Scientists have known for decades that it takes hundreds of thousands of cancer cells injected into an animal model to induce a tumor. For years, many researchers explained this observation as either a limitation of the assays ability to support tumor growth or the overall inefficiency of tumor formation.
What that data really suggest is that only a small proportion of cancer cells may actually have the capacity to form a tumor and that one must inject a large number of cells to ensure that some of those with regenerative properties will be present, said John Dick, Ph.D., from the Toronto General Research Institute in Canada, who has led the effort to identify and characterize these so-called cancer stem cells in leukemia. "There are decades of work pointing in this direction, but people just havent been talking about it in terms of cancer stem cells."
Although it is too early to say whether all or even most cancers contain stem cells, some researchers think it is likely to be a common feature of the disease. "The odds are very high that it will hold for most solid tumors and all liquid tumors," said Michael F. Clarke, M.D., of the University of Michigan Comprehensive Cancer Center, Ann Arbor.
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A decade ago, Dick and his colleagues were the first to prove the existence of cancer stem cells in acute myeloid leukemia. More recently, Clarke and his colleagues showed that there are cancer stem cells in breast tissue. (See News, Vol. 95, No. 11, p. 774, "Work on Breast Cancer Stem Cells Raises Questions About Treatment Strategies.") They found that as few as 200 human breast cancer cells expressing specific cell surface antigens induced tumor growth in a mouse model. Furthermore, when those tumorigenic cells were injected into mice, the tumors that formed contained multiple cell types, similar to the original tumor. This point, say both Clarke and Dick, is critical because it demonstrates that the injected cells are capable not only of self-renewal but also of generating a wide variety of cells, as are normal stem cells.
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The next step will be to see if these self-renewing cells can form a tumor when injected into the brains of rodentsdata that would confirm that these cells, like the breast and leukemic cells, are cancer stem cells.
Implications for Treatment
If cancer growth and metastases do rely on stem cells, as the recent work suggests, then clearing the tumor of such cells should cure the disease because the remaining cells have only limited proliferative capabilities. However, the majority of the treatments developed in recent years have been directed at rapidly dividing cells and at molecular targets that are common in the bulk of the tumor. These treatments are efficient at removing tumor mass but not at curing the disease, a fact that Dick said is consistent the stem cell theory.
"We have exquisite knowledge of signaling pathways that are disrupted in cancer," he said, but that information has been gained through biochemistry and molecular experiments that started by grinding up the whole tumor, an approach that masks information on minority cell populations and heterogeneity in general.
This approach seems particularly problematic when one realizes that leukemia stem cells, which are the best characterized of the cancer stem cells thus far, are relatively quiescent and do not appear to have the hyperproliferation signals activated, such as tyrosine kinases, that are present in the bulk of the tumor. Thus, drugs that block such signaling cascades will reduce the tumor load but will not be able to clear the stem cells. That means recurrencewhich occurs frequently with current chemotherapy treatmentsis likely because it is the stem cells that escape therapy and are responsible for tumor regeneration, said Dick.
Rudolf Jaenisch, M.D., from the Whitehead Institute at MIT in Cambridge where he studies mouse models of cancer, concurs. "I think cancer stem cells are a very important new paradigm," he said. "The evidence from breast cancer and especially from leukemia tells us that the bulk of the tumor is not the problem, that it is a few cells. And the fact that they may not even be very fast growing has important implications for therapy."
If this scenario is true, then researchers need to find ways to distinguish between normal stem cells and cancerous ones, which may not be easy, say the scientists involved. In leukemia and brain cancers, the cancer stem cells express cell surface markers that resemble those of normal stem cells. This implies that cancer cells are not wildly deranged, as is often thought to be the case, but rather that the changes may be more subtle than expected. Therefore, developing therapies that can block their propagation without disrupting other stem cell populations will be a bit like threading a very fine needletheoretically possible, but difficult.
The second implication of the similarity between cancerous and normal stem cells, said Dick, is that it suggests that cancer forms when a developmentally primitive cell becomes dysregulated, rather than a differentiated one dedifferentiating or taking on new behaviors.
