A new study has found that a regulatory gene that directs stem cells during normal brain development may also play a role in the growth of the most common form of primary brain cancer. Researchers at Harvard Medical School's Dana-Farber Cancer Institute report in this week's issue of Neuron that Olig 2 is apparently a "gateway" gene to formation of malignant brain tumors known as gliomas. They say the discovery could lead to new therapies for this type of tumor, which strikes some 19,000 Americans a year.

"It turns out that the way people are starting to think about brain cancer—and other solid tumors [like breast cancer and prostate cancer] in general—is that they may be actually 'developmentally stalled' stem cells," says study co-author Charles Stiles, a Dana-Farber cancer biologist, "not normal stem cells, [but] mutated stemlike cells that are developmentally arrested, sort of halfway en route to making a perfectly good neuron, oligodendrocyte or whatever." Olig2 codes for a transcriptional factor, OLIG2, which, Stiles explains, acts like "air traffic control" for stem cells; the protein maintains the cells' ability to replicate early in brain development and then directs them to their designated roles as either motor neurons or oligodendrocytes (a type of glial cell that anchors and provides a protective sheath for a neuron's axons). Two years ago, study co-author and pediatric oncologist Kenneth Ligon determined that all malignant gliomas—every tumor but not necessarily every cell in the tumor—express Olig2.

Stiles notes that this finding prompted the team to question whether Olig2 played a role in the tumor's formation.

To find the answer, researchers inserted a pair of mutations normally found in human malignant gliomas into mice, some of which had the functions of Olig2 and Olig1—the latter being a gene coding for a protein that aids in the maturation of oligodendrocytes during normal development—knocked out. All the control mice died within 100 days of being injected with a virus containing the two cancerous mutations. However, 91 percent of the mice lacking the OLIG1 or OLIG2 transcription factors showed no sign of tumor growth for 39 weeks after injection. To determine whether OLIG2 was solely responsible for promoting tumor growth, the scientists reexpressed OLIG2 in some of the knockout mice. They all developed fatal tumors within the next 70 days.

"It appears that the stem cell that drives malignant glioma has stolen—co-opted, if you will—the molecular mechanism that is required to sustain development of the very cells you need to build the normal brain," Stiles says. He adds that the gene works the same way in both normal and malignant development: It maintains the replication of stem cells by stopping the expression of p21, a tumor suppressor, which he describes as "the brake pedal for cell-cycle control." Because of this dual function, the researchers refer to Olig2 as a "gateway" or "gatekeeper" gene.

The authors say their findings point to the protein OLIG2 as "an important candidate for antitumor therapeutics." But, Stiles says, it is unlikely there will soon be a pill to suppress Olig2, because the drug industry has not embraced transcriptional factors as attractive targets. Rather, he says, Big Pharma prefers to take aim at growth factor receptors, which are like accelerator pedals for cell proliferation. In the case of brain cancer, the primary growth factor involved is epidermal growth factor. But receptors for it are not specific to the brain—they can be found in the lining of the gut as well as in blood cells—making them poor drug targets.

"The charm of the Olig2 gene as a potential therapeutic target," Stiles explains, "is that it is expressed only in the brain and that it is expressed only in a minor population of cells in the brain—in stem cells and mature oligodendrocytes,"

Jeremy Rich, a neurologist at the Duke University Medical Center, says the current work presents an exciting insight into the regulation of cancer stem cells. "It is enticing to think that these studies might lay the foundation for new therapies, but we have much to learn about how to best inhibit cancer stem cells without affecting normal stem cells," he says. "Also, we have yet to develop drugs that readily inhibit the functions of transcription factors like OLIG2."