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Reprogrammed nucleus model could offer valuable clues to how certain influencing factors combine with DNA mutations to cause tumors
Nuclei removed from mouse brain tumor cells and transplanted into mouse eggs whose own nuclei have been removed, give rise to cloned embryos with normal tissues, even though the mutations causing the cancer are still present. This research, from scientists at St. Jude Children's Research Hospital, appears in the June 1 issue of Cancer Research.
The finding demonstrates that the cancerous state can be reversed by reprogramming the genetic material underlying the cancer, according to James Morgan, Ph.D., a member of the St. Jude Department of Developmental Neurobiology, and lead author of the study. The findings also indicate that genetic mutations alone are not always sufficient to cause a cell to become cancerous.
“Specifically, it shows that so-called epigenetic factors are key elements in the development and maintenance of tumors,” Morgan said.
Epigenetic factors are those that influence the cell’s behavior. Examples include environmental effects and chemical modification.
“The concept of epigenetic factors having a role in cancer is already largely accepted,” Morgan said. “In fact, it’s already known that epigenetic alterations of chromosomes can cause certain rare forms of cancer. And some anti-cancer agents actually target epigenetic changes. But this is the first formal proof of the theory in a living animal.”
Unlike mutations, epigenetic modifications of DNA are potentially reversible molecular events that cause changes in gene expression. Some genes that help prevent the development of cancer (e.g., tumor suppressor genes) can be targets of epigenetic factors. The inactivation of such a gene might make the DNA more vulnerable to developing a cancer-causing mutation.
The St. Jude researchers used nuclei from mouse medulloblastoma cells to create the clones. Medulloblastomas are brain tumors that tend to spread to the spinal cord. They account for about 20 percent of childhood brain tumors and most often occur in children under ten years of age.
The team, led by Morgan and department chair Tom Curran, Ph.D., placed nuclei from medulloblastoma cells into mouse eggs whose own DNA had been removed.
“Since the embryos did not develop tumors, we conclude that the cancerous properties were removed by reprogramming,” Morgan said.
“The use of mouse eggs to reprogram cancer cell DNA represents a new strategy for investigating the molecular basis of cancer,” Curran said. “By studying this model we hope to identify which epigenetic factors may contribute to this form of brain tumor. In addition, it also gives us a valuable tool for testing new therapies.”
Other authors of the study include Leyi Li, Michele Connelly and Cynthia Wetmore.
This work was supported in part by a National Institute of Health (NIH) Cancer Center Support CORE grant, ALSAC, the Pediatric Brain Tumor Foundation and NIH grants.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tenn., St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fund-raising organization.
Last update: June 2003