For release: Monday, January 29, 2007
The existence of rogue stem cells that refuse to die explains why an aggressive brain tumor known as glioblastoma typically isn’t extinguished by radiation therapy. A study in the December 7, 2006 issue of Nature* shows that the therapy fails to kill a small but potent fraction of cancerous cells – about 5 percent of those in the tumor.
“In order to keep the cancer from coming back, we need to figure out how to kill that 5 percent of resistant cells,” said Jeremy Rich, M.D., the study’s senior author and a neurologist at Duke University Medical Center in Durham, North Carolina. Dr. Rich’s work was funded in part by the National Institute of Neurological Disorders and Stroke (NINDS), which also supports Duke’s Specialized Program of Research Excellence (SPORE) in Brain Cancer.
Glioblastoma is the most lethal form of brain cancer, with about half of patients expected to die within a year of diagnosis. It gets its name from the fact that the cancerous cells have properties of glial cells, which support and nourish the brain’s workhorses, the neurons. Ionizing radiation, powerful enough to kill cancer cells by breaking apart their DNA, is a common but largely ineffective treatment. It typically extends life by just a few months.
Dr. Rich’s experiments showed that when mice with glioblastoma were exposed to radiation, cancerous brain cells harboring a surface protein known as CD133 survived the treatment and multiplied, eventually reconstituting the tumor. When implanted into the brains of healthy mice, CD133+ cells caused glioblastoma.
CD133+ cells have some of the characteristics of the brain’s normal stem cells – cells that have the capacity to generate brain tissue during embryonic development and, scientists hope, to regenerate brain tissue after injury.
Dr. Rich found that the key to the cells’ resilience is an overactive set of checkpoint proteins – proteins that repair DNA and are somehow mobilized faster in CD133+ cells than in other cells. Exposing the cells to a chemical inhibitor of checkpoint proteins (before implanting them into mice) left them defenseless against radiation therapy, he showed. Neither radiation nor the chemical alone could stop the cells from forming tumors in the mice, but the combined treatment all but eradicated them.
Some drug companies are investigating whether checkpoint inhibitors could be developed into drugs to supplement radiation therapy, Dr. Rich said.
In another study published in the same issue of Nature,** Italian researchers showed that bone morphogenetic protein 4 (BMP4), or a drug that mimics its actions, might also become a useful treatment for glioblastoma. In the normal developing brain, BMP4 directs stem cells to become a type of glial cell.
Led by Angelo Vescovi, Ph.D., a cell biologist at the University of Milan-Bicocca, the Italian group found that pre-exposing CD133+ cells to BMP4 could prevent them from forming tumors when implanted into mice. Moreover, injecting BMP4 into the brains of mice already seeded with the tumor-forming cells significantly extended the mice’s survival.
Dr. Rich noted that scientists do not understand the origins of the cancerous, CD133+ stem cells or their relationship to normal stem cells. Still, there is general consensus that “cancer is development gone bad,” he said.
Jane Fountain, Ph.D., a program director in the NINDS Division of Extramural Research, noted that a growing number of studies are bridging brain cancer research and stem cell research. “There is great potential that these interactions will lead to breakthroughs in the development of tailored therapeutics for brain tumor patients,” she said.
In the less distant future, parsing CD133+ cells into smaller classes and identifying them in the brains of patients also might allow clinicians to make more accurate assessments about the course of brain cancer and the treatments most likely to be effective in different people.
*Bao S et al. “Glioma Stem Cells Promote Radioresistance by Preferential Activation of the DNA Damage Response.” Nature, December 7, 2006, Vol. 444, pp. 756-760.
**Piccirillo SGM et al. “Bone Morphogenetic Proteins Inhibit the Tumorigenic Potential of Human Brain Tumour-Initiating Cells.” Nature, December 7, 2006, Vol. 444, pp. 761-765.
-By Daniel Stimson, Ph.D.
Last Modified May 23, 2008