Researchers at the University of Michigan Comprehensive Cancer Center have found a marker that can be used to identify stem cells in breast tumors, suggesting a potential simple test that could help determine the best treatment for breast cancer.
The finding also provides strong support for the hypothesis that a small number of cells, called cancer stem cells, are responsible for fueling a tumor's growth.
U-M researchers were the first to discover stem cells in a solid tumor, finding them first in breast cancer. Generally, stem cells make up fewer than 5 percent of all the cells in a tumor, but they may be the key cells in cancer progression. The process of looking at the cell surface to identify stem cells, however, is too complex to apply to patient care.
In the new study, published in the November issue of Cell Stem Cell, the researchers found that cells from normal and cancerous breast tissue that had high levels of the enzyme aldehyde dehydrogenase activity, or ALDH, acted like breast stem cells. Further, of 577 human breast cancer tissue samples studied, those that expressed the specific form ALDH1 had the worst outcomes, suggesting this easily detected marker could be used to assess prognosis.
"This study is a big step because it provides a marker that's easy to use in both normal and cancer cells. Clinical applications were really not possible with the previously described markers. The fact that ALDH1 was identified in stem/progenitor cells from both normal and cancer tissue lends support to the idea that those cells are the primary target of transformation to malignancy. We believe it is only a very small population of cells that really are capable of unlimited growth and therefore drive cancer recurrence and metastasis," says senior study author Gabriela Dontu, M.D., Ph.D., research assistant professor of internal medicine at the U-M Medical School.
Researchers used a reagent called ALDEFLUOR to detect the ALDH activity in the cells. Cells with high levels of this enzyme become fluorescent and can be detected. Cells can then be sorted to pull out the stained cells.
When they did this, researchers found that the ALDEFLUOR-positive cells acted like stem cells, while the ALDEFLUOR-negative cells did not. Stem cells are defined by their ability to generate identical cells as well as to differentiate into other types of cells.
The study also tested whether the separated cells could produce a breast tumor. Tumors formed only from the ALDEFLUOR-positive cells, even when as few as 500 cells were used. On the other hand, 50,000 ALDEFLUOR-negative cells did not generate tumors.
In addition to identifying the stem cells, the researchers found ALDH1 can indicate how aggressive a tumor is. In tissue samples from 577 patients with breast cancer, those bearing ALDH1-positive tumors had lower overall survival and were 1.76 times more likely to develop metastases than patients with ALDH1-negative tumors. ALDH1 was expressed in 19 percent to 30 percent of the tumors.
"The ALDH1 marker correlates with more aggressive tumors, possibly reflecting a different rate of renewal of cancer stem cells in these cancers. It's possible to use ALDH1 in association with other markers as a prognostic marker to help determine what treatment is necessary. More research is needed, though, before we can apply these findings in the clinic," Dontu says.
While this work was done specifically in breast cancer, the researchers believe it could have implications for other cancer types. U-M researchers are actively involved in stem cell research in virtually all cancer types. In addition to the initial breast cancer stem cell discovery, U-M researchers have been the first to identify stem cells in pancreatic and head and neck cancers. Work is ongoing to develop and test treatments that target these cells.
"The lessons we've learned from breast cancer stem cells have been very valuable to us as we attack the cancer stem cells in other organs. Our hope is that some of the treatments we develop for one type of tumor like breast cancer may also work in targeting the cancer stem cells in these other types of tumors, and so we actually may make great progress in treating a wide variety of cancers," says Max S. Wicha, M.D., Distinguished Professor of Oncology and Director of the U-M Comprehensive Cancer Center.
This research is still in the laboratory stage and no clinical tests or treatments are currently available. For information about currently available treatments, call the U-M Cancer AnswerLine at 800-865-1125 or visit mcancer.org.
The first author of this study is Christophe Ginestier. In addition to Dontu, Ginestier and Wicha, U-M study authors were, Julie Dutcher, Marty Brown, Celina Kleer, M.D., Suling Liu, Anne Schott, M.D., and Daniel Hayes, M.D. Other authors were Min Hee Hur, M.D., from Cheil General Hospital in Seoul, South Korea; and Emmanuelle Charafe-Jauffret M.D., Ph.D.; Florence Monville; Jocelyne Jacquemier M.D.; Patrice Viens, M.D.; and Daniel Birnbaum M.D., Ph.D., all from Laboratoire d'Oncologie Moleculaire in Marseille, France.
Funding for the study was from the National Institutes of Health, Ligue Nationale Contre le Cancer and Institut National du Cancer.
Reference: Cell Stem Cell, Vol. 1, Issue 5, pp. 555-567, November 2007
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