Cell signaling pathway goes awry in common pediatric brain tumor
A new study links a well-known cell communication pathway called Notch to one of the most common, but overall still rare, brain tumors found in children.
The study, described in the Journal of Neuropathology & Experimental Neurology (2015; doi:10.1097/NEN.0000000000000155), suggests the pathway's involvement with a low-grade brain tumor called pilocytic astrocytoma (PA).
The tumor, which makes up an estimated 15% of primary brain tumors in children and adolescents, is slow growing. Surgical removal is usually the only treatment necessary, although cases occur in hard-to-reach spots in the brain where they may grow and cause seizures, vision loss, and physical coordination problems. PA is diagnosed in an estimated one in 100,000 children each year in the United States, according to the Central Brain Tumor Registry of the United States.
According to Fausto Rodriguez, MD, associate professor of pathology at the Johns Hopkins University School of Medicine and a member of the Johns Hopkins Kimmel Cancer Center in Baltimore, Maryland, he and his colleagues made their discovery while comparing the expression of genes, as measured by the amount of RNA the genes made, in the Notch pathway between brain tissue from a mix of healthy children and those with PA.
They found that by this measure, one or more of the pathway's genes were overexpressed in nearly all 22 samples of PA brain tissue, as compared with normal brain tissue. Depending on the gene under study, overexpression spanned from four to up to 21 of the 22 samples. Notch-related proteins, specifically HES1, were present in 58 of 61 additional samples, and 40 of those 61 samples showed moderate to strong protein expression.
"Notch is a very basic signaling pathway used for cell-to-cell communication during development," Rodriguez explained. "We know that cancer can abnormally activate such signaling pathways to promote cell growth and survival, and our new findings line up with that knowledge."
Rodriguez said that changes in the Notch pathway have been implicated in various cancers, from leukemia to breast cancers. His Johns Hopkins colleague and co-author Charles Eberhart, MD, also have shown the pathway to be critical for medulloblastoma and glioblastoma, two other far more lethal brain cancers affecting children and adult patients.
"We wanted to see if Notch also was inappropriately active in lower-grade tumors like PA, and that appears to be the case," Rodriguez said.
In further experiments with implications for improved treatment of PA, the scientists were able to block the Notch pathway's abnormal activity in PA tumor cells with two methods: a technique that uses "short hairpin" RNA, a form of genetic material, to specifically silence the genes' expression, and a drug class called gamma secretase inhibitors that are being tested in several cancer clinical trials.
The new findings, said Rodriguez, suggest that Notch might someday be a therapeutic target for PA treatment, especially for tumors that cannot be reached surgically. This type of tumor, Rodriguez said, often does not respond as well to other therapies, such as radiation or chemotherapy, because it is very slow growing.