Link Revealed Between Adult Progenitor Cells and Malignant Brain Tumors
A group of CUMC researchers is making considerable progress in the study of diffusely infiltrating gliomas, the most common type of brain tumor. Glioma cells have a remarkable capacity to disperse widely throughout the brain, making complete surgical resection impossible.
|Double fluorescence confocal micrograph taken at the edge of a PDGF driven glioma shows retrovirally infected glial progenitors (green) infiltrating the adjacent brain tissue along blood vessels (red) stained with an antibody against rat endothelial cell antigen (RECA).
Using time-lapse microscopy to monitor the behavior of green fluorescent protein (GFP) expressing glioma cells in slice culture, Peter Canoll, M.D., Ph.D., assistant professor, pathology, and colleagues Jeffrey Bruce, M.D., associate professor of neurosurgery, Department of Neurological Surgery, and James Goldman, M.D., Ph.D., professor of pathology, Department of Pathology and the Center for Neurobiology and Behavior, recently published a paper showing that transplanted glioma cells infiltrate the host brain by migrating along the abluminal, or outside, surface of blood vessels. The migrating glioma cells proliferate en route, pausing briefly to divide at vascular branch points.
“This study provided a first glimpse at the way glioma cells migrate through living brain tissue,” Dr. Canoll says. “The findings suggest that glioma migration and proliferation is regulated by interactions with the brain vasculature.”
Another finding was that the migratory behavior of the glioma cells closely resembled the migration of glial progenitors that occurs during brain development. Glial progenitors normally give rise to the brain’s two major support cells (astrocytes and oligodendrocytes). A subpopulation of glial progenitors remains immature and proliferates throughout life, accounting for one of the largest population of cycling cells in the adult brain. “The similarities between glioma cells and glial progenitors are remarkable, and strongly support the idea that gliomas arise from transformation of glial progenitors,” Dr. Canoll says.
Following up on this lead, Marcela Assanah, Ph.D., a postdoc working with Dr. Canoll, recently published a study showing that glial progenitors in the adult white matter can be induced to form malignant brain tumors when infected with retroviruses that express platelet-derived growth factor (PDGF), a strong mitogen (a substance that triggers cell division) and motogen (a trigger of cell migration) for glial progenitors. As was seen in the previous study with transplanted glioma cells, the PDGF-driven tumor cells infiltrated the surrounding brain tissue by migrating along blood vessels (see figure). The infected cells also migrated along nerve fiber tracts and the tumors extended across the corpus callosum the thick band of nerve fibers that connects the two hemispheres of the brain into the contralateral hemisphere, a pattern of invasion frequently seen in human gliomas.
“As a neuropathologist, I was impressed with how closely the retrovirus induced tumors resembled the malignant gliomas we see in human patients,” Dr. Canoll says. “But most surprising was how rapidly and consistently the tumors formed 100 percent of the animals formed tumors within two weeks of infection. It is well established that PDGF can drive tumor formation, but this was the first study to identify a group of cells in the adult brain that have the proliferative capacity to form tumors.”
The retroviruses that Dr. Assanah and colleagues are using in their studies also express GFP, allowing them to monitor the behavior of individual infected cells in slice culture by time-lapse microscopy. “Slice cultures provide a convenient system to test the effects of drugs on the migration and proliferation of cells within the context of living brain tissue,” says Dr. Canoll. “We are currently using this approach to treat the PDGF driven tumors with a variety of small molecule inhibitors that block different steps in the PDGF signaling pathways.
Our goal is to understand how PDGF drives glial progenitors to form tumors and to use this information to develop more effective targeted therapies.”
Articles cited: GLIA 53: 799-808 and The Journal of Neuroscience 26(25) 6781-6790. Research supported by grants from the Sontag Foundation in conjunction with the American Brain Tumor Association, the Children’s Brain Tumor Foundation, the NIH, and the Reza Khatib Fellowship.
Antidepressants Found Not Helpful in Anorexia Nervosa
Though patients with anorexia nervosa experience the same symptoms as many with other serious psychiatric illnesses, research suggests that treatment with antidepressant medications known to be effective for depression, anxiety and obsessive-compulsive disorders has little impact on the course of anorexia nervosa. B. Timothy Walsh, M.D., Ruane Professor of Pediatric Psychopharmacology, and a team of researchers from the New York State Psychiatric Institute, the University of Toronto and Toronto General Hospital have found that patients with anorexia nervosa taking fluoxetine in conjunction with individual therapy sessions showed essentially the same rate of relapse as those whose medication was replaced with a placebo.
While most controlled trials done to date have shown no significant benefit over a placebo, these studies were done during the initial, weight restoration phase of treatment. Since the efficacy of medications may be compromised among patients at a low body weight, researchers have been studying the effects of medications on patients who have successfully undergone weight restoration. These patients, however, are still at high risk for relapse. In fact, 30 percent to 50 percent of patients need to be re-hospitalized within one year of discharge.
Though antidepressants are routinely prescribed for patients with anorexia nervosa, Dr. Walsh and his team have found that these medications have no substantial benefit and believe that to improve patients’ prognoses, alternative methods must be developed. There is already some evidence that psychological and behavioral therapies can show positive results, so further examination of the basic behavioral and cognitive problems underlying anorexia nervosa may lead to far more effective treatments.
JAMA 295: 2605-2612. This study was supported in part by the NIH. Eli Lilly supplied fluoxetine and placebo.
Trucks, Vans and Children A Lethal Mix
Children face a significantly higher risk of injury or death from pedestrian traffic crashes involving light trucks and vans, according to a study conducted by Charles DiMaggio, Ph.D., assistant professor of clinical epidemiology at the Mailman School of Public Health.
While a great deal of research addresses factors leading up to traffic crashes in an effort to help prevent them, Dr. DiMaggio’s work focused on the consequences of these incidents on pedestrians in particular, children and teens aged 5 to 19.
“I worked in emergency medicine for many years and wanted to help decrease what I considered the most objectionable and preventable serious trauma we commonly saw pediatric pedestrian injuries,” Dr. DiMaggio says. “Sports utility vehicles and the like seemed to be disproportionately involved in severe injuries to children. I wanted to help find ways to make them safer.”
Not only are these vehicles twice as likely as cars to be involved in fatal injuries to children, they’re also four times more likely to result in the deaths of 5- to 9- year olds. “Kids need to safely share the outdoors with vehicles,” Dr. DiMaggio says. “Pediatric pedestrian injuries are severe and unforgiving, so much of the emphasis has been on preventing them from occurring in the first place. This has, in fact, been a largely successful effort, but part of this success may be coming at the expense of children’s mobility. If children are less likely to play outdoors, it may contribute to other problems, like obesity. Given the popularity and ubiquity of these types of vehicles, even modest reductions in risk could translate into an appreciable impact on outcomes, such as severe head injuries or death.”
Int J Inj Contr Saf Promot 13(2): 95-99. The work was funded in part by the New York City Department of Transportation Safety Division.