October 2, 2017Oncology
High-grade gliomas cause more deaths than any other form of brain cancer, partly due to the extreme difficulty surgeons have in removing all of the tumor cells. This leaves clinicians dependent on traditional chemotherapy and radiation treatments that have limited success. Depending on the specific subtype of tumor, more than three-quarters of patients die within five years, and for the most common childhood glioma that number exceeds 99%.
According to an article published in Nature (20 September 2017), a study conducted in mice provides evidence that highly lethal brain tumors, called high-grade gliomas, stop growing when deprived of a specific molecule naturally produced when brain cells fire. The study suggest that targeting a protein called neuroligin-3 may prove beneficial in patients with these diseases. According to the NIH, this study transforms our understanding of how neurons influence the growth of gliomas, and opens a new door for potential treatments.
In a 2015 paper published in Cell, the research team identified several chemicals released by brain cells in response to neural activity that cause high-grade gliomas to grow. One of them was neuroligin-3, a protein that helps neurons communicate. In the current study, the authors extracted tumor cells from patients with several varieties of high-grade gliomas and inserted them into the brains of two breeds of mice, one normal and one lacking the gene that produces neuroligin-3. In the latter, none of the tumors grew substantially for four and a half months and roughly half remained stagnant after six months, whereas tumors grew markedly in the mice with an intact neuroligin-3 gene. Further experiments suggested neuroligin-3 triggers a series of chemical reactions that stimulates multiple signaling pathways involved in glioma growth, causing the tumors to expand.
The team also discovered that neuroligin-3 release is triggered when active neurons secrete a protein called ADAM10, which causes neuroligin-3 to detach from the surface of cells. Stopping neurons from firing prevented the release of both ADAM10 and neuroligin-3, and genetically deleting ADAM10 from neurons in mice reduced neuroligin-3 release. In addition, the team found that a group of brain cells called oligodendrocyte precursor cells can release neuroligin-3, suggesting those cells may play a role in accelerating glioma growth. Finally, the authors showed that blocking ADAM10 activity with a drug designed to treat other types of cancers dramatically reduced the growth of two types of gliomas implanted into the brains of mice.
In addition to working towards a better understanding of why gliomas are so dependent on neuroligin-3 for growth, the authors are planning to initiate a clinical trial using an ADAM10 inhibitor in human glioma patients. Although treatments targeting ADAM10 and neuroligin-3 might extend patients' lifespans, they would not kill the tumors, making additional treatments necessary to cure the disease.