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."
Reference: 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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