During early development, the usual function of nerve growth factor (NGF) is to assist immature neuronal cells to survive and differentiate into a variety of nerve and brain tissues. Now, researchers at the University of Pennsylvania Medical Center have discovered that, paradoxically, NGF is also able to induce cells from a common type of childhood brain tumor called a medulloblastoma to undergo massive apoptosis, or cell suicide, when those cells have been engineered to express a receptor for NGF. A report on the study appears in the January 15 issue of The Journal of Neuroscience.
The surprising findings indicate that a gene therapy approach based on the mechanism might be useful in treating such cancers. Additionally, based on this and other studies, scientists may have to expand their understanding of the roles played by NGF and related biochemicals, also known as trophic or survival factors, in the development of the organism.
"One could say that these so-called growth factors have a dark side, too," observes Virginia M.-Y. Lee, PhD, a professor of pathology and laboratory medicine and senior author on the report. "They appear to be able to able to act in two directions, supporting the survival of cells or killing them depending on the stage of development."
NGF has been shown to serve a crucial purpose in helping early-stage neurons to thrive and reach their fully differentiated state, Lee explains. In fact, a number of investigators have conducted experiments showing that these cells die in the absence of NGF. In neural systems, however, it is also true that cells must cease to proliferate at a certain point, since mature nerve and brains cells are nondividing. So, the only neural cells that might continue to divide would be primitive, progenitor cell types or cancerous cells, neither of which should be present among most mature nerve or brain cell populations.
"Our study suggests that NGF may provide a single, needed mechanism by which dividing cells are killed while nondividing cells continue to differentiate," Lee says.
For their experiments, Lee and her colleagues infected two human medulloblastoma cell lines with a retroviral vector engineered to incorporate a gene that codes for the NGF-specific receptor. Cells thus infected subsequently expressed the receptor, referred to as TrkA, on their surfaces. Only about 25 percent of wild-type medulloblastoma cells naturally display the TrkA receptor.
Counter intuitively, the cancer cells underwent massive apoptosis when subsequently treated with NGF, a substance known to promote survival of neuronal progenitor cells and immature neurons of the central and peripheral nervous systems. Similar NGF-treatments of wild-type cells uninfected with the gene-bearing retroviral vector or cells infected with an empty vector did not induce cell suicide, and cells expressing other Trk-family receptors were likewise unaffected.
Yoshihiro Muragaki, MD, affiliated with both Penn and the Tokyo Women's Medical College, and Thomas T. Chou, BS, an MD-PhD student, are lead authors on the paper, having contributed equally to the work. John Q. Trojanowski, MD, PhD, a professor of pathology and laboratory medicine, is a coauthor, as is David R. Kaplan, PhD, formerly with the National Cancer Institute and now at McGill University in Montreal, Canada. Funding support was provided by the National Institutes of Health and the Alzheimer's Association.
Dr. Virginia M.-Y. Lee can be reached at (215) 662-6920.
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