Much of the current excitement involving the study of neural stem cells (NSCs) is associated with their potential use in replacement therapies for a variety of neurodegenerative disorders. NSCs are immature cells that can differentiate into many (if not all) neuronal and glial subtypes.1 Of particular interest are reports demonstrating region-specific dopaminergic or cholinergic differentiation, neuronal phenotypes lost in disorders such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis (ALS).2,3
Transplanted NSCs are highly motile and can migrate great distances in vivo where they have been shown to integrate seamlessly into the host’s cytoarchitecture.4 When genetically engineered to express therapeutic molecules, they exhibit great potential for use as a vehicle for widespread gene delivery in the central nervous system (CNS).5 NSCs also exhibit an unusual propensity for attraction to areas of CNS pathology, and recent studies suggest that this behavior might be harnessed for use as a mechanism for targeting CNS neoplasms.6,7
|Figure 1. Because the margins of gliomas are diffuse and glioma cells often migrate from the main tumor mass, treatment of these CNS neoplasms is often unsuccessful. In vivo, neural stem cells (NSCs) can "track" invasive glioma cells migrating from the main tumor mass. When genetically engineered to secrete IL-12, NSCs promote survival of tumor-bearing mice.
With a five-year survival rate of 2%, high-grade gliomas are the most lethal of CNS cancers.8 Glioma cells exhibit the ability to migrate from the main tumor mass and invade surrounding normal brain tissues. As a result, the tumor margins are diffuse, often making complete surgical resection impossible. A recent study by Ehtesham et al. has shown that NSCs can track migrating glioma cells in vivo, and when genetically altered to secrete interleukin-12 (IL-12), significantly prolong the survival of tumor-bearing mice.9 Following transplantation into established intracranial gliomas, NSCs were found not only interspersed within the main tumor mass but also had migrated to small neoplastic pockets in adjacent normal tissues. Remarkably, NSCs transplanted into the contralateral brain did not disperse randomly but exhibited directed migration toward the distant tumor in the opposite hemisphere. Gliomas treated with IL-12-secreting NSCs exhibited significant CD4+ and CD8+ T cell infiltration suggesting that the survival promoting effects were due to a targeted cell-mediated immune response (Figure 1).
The significant tropism that NSCs exhibit for sites of CNS neoplasm, coupled with the ability to genetically modify them to deliver therapeutic molecules, may one day represent a promising new treatment for malignant gliomas.
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- Kim, J.-H. et al. (2002) Nature 418:50.
- Wu, P. et al. (2002) Nat. Neurosci. 5:1271.
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- Ehtesham, M. et al. (2002) Cancer Res. 62:5657.