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By
Michael Purdy
April
11, 2007 -- Developing brain tumors can coax assistance
from nearby cells known as microglia, according to a
new study from scientists at Washington University School
of Medicine in St. Louis. The researchers have identified
one protein made by microglia that helps accelerate
tumor growth and are looking for others.
The
results, published online this month in Human Molecular
Genetics, come from a mouse model of neurofibromatosis
1 (NF1), a genetic condition that significantly increases
childhood brain tumor risk. But senior author David
Gutmann, M.D., Ph.D., the Donald O. Schnuck Family Professor
of Neurology, says the findings also have implications
for sporadic brain tumors, which affect many more people.
"Until
now, we've never really had a good system for studying
how microglia may contribute to general brain tumor
formation," says Gutmann, who is director of the
Neurofibromatosis Center and co-director of the neuro-oncology
program at the Siteman Cancer Center at Washington University
and Barnes-Jewish Hospital. "We're going to use
this model to better understand how brain cells that
become tumors interact with microglia, and to probe
how we might block those interactions."
Gutmann
hopes to create approaches for shutting down microglia,
which exist both in a resting state and an activated
state. Tumors likely need microglia to be activated
before they can convince them to send out growth signals.
The tumor then exploits these signals to enable its
rapid growth. If scientists can block microglia activation,
they place the tumor's potential partner in crime out
of its reach.
"From
a therapeutic standpoint, we're very focused in cancer
therapy on poisoning the cancer cell," Gutmann
says. "But why not also deprive the cancer cell
of the growth signals it receives from the normal surrounding
tissue? These cells may actually decide whether a tumor
forms at all and whether it continues to grow."
To
learn more about the neighboring cells' effects on brain
tumors, Gutmann turned to NF1, which affects more than
100,000 people in the United States. Gutmann has studied
the condition for years both to help improve NF1 treatment
and to develop insights into brain tumors generally.
As a part of that research, his lab developed a mouse
model of NF1.
Brain
tumors in human patients and in the mouse model arise
from brain support cells known as astrocytes. To begin
the new study, Gutmann and his postdoctoral fellow Girish
C. Daginakatte, Ph.D., studied these brain tumors early
in their development to see if any other cell types
were consistently nearby. They found microglia, a cell
type they had previously noted in human tumor samples.
Microglia
are similar to monocytes, immune system cells that circulate
throughout the body. Scientists are still debating the
role of microglia."I
think people recognize now that microglia can be both
good guys and bad guys," Gutmann says. "We've
shown that they can definitely be subverted into a bad
guy role by tumors."
When
researchers gave the mice drugs that dampen immune system
function, blocking activation of the microglia, tumor
growth slowed. To get a sense for what the microglia
was making that boosts tumor growth, they compared the
proteins produced by microglia from the mouse model
and microglia from normal mice.
Among
other differences, microglia from the mouse model made
more of an enzyme called hyaluronidase. Other scientists
had previously identified hyaluronidase as a contributor
to processes that trigger healing and regrowth after
brain and spinal cord injury. In a series of test tube
experiments, Gutmann showed that hyaluronidase can promote
astrocyte growth, and that inhibiting microglia production
of hyaluronidase slowed their growth-promoting effects."Now
we have to wait for pharmaceutical scientists to develop
inhibitors of hyaluronidase activity that can be used
as potential treatments," Gutmann says. "In
the meantime, though, we'll be looking at other factors
made by microglia to see if they're also contributing
to brain tumor growth as well as searching for ways
to deactivate microglia."
Daginakatte
GC, Gutmann DH. Neurofibromatosis-1 (Nf1) heterozygous
brain microglia elaborate paracrine facts that promote
Nf1-deficient astrocyte and glioma growth. Human Molecular
Genetics, online publication.
Funding
from the Department of Defense supported this research.
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