Mouse Brain Tumors Mimic Those In Human Genetic Disorder

After validating their animal model, the team made two important discoveries: New blood vessels and immune system cells may be essential to the initial formation of tumors and therefore may be promising drug targets; and brain images often used to determine the need for treatment may not actually be diagnostically informative.

"These 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 mice.

"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 and microglia."

Next, the researchers 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 approaches."

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.

Funding from the National Institutes of Health, the United States Department of Defense, the National Cancer Institute, the Alvin J. Siteman Cancer Center and the National Eye Institute supported this research.

Washington University School of Medicine's full-time and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked second in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.