A multi-institutional study led by researchers at Cincinnati Children's Hospital Medical Center has led to new insights and a model to help unravel the cause of fibrous, non-cancerous nerve tumors called neurofibromas, which can lead to disfigurement and in rare cases death by compressing vital organs. Writing for the February Cancer Cell, researchers said their findings also provide a means for testing therapies that could eventually help patients who now have limited options for treating the disease, called Neurofibromatosis type 1.
"We have developed a mouse model that allows us to mimic as closely as possible the formation in humans of two kinds of neurofibromas, which are non-cancerous tumors that affect children and adults," said Nancy Ratner, Ph.D., study co-author and a researcher in the Division of Experimental Hematology and Cancer Biology at Cincinnati Children's. "Our findings give us a way to begin clarifying the biological mechanisms underlying the tumor formation in Neurofibromatosis and to have a platform for therapeutic testing."
Previous research has determined that neurofibromas result from a mutation in a gene (called Nf1), which normally acts as a tumor suppressor by producing a complex protein called neurofibromin to help regulate cell growth. Mutation of the Nf1 gene inhibits neurofibromin production, leading to irregular cell growth and possible tumor development. Dr. Ratner and her colleagues suggest in their study that the timing of this gene mutation is critical to whether neurofibroma tumors form.
In one set of experiments, the researchers worked with genetically engineered nerve root cells from embryonic mice. They discovered that mutating both of two mouse Nf1 genes at 12.5 days after conception (a critical stage in mouse embryonic development when cells that eventually differentiate to form the nervous system are just getting ready to do so) would create cell colonies. In another set of experiments, researchers worked with mice that were genetically engineered for expression of a gene called Desert Hedgehog (Dhh) using a genetic trick to cause Nf1 mutation only in cells that express that gene.
Again, the researchers discovered that by mutating both Nf1 genes at 12.5 days post conception in developing nerve cells, the resulting adult mice developed neurofibromas and had shorter life spans than their littermates whose genes were not mutated. If the mutations occurred earlier or later than 12.5 days, in both sets of experiments neurofibroma cells did not begin to form.
Dr. Ratner and her colleagues report that because nerves from patients with Neurofibromatosis type 1 have not been analyzed, direct comparisons between disease formation in humans and mice can not yet be made.
Neurofibromatosis 1 is an autosomal dominant inherited disease, which means the gene mutation only needs to occur in one chromosome for a person to get the disease. Disease symptoms may be evident at birth, during infancy and almost always by the time a child is 10 years old. The condition affects one of every 3,000 people worldwide with nearly 90 percent of the patients developing neurofibromas. Many NF1 patients conduct normal lives with the disease, with the primary manifestation being numerous soft brown pigment spots on the skin, and numerous tumors that are very small under the skin. Other patients, however, develop learning disabilities, scoliosis, and benign brain tumors as children, and are at risk for cardiovascular problems and malignant tumors as adults. Cincinnati Children's has a leading multi-disciplinary clinic for diagnosis and management of NF1.
The study included researchers from the Hoxworth Blood Center, University of Cincinnati College of Medicine; Departments of Pathology at Massachusetts General Hospital and Harvard Medical School (Boston) and the Departments of Cell Biology and Genetics at Erasmus University Medical Center (Rotterdam, Netherlands). Also offering assistance through provision of genetically engineered mice and other materials were the University of Texas Southwestern, the Stowers Institute and Rockefeller University. Funding support came from the National Institutes of Health.
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