Using New Approach, Scientists Find Evidence for Cancer Stem Cells
With the help of genetic tools, researchers have identified subsets of cells that appear to drive the growth of tumors in mice. The findings, from three independent studies, provide new support for the cancer stem cell hypothesis—the idea that some tumors are sustained by self-renewing cells that give rise to all types of tumor cells. Two of the studies appeared August 1 in Nature, and the third was published on the same day in Science.
Each research group used the genetic tools to "label" tumor cells and track their ancestry in a different mouse model. The results of each study suggested that at least some tumors contain certain populations of cells that drive the growth and survival of the tumor. These would be the cancer stem cells, also known as tumor-initiating cells.
"The three studies provide nice additional support for the cancer stem cell hypothesis," said Dr. Max Wicha, director of the University of Michigan Comprehensive Cancer Center and a cancer stem cell researcher who was not involved in the three studies. "They are technically challenging and very well done."
The authors of one of the Nature reports identified a population of brain tumor cells that appeared to allow brain tumors to grow back after treatment with the drug temozolomide. The drug initially depleted proliferating cancer cells, slowing tumor growth. But it did not harm a population of less active cells—the cancer stem cells. As a result, the tumors recurred.
"We think this is a clear and rigorous demonstration that the cancer stem cell hypothesis is alive and well in at least one solid tumor," said lead researcher Dr. Luis F. Parada of the University of Texas Southwestern Medical Center in Dallas. "Time will show how frequently this type of tumor mechanism holds true for other solid tumors."
A second study in Nature identified distinct populations of cancer cells in a mouse model used to investigate the development of skin tumors. Consistent with the cancer stem cell hypothesis, a relatively small population of long-lived tumor cells ultimately gave rise, during tumor growth, to progeny cells that made up a substantial part of the tumor.
"The new method of tracking the fates of tumor cells in situ has demonstrated the existence of cancer stem cells that fuel the growth of tumors in vivo," lead investigator Dr. Cedric Blanpain of the Université libre de Bruxelles wrote in an e-mail message.
The third study, in Science, found evidence of cancer stem cells in precancerous intestinal lesions in mice. Although all three studies point to the existence of cancer stem cells, the relevance of the mouse findings to human cancers is not yet known.
Moving the Field Forward
First discovered in leukemia, cancer stem cells have since been reported in solid tumors such as brain, breast, and colon cancers. Evidence for their existence has come primarily from experiments in which only a small proportion of human tumor cells are able to proliferate extensively and to form new tumors when transplanted into mice.
But factors other than cancer stem cells could explain the formation of new tumors from only certain transplanted cells, researchers have argued. Whether tumors form in mice may depend on how the transplantation was done and the type of mouse model used in the experiment.
There are too many variables to be able to draw firm conclusions about cancer stem cells from these transplantation experiments, noted Dr. Parada. The emergence of genetic tools used to tag tumor cells offered a chance to study potential cancer stem cells in their natural environments.
"The new studies put to rest the idea that you see cancer stem cells only if you perturb the human tumor and transplant it into an animal," said Dr. Wicha. "[These new findings] will move the field forward."
The results also suggest that the same pathways used in normal tissue development may be active in tumor development. "The cellular hierarchy found in early tumor progression is a corruption of the cellular hierarchy found in normal tissue," Dr. Blanpain noted.
The concept of cancer stem cells has potential implications for treatment. If these cells exist in human tumors, they would need to be eradicated to achieve long-term survival. The new studies suggest that "to cure a cancer you have to be able to identify and target the cancer stem cells," said Dr. Parada.
Several dozen clinical trials are already testing approaches to target cells with stem-cell-like properties in patients, according to Dr. Wicha. Yet, even with the new findings, cancer stem cells are likely to remain controversial. As Dr. Wicha noted, however, this is not necessarily a problem.
"Controversy is healthy, and questions about cancer stem cells are good for science," he said, adding, "There will always be controversies in the field."
The study led by Dr. Parada was funded in part by the National Institutes of Health (R01 CA131313).