth in research in the coming years.

* Special thanks to Jiayi Hu for contributing to this article References

Bjerkvig R, Tysnes B, Aboody K, Najbauer J, Terzis A: The origin of the cancer stem cell: current controversies and new insights. Nature 2005, 5:899-904

Clarke M, Dick J, Dirks P, Eaves C, Jamieson C, Jones D, Visvader J, Weissman I, Wahl G: Cancer Stem Cells – Perspectives on Current Status and Future Directions. Cancer Res 2006, 66:9339-9344

Huntly B, Gilliland D: Summing up cancer stem cells. Nature 2005, 435:1169-1170

Wu C, Wei Q, Utomo V, Nadesan P, Whetstone H, Kandel Ri, Wunder J, Alman B: Side Population Cells Isolated from Mesenchymal Neoplasms Have Tumor Initiating Potential. Cancer Res 2007, 67:8216-8222

Written by Dennis Jiang

Reviewed by Ben-Griffin Smith, Pooja Ghatalia

Published by Pooja Ghatalia.