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Researchers at St. Jude have demonstrated for the first time that tiny molecules called microRNAs participate in the initiation and progression of one form of human medulloblastoma, the most common malignant brain cancer in children.
The discovery provides new insights into the complex biochemical processes that underlie medulloblastoma and suggests a novel approach to battling one of its five distinct subgroups. The findings also might help physicians to better distinguish one medulloblastoma subgroup from another, which could have important implications for choosing more specific treatments.
“What is important, based on the small number of studies we’ve done so far, is that the microRNAs we identified would play a role in about 25 percent of all medulloblastomas in children,” said Martine Roussel, PhD, Genetics and Tumor Cell Biology.
Medulloblastoma develops in the cerebellum, a portion of the brain involved in controlling complex motor functions, such as maintaining balance. Some cases originate in cells called cerebellar granule neuron progenitors (GNPs) that do not reach their proper place in the cerebellum and fail to mature.
About 500 new medulloblastoma cases are diagnosed annually in the United States, some 350 of which occur in children. “We see a lot of them here at St. Jude,” said Roussel, the senior author of a report on this work that was published February 5 in the online edition of Proceedings of the National Academy of Sciences.
MicroRNAs regulate many aspects of cell development and function. They have been well studied in lower organisms and plants, but research into their role in mammalian development began only relatively recently. To date, scientists have identified 678 of these tiny bits of genetic material in humans and 472 in mice.
Some microRNAs have been implicated in the initiation, progression and spread of human malignancies outside the brain. Others appear to suppress the development of cancers, creating a delicate and precarious balance in one control mechanism of cell division.
“We hypothesized that microRNAs might play an important role in normal cerebellar development, and that alterations in the expression of microRNAs might contribute to the development of medulloblastoma,” Roussel said. “MicroRNAs suppress the expression of genes that could be tumor suppressors and lead to cancer.”
She and her colleagues demonstrated that a number of microRNAs are expressed in mice during normal development of the cerebellum. The scientists made this discovery by using a technique that allowed them to distinguish between progenitor and mature cells.
When the team examined microRNA activity in replicating GNP cells and medulloblastoma tumors in mice, they found that 26 were overexpressed and 24 underexpressed as compared to their levels in normal mature cerebellar cells.
“The expression of these microRNAs during development and in tumors is completely opposite to that seen in mature neurons,” Roussel said.
The researchers posited that the overexpressed microRNAs served as oncogenes, which can override the mechanisms that control the division of a normal cell and turn it cancerous. The underexpressed RNA bits, the researchers suggested, served as suppressor genes, ones that can prevent a cancer.
Among the 26 overexpressed mouse microRNAs, nine came from a single group known as the miR-17~92 cluster.
Mouse and human cancers associated with a faulty signal-transmission system known as the Sonic Hedgehog/Patched (SHH/PTCH) pathway share similar gene expression patterns, or signatures. For that reason, the researchers analyzed tissue from five normal human cerebella and 10 previously characterized medulloblastoma tumors—provided by Richard Gilbertson, MD, PhD, Developmental Neurobiology and Oncology—without knowing the subgroup of each cancer.
Five tumors showed the SHH/PTCH gene signature. Three of these cancers showed a mutation in PTCH, a receptor vital to signal transmission, and in each of these five tumors, three microRNAs from the miR-17~92 cluster were overexpressed. None of the other medulloblastoma subtypes showed indications of SHH/PTCH pathway activation.
The team also showed that the overexpression of the miR-17~92 cluster can transform a cell from normal to cancerous. Using a technique Roussel had helped develop, the researchers removed proliferating neurons from mice, purified and altered them so they expressed the miR-17~92 cluster, injected the cells with a green-fluorescent protein, and transplanted them into the cerebella of other mice. The colored protein enabled the scientists to follow the formation and growth of tumors in real time.
“These results implicate the miR-17~92 cluster in the development of human medulloblastomas whose formation is driven by a defective SHH/PTCH pathway,” Roussel said. “Now you can think about making anti-microRNAs that will hopefully suppress tumor progression in patients.”
Currently, she and her colleagues are trying to identify microRNAs that act as suppressors of medulloblastoma. Roussel is also collaborating with Gilbertson and Amar Gajjar, MD, Oncology co-chair, to sequence the microRNAs of a large cohort of medulloblastoma tumors surgically removed as part of a clinical trial.
Other authors of this paper include Gajjar; Gilbertson; Yong-Dong Wang of the Hartwell Center; and David Ellison, MD, PhD, Pathology chair.
This research was supported in part by the National Cancer Institute, the K99 Pathway to Independence Award, the Children’s Brain Tumor Foundation, the Emily Dorfman Foundation for Children through the American Brain Tumor Association, the Collaborative Ependymoma Research Network, the American Cancer Society Postdoctoral Fellowship and ALSAC.