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."
medinfo.wustl
"In the future, we hope to develop DNA microarrays or gene chips specific to the macaque, which will enable us to pinpoint the level of gene expression in various studies such as those that look at the virulence and pathogenicity of pandemic strains of the influenza virus," said Dr. George Weinstock, co-director of the BCM Center.
"For example, a complete description of all the different macaque immune function components will enable an even more thoughtful use of rhesus macaques in areas such as AIDS research and for vaccine production," the authors wrote.
An important part of the study was a survey of DNA sequence differences between macaque individuals. This established that macaques show a similar overall genetic conservation to humans but that the Indian subpopulation was affected by a recent bottleneck in size. This work will speed future genetic studies of macaques, both in the laboratory and in the wild.
"A comparison of different individuals at the DNA sequence level is key to the understanding of the role of genetic variation in governing individual disease response," said Dr. Kim Worley, a senior HGSC scientist working on the project.
The information will also enable researchers to explore the basic biology of these animals, who live healthily across a broad geographic area. Finally, the researchers noted, the variations in genetic material, rearrangements, duplications, expansions in genes and measurements of the impact of natural selection reveal the rich and heterogeneous genomic changes that have occurred during the evolution of the human, chimpanzee and macaque.
"The analysis of this important primate is another milestone of the achievements of the College and marks its ongoing contributions to basic research", said Dr. Peter G, Traber, president of BCM.
bcm