A new study has revealed a rare cell type that gives rise to a type of brain cancer called medulloblastoma. The unusual cells, called “nestin-expressing progenitors” (NEPs), are more efficient at generating medulloblastoma than other brain cells. The research, published in Nature Neuroscience and conducted by Sanford-Burnham researchers in collaboration with scientists at Fox Chase Cancer Center, provides critical insight into how normal cells transform into tumors and may yield new approaches for targeting brain tumors.
Medulloblastoma is an aggressive tumor that is located in the cerebellum, and accounts for 18 percent of all pediatric tumors. Medulloblastoma is thought to arise during development of the cerebellum, from cells called granule neuron precursors (GNPs) that reside in the external granule layer (EGL) on the outside of the cerebellum. Until now, most scientists believed that GNPs were the only cells that could give rise to medulloblastoma.
The study team, co-led by Robert Wechsler-Reya, Ph.D., of Sanford-Burnham, and Zeng-jie Yang, Ph.D, of Fox Chase Cancer Center, used genetically engineered mice to identify a new cell type in the EGL—NEPs. Like GNPs, NEPs are committed to generating granule neurons—very small neurons that make up 75 percent of all brain cells. But unlike GNPs, NEPs have high levels of a protein called nestin, which is commonly found only in stem cells. The presence of nestin suggested that NEPs might be more primitive than GNPs, and like stem cells, more capable of long-term growth and survival.
“Another major difference between NEPs and GNPs is that the DNA repair mechanisms of NEPs are less active,” said Wechsler-Reya. “Since DNA repair protects cells from becoming cancerous, we speculated that NEPs might be more likely than GNPs to give rise to brain tumors.”
To directly compare the tumor-forming ability of NEPs and GNPs, the researchers performed a series of transplantation experiments, using NEPs and GNPs carrying a cancer-causing mutation. When they transplanted large numbers of cells, both NEPs and GNPs gave rise to tumors. But when they transplanted very few cells, GNPs did not cause tumors, whereas NEPs were still capable of doing so. These results confirmed that NEPs have an increased capacity to form tumors.
“Identifying the cells that can give rise to medulloblastoma allows us to compare tumor cells to their normal counterparts, so that key differences and vulnerabilities of tumor cells can be identified. Our study describes a novel ‘tumor-prone’ cell population that may provide new insights into the mechanisms of cancer development. By studying these cells, we may find new approaches to targeting brain cancer,” Wechsler-Reya said.
Medulloblastoma is the most common malignant brain tumor, affecting about 500 children in the United States annually. Current treatment options for medulloblastoma include aggressive surgery, radiation, and chemotherapy. Today, over two-thirds of children are successfully treated. However, survivors generally suffer long-term side effects such as cognitive and developmental disabilities due to the aggressive treatment, and in many cases the tumor reappears within a few years after treatment.
Li P, Du F, Yuelling LW, Lin T, Muradimova RE, Tricarico R, Wang J, Enikolopov G, Bellacosa A, Wechsler-Reya RJ, & Yang ZJ (2013). A population of Nestin-expressing progenitors in the cerebellum exhibits increased tumorigenicity. Nature neuroscience PMID: 24141309