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Imaging Stem Cell Division Helps Identify Cancer Treatment Targets

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Duke Health News 919-660-1306

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.

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