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'Gateway' Gene Allows Brain Stem Cells to Grow into Tumors

For release: Friday, April 6, 2007

According to a new study, a gene that supports normal brain development also supports the growth of a brain tumor called glioblastoma.

The gene is active in neural stem cells, which seed the brain during embryonic development to eventually generate billions of neurons and other cell types.  Although they were once believed to disappear after embryonic development, stem cells are now known to persist in the adult brain, lying mostly dormant within small pockets.  Scientists believe that the cells are capable of awakening and morphing – or "differentiating" – into new neurons.  But a growing body of work also points to the cells as the cause of brain cancers.

Glioblastoma is the most lethal form of brain cancer, and typically does not respond to radiation therapy.  It gets its name from the fact that some of the cancerous cells have properties of glial cells, which support and nourish the brain's workhorses, the neurons.

Charles D. Stiles, Ph.D., a co-author of the new study and a Professor of Microbiology and Molecular Genetics at the Dana-Farber Cancer Institute and Harvard Medical School in Boston, said that examination of autopsied brain tissue has long hinted at a connection between glioblastoma and neural stem cells. 

"When pathologists looked at the tumors they could see cells that looked like neurons, and some that looked like glia, but none that looked like mature [glia].  This led to the idea that the unidentified cells might be developmentally arrested neural stem cells," said Dr. Stiles, who is supported in part by the National Institute of Neurological Disorders and Stroke (NINDS).

Indeed, recent studies have confirmed that glioblastoma arises from wayward neural stem cells that have chosen to keep dividing rather than differentiate into neurons or glia.  The work by Dr. Stiles and his colleagues, published in Neuron,* shows that a gene called Olig2 acts as a "gateway" at this decision point.

"We believe that Olig2 keeps the cells stalled in a replication-competent state," he said.

The Olig2 gene encodes a transcriptional repressor protein, a switch that turns off other genes.  The protein is found only in the brain.  During embryonic life, it promotes the development of a class of glial cells known as oligodendrocytes, which form insulating sheaths around axons – the tendrils that neurons use to connect with each other. 

Dr. Stiles and his colleagues showed that Olig2 is also active in cancerous cells within human glioblastomas.  In experiments on cancerous cells derived from the mouse brain, they showed that Olig2 suppresses genes that would normally tell the cells to stop dividing.   Finally, they showed that when these cancerous mouse cells were implanted into the brains of healthy mice, they multiplied and formed tumors – unless they lacked the Olig2 gene.  All mice that received Olig2-positive cells developed tumors and died within 100 days, while 91 percent of mice that received Olig2-negative cells remained tumor-free after 39 weeks.

Dr. Stiles said it might be possible to design drugs that shrink glioblastomas by inhibiting Olig2.  Because the Olig2 protein is found only in the brain, he said, those drugs could specifically target cancerous brain cells without causing side effects in other tissues.  Many cancer drugs, for example, inhibit stem cells within bone marrow, causing a potentially dangerous drop in the production of blood cells.

*Ligon K et al.  "Olig2-Regulated Lineage-Restricted Pathway Controls Replication Competence in Neural Stem Cells and Malignant Glioma."  Neuron, February 15, 2007, Vol. 53, pp. 503-517.

-By Daniel Stimson, Ph.D.

Last Modified May 23, 2008