mice develop brain tumors with many of the same features as those seen
in children with NF1, and studying those tumors has helped us
understand the cellular events involved in NF1 brain tumor
development," says principal investigator David H. Gutmann, M.D.,
Ph.D., the Donald O. Schnuck Family Professor of Neurology.
The study appears online and will be published in the January 2005
issue of the journal Annals of Neurology.
NF1 is one of the most common neurological disorders caused by a single
gene mutation. The disorder can lead to a variety of complications
including brain cancer.
To supplement their clinical research, Gutmann's team developed a mouse
model in which the animals, like humans with the disease, have one
abnormal copy of the gene for NF1 in every cell in their body, while
specific support cells in the brain called astrocytes have two abnormal
copies of this same gene.
Their latest paper shows that brain tumor formation in these mice has
several of the same distinguishing clinical characteristics as tumor
development in children with NF1.
First, the mice developed tumors along the optic nerve and optic
chiasm, which transmit visual information from the eye to the brain.
This type of tumor, called an optic pathway glioma, is the most common
tumor in children with NF1.
Second, the time course of tumor development was
similar to that seen
in humans. Unlike most tumors, optic pathway gliomas associated with
NF1 typically stop growing after a few years. Moreover, they almost
always occur in children ?these tumors generally start growing in
children younger than 5 years old and usually do not progress after age
10. A similar pattern occurred in the mice: The optic nerve and chiasm
were enlarged and astrocytes along the optic pathway began multiplying
and growing when the animals were around three weeks old, developing
into optic pathway gliomas by two months of age. After that
time-period, which is roughly equivalent to teenage years in humans,
the cells slowed down to the same growth speed as astrocytes in control
"The fact that cell growth is dramatically reduced after a few months
in mice and after a few years in humans tells us there may be growth
signals that are produced early in life, which are critical for tumor
formation and expansion," Gutmann explains.
Optic pathway gliomas in humans are typically surrounded by blood
vessels and microglia, which are immune system cells in the brain. But
it was unclear whether the development of blood vessels and recruitment
of microglia helped trigger tumor formation or if they appeared only
after the tumor was fully developed. The researchers found that by
three weeks of age, the mutant mice had about four times the number of
small blood vessels in the optic nerves and chiasm as control mice.
Similarly, microglia were also found in the nerve and chiasm of mutant
mice prior to tumor formation.
"In our judgment, the fact that recruitment of new blood vessels and
infiltration of immune system cells occurs before actual tumor
formation suggests that these events are important for the development
of tumors," Gutmann says. "These findings raise the possibility that
targeted therapies for NF1 brain tumors may involve agents that prevent
the supply of growth promoting factors provided by new blood vessels
Next, the research
ers used the mouse model to investigate a clinical
concern. Physicians rely on several tests to determine whether a child
with an optic pathway glioma should undergo treatment for the tumor,
including the tumor's size and the patient's clinical symptoms. But
often those tests aren't sufficiently informative, so experts also
examine pictures of the patient's brain taken with magnetic resonance
imaging (MRI). To capture such brain images, physicians inject a
contrast dye into a patient's bloodstream and look for accumulation of
dye around the tumor. Though dye accumulation may be a sign of tumor
progression, it is unclear whether that is always the case,
particularly in optic pathway gliomas associated with NF1.
Results from this latest study suggest that the two are not necessarily
correlated. Gutmann's team found that optic pathway gliomas lit up just
as brightly in 2-month-old mice as in 8-month-old mice, despite the
fact that the tumors were actively growing only in the younger mice.
"If this finding is also true in humans, this strongly argues that
contrast enhancement on MRI alone is not a reliable test of tumor
progression," Gutmann says. "If we rely on contrast enhancement in
children with NF1 optic pathway gliomas, we may be treating kids who
don't need to be treated. Using this mouse model, we hope to continue
to hone in on more accurate diagnostic, prognostic and treatment
Bajenaru ML, Garbow JR, Perry A, Hernandez MR, Gutmann DH. Natural
history of neurofibromatosis 1-associated optic nerve glioma formation
in mice. Annals of Neurology, January 2005.
Source:Washington University of St Louis
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