Treating the disease is substantially more difficult if the stem cells are the root cause of the problem because of their inherent traits, said Toru Kondo, from the University of Cambridge in the United Kingdom and Kumamoto University in Japan, where he is studying stem cells in established cancer cell lines. "There is accumulating evidence that many stem cells express various types of multidrug-resistant genes, including MDR and BCRP1, suggesting that the stem cells can pump out many kinds of anticancer drugs. Also they tend to divide slowly ... which means that the stem cells might be also resistant to irradiation and DNA-damaging reagents since they have plenty of time to repair their DNA."
Bmi-1 and Epigenetic Controls
During the time that stem cells regenerate a tumor when transferred to a new host, it is unlikely that the nontumorigenic cells that make up the bulk of the tumor take on new mutations. Therefore, the tumorigenic and nontumorigenic cells have the same genetic properties, yet the two populations have very different potentials. One possibility to explain their differential behavior then is that some nongenetic changes occur when the self-renewing population produces the rest of the cells in a new tumor. A hint to what that might be controlling these changes recently came from two separate directions.
One of the genes that appears to be a common factor in the leukemic and normal hematopoietic stem cells is Bmi-1, which is known to regulate gene expression by epigenetic mechanismschanges that regulate gene expression without affecting the genes structure, such as chromatin methylation and deacetylation. Researchers in both Clarkes laboratory and Guy Sauvageaus laboratory at the Clinical Research Institute of Montreal found that Bmi-1 is critical for both healthy and cancerous stem cell proliferation.
Meanwhile, Jim Morgan, Ph.D., and colleagues at St. Jude Childrens Research Hospital in Memphis, Tenn., found that when they removed the nucleus from a medulloblastoma cell that had developed in a mouse model and transferred it to a mouse oocytea process that resets the epigenetic controls that have accumulated during somatic developmentthe embryo developed relatively normally through early development.
"If both epigenetic and genetic changes are important for cancer and we get rid of the epigenetic changes, then it should restore some semblance of normality to the cell," said Morgan.
Although he declined to talk about it in any detail because the work is still in review, Jaenisch acknowledged that his group has performed similar experiments and has had mixed results. (He presented the work at a Keystone meeting last fall.)
These nuclear transplantation experiments not only demonstrate that epigenetic controls are critical for cancer but also provide a plausible mechanism for how cancer stem cells in a spontaneous tumor can give rise to nontumorigenic cells. It suggests, said Clarke, that epigenetic changes could be sufficient to switch off the self-renewal function of the cancer stem cells as they form the nontumorigenic cells.
Genetic Influences
There are numerous other genes that are known to be important in the regulation or maintenance of stem cells and also are implicated in cancer, such as PTEN, sonic hedge hog, Notch and WNT. These commonalities further support the idea that self-renewing cells are critical to cancer, rather than just proliferation, but the trick will be to find differences between healthy and diseased cells.
"We are still trying to figure out what is a leukemia stem cell," said Dick, likening the current situation to that of stem cell biologists studying healthy cells 20 years ago. Interestingly, his team has found that leukemia stem cells are not a homogeneous group themselves. Rather, there are long- and short-term leukemia stem cells, which again resemble the developmental pattern seen with normal stem cells.
Both his laboratory and Clarkes, as well as several others, are trying to find the distinguishing characteristics using genomics, proteomics, and genetics. One of the major questions is whether transgenic mouse models of cancer have self-renewing subpopulations or whether they are more homogeneous than naturally arising human cancers. If all of the cells are similar, then genetics will continue to be valuable; if, however, there are subpopulations, then the experiments become more difficult.
"There has been a lot of important work that has gone on in terms of identifying cancer pathways and identifying potential therapeutic targets in many different systems and organ systems and cancers," concluded Dick. "Now people need to take into account the functional heterogeneity that likely exists between those tumors so that ultimately the focus can be on the most primitive cells within the tumor that have the ability to sustain that tumor and need to be eradicated to cure it."
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