The cerebellum is the brain's control center for motor coordination and cognitive function, yet little has been known about the origins of the neurons and supporting "glial" cells that populate this region.
The Duke discovery of stem cells in the cerebellum suggests a possible origin for these normal cells and provides a starting point for understanding the basis of medulloblastoma, the most common malignant brain tumor in children, said the researchers.
Medulloblastomas arise in the cerebellum but their cells of origin have remained unclear. However, a number of these tumors have been shown to contain proteins that are normally found on neural stem cells. This finding perplexed scientists, as stem cells had never been shown to exist in the cerebellum.
The Duke study provides the first evidence that stem cells actually exist in the cerebellum and supports the theory that medulloblastomas could arise from these cells, said the researchers. They hope their discovery will eventually lead to more targeted, less toxic treatments that disrupt the process by which stem cells could give rise to brain tumors.
Their results are published in the June, 2005 issue of Nature Neuroscience. The study was funded by the Sidney Kimmel Foundation for Cancer Research, the James S. McDonnell Foundation and the National Institute of Mental Health.
"Some medulloblastomas are believed to arise from a type of cell called a granule cell," said Robert Wechsler-Reya, Ph.D., Assistant Professor of Pharmacology and Cancer Biology and senior author on the study. "However, the majority of medulloblastomas have no clear cell of origin. Our discovery demonstrates for the first time th at stem cells reside in the cerebellum and provides us with a starting point for identifying the cells and genes involved in many medulloblastomas."
The researchers hypothesize that tumors could arise when stem cells in the cerebellum become inappropriately activated and multiply uncontrollably. Identifying the source of medulloblastoma could enable researchers to more effectively disrupt the genes and proteins that fuel its growth.
Stem cells are immature cells that have the potential to differentiate into multiple types of adult cells. They are known for their unique ability to proliferate extensively and give rise to both new stem cells as well as a host of specialized cells that perform designated tasks in a particular tissue or organ. But when stem cells become activated at the wrong time or place, rapid proliferation can give rise to cancer, said Wechsler-Reya.
The researchers discovered the stem cells while studying the development of granule cells, the most abundant type of neuron in the cerebellum. While purifying granule cell precursors, they discovered what they believed to be contaminating cells. But upon closer examination, these turned out to include a small population of neural stem cells, said Audra Lee, a research associate in Wechsler-Reya's lab who carried out the majority of the work.
The stem cells they isolated represented less than one percent of the total number of cells in the cerebellum, said Lee. Yet they were clearly identified as stem cells based on three distinct properties: their expression of a protein called Prominin-1 or CD133, which is commonly found on stem cells; their ability to divide indefinitely in response to stem cell growth factors; and their ability to generate all the major cell types in the cerebellum when transplanted into the cerebellum of neonatal mice.
Identifying stem cells in the cerebellum provides the research team with a target for studying both normal development and can cerous growth, said Lee. Other research teams have shown that certain genes are mutated in medulloblastoma, but it has not been clear in which particular cells these genes are mutated.
The Duke team hopes to develop animal models in which they alter genes in neural stem cells and determine whether these alterations give rise to tumors. The goal is to identify the most crucial genes involved in medulloblastoma, and then develop drugs to disrupt these genes, said Wechsler-Reya.
"If we found a gene specific to tumor cells, we could develop an agent to shut down its activity without disrupting the growth of normal cells," he said. "Chemotherapy targets all dividing cells ?not just those involved in cancer ?so it is highly toxic. Our hope is to provide the basis for less toxic, more targeted therapies."