The research, conducted in mice, appears in the August issue of the journal Cancer Cell. The findings support growing evidence that adult stem cells may play a role in the development of some forms of cancer, said Dr. Luis Parada, senior author on the paper and director of the Center for Developmental Biology and the Kent Waldrep Center for Basic Research on Nerve Growth and Regeneration at UT Southwestern.
"Continued research into the biology of adult stem cells will aid in the understanding of how cancers originate and develop and may lead to possible new therapies for treating aggressive, currently incurable brain tumors," said Dr. Parada.
Malignant astrocytoma, or glioma, is one of the most common types of brain tumor in adults. The tumors are thought to arise from glial cells, which are non-nerve cells that provide support and nutrition to cells of the nervous system.
Because these incurable cancers generally are not detected until they are advanced, when symptoms have begun to develop, scientists have been unsure where, or what, initiates the process of uncontrolled cell replication that leads to the formation of the tumors.
Dr. Parada and his research group, including former UT Southwestern postdoctoral researcher and lead author Dr. Yuan Zhu, now at the University of Michigan Medical School, developed a strain of genetically engineered mice that served as models for their human brain-cancer studies and allowed researchers to track down the origins of such tumors. The mice lacked a tumor suppressor gene called p53 and also had a mutated version of another tumor suppressor gene called NF1. The mutated NF1 resulted in an increase in a biochemical reaction called Ras signaling, which has been implicated in the initiation of some cancers.
As infants, the mutant mice showed no sign of cancer, but as they grew older, they all developed brain tumors. By observing and evaluating "snapshots" of changes in the mouse brains over time, Dr. Parada's research team determined that the tumors originated in neural stem cells. Those cells that became cancerous then migrated to other areas of the brain and caused tumors.
Previous research has demonstrated that adult neural stem cells are isolated in only a few regions of the mammalian brain, with the highest densities of such cells occurring in the hippocampus, an area important for learning and memory, and the subventricular zone of the forebrain.
The UT Southwestern researchers found that stem cells in the subventricular zone gave rise to malignant astrocytoma in the genetically engineered mice.
"While our study cannot rule out alternative explanations for the initiation of astrocytoma, the identification of the subventricular zone as the site of tumor origin in our models may have implications on therapeutic strategies for preventing and treating a subset of human malignant astrocytomas," Dr. Parada said. "Our results challenge current dogma, which assumes that tumors of this type arise from glial cells located throughout the brain."
The results offer an explanation for why current treatment for malignant astrocytoma in humans ultimately fails. Strategies that focus only on treating localized lesions would not be sufficient to eradicate tumor cells because these cells may eventually be replenished from the cell pool within the subventricular zone, the researchers said.
They also determined that inactivation of both p53 and NF1 is sufficient to initiate the formation of the brain cancer, and that the timing of the inactivation of each gene is critical. For the malignant astrocytoma to begin forming, p53 inactivation must either precede or coincide with the increase in Ras signaling associated with the loss of NF1.
Stem cells are unspecialized cells, capable of dividing and renewing themselves for long periods of time. They can give rise to many types of specialized cells, such as blood, nerve and muscle cells. While embryonic stem cells, which are derived from very early embryos, are capable of generating all types of cells in the body during normal development, adult stem cells have lost this potential. Adult stem cells differentiate to produce cells from the tissue where they originate.
Other UT Southwestern researchers involved in the study are Dr. Dawen Zhao, assistant professor of radiology; Dr. Dennis Burns, professor of pathology; Dr. Ralph Mason, professor of radiology; and Frantz Guignard, research assistant. Researchers at the University of Wisconsin-Madison also contributed to the research.
Dr. Parada's research is supported by the National Institute of Neurological Disorders and Stroke and the Department of Defense.
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