Scientists at the University of Alabama at Birmingham have identified a molecular pathway that seems to contribute to the ability of malignant glioma cells in a brain tumor to spread and invade previously healthy brain tissue. Researchers says the findings, published in the journal PLOS ONE, provide new drug-discovery targets to rein in the ability of these cells to move.
“Malignant gliomas are notorious, not only because of their resistance to conventional chemotherapy and radiation therapy, but also for their ability to invade the surrounding brain, thus causing neurological impairment and death,” says Hassan Fathallah-Shaykh, associate professor in the UAB Department of Neurology. “Brain invasion, a hallmark of gliomas, also helps glioma cells evade therapeutic strategies.”
Fathallah-Shaykh says there is a great deal of interest among scientists in the idea that a low-oxygen environment induces glioma cells to react with aggressive movement, migration and brain invasion. A relatively new cancer strategy to shrink tumors is to cut off the tumor’s blood supply– and thus its oxygen source– through the use of anti-angiogenesis drugs. Angiogenesis is the process of making new blood vessels.
Gliomas account for about a third of brain tumors, and survival rates are poor; only about half of the 10,000 Americans diagnosed with malignant glioma survive the first year, and only about one quarter survive for two years.
“Stop angiogenesis and you shut off a tumor’s blood and oxygen supply, denying it the components it needs to grow,” says Fathallah-Shaykh. “Drugs that stop angiogenesis are believed to create a kind of killing field. This study identified four glioma cell lines that dramatically increased their motility when subjected to a low-oxygen environment – in effect escaping the killing field to create a new colony elsewhere in the brain.”
Fathallah-Shaykh and his team then identified two proteins that form a pathway linking low oxygen, or hypoxia, to increased motility.
“We identified a signaling protein that is activated by hypoxia called Src,” says Fathallah-Shaykh. “We also identified a downstream protein called neural Wiskott-Aldrich syndrome protein (N-WASP), which is regulated by Src in the cell lines with increased motility.”
The researchers then used protein inhibitors to shut off Src and N-WASP. When either protein was inhibited, low oxygen lost its ability to augment cell movement.
“These findings indicate that Src, N-WASP and the linkage between them– which is something we don’t fully understand yet– are key targets for drugs that would interfere with the ability of a cell to move.” says Fathallah-Shaykh. “If we can stop them from moving, then techniques such as anti-angiogenesis should be much more effective. Anti-motility drugs could be a key component in treating gliomas in the years to come.”
Fathallah-Shaykh’s research is funded by the National Institutes of Health and the Gaining Life Initiative. GLI is a foundation created by Birmingham resident Bill Cash, who was diagnosed with a glioma in 2008. Following therapy at UAB, Cash set up the foundation to build awareness of brain cancer and raise money for neuro-oncology research at UAB. Bill Cash succumbed to cancer in the fall of 2012, but GLI continues to provide hope and support for cancer research.