Defining a developmental pathway for medulloblastoma
October 7, 2008 —Medulloblastoma, a rapidly growing tumor of the cerebellum, accounts for almost 1 in 5 of all childhood brain tumors(1). Younger children have poor outcomes, while those who survive are at risk for long-term neurological effects. Understanding of the underlying mechanisms of medulloblastoma is necessary in order to develop better therapies for this devastating disease(2). Previous research has shown that the GLI1 oncogene, part of the Sonic hedgehog (Shh) pathway, is overactive in a subset of medulloblastomas.
In a forthcoming publication in the International Journal of Cancer, Joon Won Yoon, PhD, David Walterhouse, MD, and colleagues studied changes in gene expression profiles in experimental cells transformed by GLI1. They compared the genes they identified to those found in the medulloblastomas with activation of the Shh pathway. Of the 25 resulting genes, several hold possibilities for further study. One of these is CXCR4, which plays a role in cerebellar development and whose expression may re-initiate developmental programs that contribute to medulloblastoma. Another is p53, a tumor suppressor. The group identified a mutation in the p53 gene in their experimental cells, suggesting that inactivation of p53 may shift the balance toward cell survival and proliferation in this subset of medulloblastomas.
"Understanding how mechanisms such as the hedgehog pathway operate in childhood cancers should one day help us develop better treatments," Walterhouse said. “There are already inhibitors of these pathways, but to improve on them we need to better understand how they work.”
Walterhouse is associate professor of Pediatrics in Northwestern University’s Feinberg School of Medicine, a member of the Developmental Biology Program of Children’s Memorial Research Center and an attending physician in the Division of Hematology, Oncology and Stem Cell T ransplant at Children’s Memorial Hospital. Co-authors on the paper are Joon Won Yoon, PhD, Richard Gilbertson, MD, PhD, Stephen Iannaccone and Philip Iannaccone, MD, PhD.
1. American Brain Tumor Association, “Focusing on tumors: Medulloblastoma.” www.abta.org/, accessed October 7, 2008.
2. Crawford JR, MacDonald TJ, Packer RJ. Medulloblastoma in childhood: new biological advances. Lancet Neurol. 2007 Dec;6(12):1073-85. Review.
Contact: Peggy Jones
Children's Memorial Research Center
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