When a tumor shrinks in size as a result of chemotherapy, it is believed that the patient is responding to treatment. However, tumors often initially shrink in response to treatment only to recur later on, suggesting that tumor shrinkage and patient response may not exactly be synonymous. Why is this?
The answer may lie with cancer stem cells. New data published in April in the Proceedings of the National Academy of Sciences suggest that only a small minority of breast cancer cellsbreast cancer stem cellswithin a tumor are tumorigenic and thus responsible for driving tumor growth and metastasis. As a result, the bulk of a tumor is actually made up of non-tumorigenic cells, which are more susceptible to standard cancer treatments than the cancer stem cells.
If the non-tumorigenic cells are the only cells that respond to current treatments, then this may explain why tumor shrinkage does not necessarily mean patient benefit. But will this prove to be the case for all cancers? If so, how will this affect current treatment strategies?
Proof of Concept
In nine human breast tumors and metastases, Michael Clarke, M.D., professor of medicine at the University of Michigan Medical School in Ann Arbor, and colleagues identified a number of different cell populations that were based on the expression of various cell surface markers. Of these subpopulations, as few as 200 cells of one type were consistently able to form tumors in mice, whereas 20,000 cells from other populations failed to do so upon implantation.
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"This is the first time that a solid tumor cancer stem cell has been isolated and characterized," said Clarke. "These cells are the only cells with the ability to metastasize and form tumors. I think that these studies will have a fundamental impact on the study and treatment of solid tumors."
But, because the cancer stem cells were found to be the only population of cells with the ability to metastasize and form tumors, the question remained of whether they would be present in all metastatic tumors. According to Clarke, not necessarily. "Non-tumorigenic cells probably have the ability to metastasize. They just have a limited ability to proliferate. They probably can form small microscopic metastases that would eventually stop growing, and this could explain why many breast cancer patients with documented cancer cells in their bone marrow never relapse," said Clarke.
Cancer cells must undergo self-renewal to become malignant. When stem cells divide, the division can give rise to a new stem cell as well as differentiated cells of the organ or tumor. Normally, the number of normal stem cells that are present in an organ are tightly regulated, but cancer stem cells lose this regulation, giving them the ability to self-renew and constantly expand themselves. Because many oncogenic mutations target pathways that regulate proliferation and self-renewal, and because most cancers arise in tissues that contain stem cells, the authors believe that stem cells are a more likely target for transformation than progenitor cells.
"I think that all cancers will turn out to be stem cell diseases," said John Dick, Ph.D., division of cell and molecular biology, University of Toronto, Canada, who has previously demonstrated that a leukemic tumor-initiating stem cell population is responsible for establishing human acute myelogenous leukemia.
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Cancer stem cells are not to be confused with normal embryonic and adult stem cells, which are currently the topic of much ethical controversy and are being studied for their ability to replace damaged cells and tissue. So what exactly is it about these cells that sets them apart?
"Normal breast stem cells have not been isolated yet, so they have not yet been characterized," said Clarke. But normal hematopoietic stem cells have been characterized and compared to leukemic stem cells. "In the blood, the normal [hematopoietic] and leukemic stem cells share some but not all cell surface markers," said Dick. For example, the leukemic stem cells have lost expression of the cell surface marker Thy1.
"In the end, the cancer stem cell is related to but not identical to the normal counterpart," said Dick. It is predicted that similar differences will also be found in cell markers that will differentiate solid tumor stem cells from normal stem cells.
"We need to understand what the normal stem cells of a tissue look like and this can only be done with functional assaysthat is, regeneration or re-population assays. Then we are in a position to compare the equivalent cancer stem cell to determine the genetic changes that occurred," said Dick, who predicts that specific cell surface markers will be reflective of the host origin. "Stem cells from many tissues seem to exclude certain DNA dyes. This pump property might be exploited as a universal marker system."
New Therapeutic Strategies
With the ability to purify the breast cancer stem cell population, gene expression analyses can now be performed on enriched populations of these cells to aid in the identification of novel diagnostic markers and therapeutic targets. This is the approach that Clarke and colleagues are taking.
"We are interested in three general topics," said Clarke. These include understanding how self-renewal is regulated in normal stem cells and how this becomes altered in cancer; identifying new markers that allow for the easy detection of the cancer stem cells; and identifying new therapeutic targets that can be exploited to eliminate cancer stem cells from patients.
In addition to differences between normal and cancer stem cells, it also needs to be determined if there are differences within the cancer stem cell population. For example, do these cells have an internal hierarchy of cancer stem cells and therefore differing abilities to sustain the tumor?
"Often therapy in the past has focused on proliferating cells, but in many cases the cancer stem cell will not be proliferating extensively," said Dick. In addition, Clarke explained that because current therapies are selected based on their tumor shrinking ability, agents that target stem cells could be overlooked during the screening process because tumor shrinkage would not be an initial observation. An example of this is teratocarcinoma, in which chemotherapy is curative in the majority of cases even though the patients are left with residual masses. So the question arises, are new measures needed to determine the effectiveness of cancer agents?
"The ability to isolate the [cancer stem] cells will allow for the identification and testing of new therapeutic targets," said Clarke.
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