DURHAM, N.C. – Using a novel method for seeing the division of stem cells in real time, Duke University Medical Center researchers believe they have identified an unexpected way to interfere with the uncontrolled cell growth that is characteristic of cancer.
By watching what two known cancer-promoting proteins did to blood-forming stem cells, the researchers believe they have seen one protein speeding up cell division, and another controlling the maturation of cells -- both hallmarks of cancerous growth.
"Aggressive leukemias are often consequences of two or more oncogenic, or cancer promoting, factors," said Tannishtha Reya, Ph.D., senior author of a paper appearing in this month's journal Cell Stem Cell. "The first oncogene leads to abnormal cell growth that can be managed in many cases, while the second oncogene comes along and forces the cells to divide only to produce immature cells. The two events together can lead to the growth of aggressive tumors that are resistant to current treatment."
Stem cells normally divide in two ways -- symmetrically and asymmetrically. In symmetric division, a stem cell either splits into two copies of itself, or into two new cells that are committed to a particular tissue type, such as blood, liver or muscle cells. In asymmetric division, a stem cell divides into one stem cell and one mature cell.
Under normal conditions, stem cells use both methods of division in a balanced, controlled way. It was unknown whether a stem cell's path was "hardwired" into the cell's machinery. However, in studies on mice, the Duke researchers demonstrated for the first time that outside factors can force mammalian stem cells into one type of division over another.
Additionally, they discovered that cancer genes could influence which path the cells followed.
"Some oncogenes appear to have the ability to alter the development of cells, forcing them to lock into a symmetric division pattern that only produces immature cells," Reya said.
When the oncogene makes symmetric division the dominant form, the resulting cells tend to be immature and undifferentiated, Reya said. Immature cells also tend to be more aggressive in their growth and are often the primary cell type within a cancer, she added.
"One of the more exciting implications of these findings is that proteins that alter the choice between symmetric and asymmetric division could be targeted to inhibit or slow the aggressive growth of cancer, such as in acute leukemia," Reya said.
For her experiments, Reya focused on blood-forming stem cells in mice. Using a novel system that recorded dividing stem cells as they "lit up" fluorescent green, the researchers produced short movies of the stem cells' division.
Once they had determined that they were actually "seeing" symmetric and asymmetric division as it occurred, the researchers added different oncogene proteins to the system and documented what happened. One oncogene (Bcr-Abl) increased the rate of cell division, yet had no effect on the symmetry of the division. Another oncogene (Nup 98-HoxA9) significantly increased the rate of symmetrical division, thus producing immature cells.
"The Bcr-Abl oncogene is associated with chronic myelogenous leukemia, which is a slow-growing cancer that can often be managed," Reya explained. "However, the Nup 98-HoxA9 oncogene forces the stem cells into mainly symmetric division, which is associated with the acute form of leukemia. Patients with this acute myelogenous leukemia do not have good options for treatment."
"Theoretically, we could develop a protein that blocks the actions of this oncogene," Reya continued. "This would allow the blood stem cells to recover their ability to divide asymmetrically. This could turn an acute, aggressive and untreatable condition into one that is chronic, but manageable."
The study was supported by the Stem Cell Research Program at Duke University, the National Institutes of Health, the Cancer Research Institute, Ellison Medical Foundation and the Leukemia and Lymphoma Society.
Other Duke members of the team were Mingfu Wu, Young Kwon, Frederique Rattis, Jordan Blum, Tim Oliver and Chen Zhao. Their colleagues were Rina Ashkenazi and Trachette Jackson, University of Michigan, and Nicholas Gaiano, Johns Hopkins School of Medicine.