Journal of Neuro-Oncology 24: 57-59, 1995. 9 1995 Kluwer Academic Publishers. Printed in the Netherlands. The neuroepithelial stem cell concept: implications for neuro-oncology Oliver Br0stle and Ronald D.G. McKay Laboratory of Molecular Biology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA Key words: nestin, stem cell, neurogenesis, cell progenitors, neuroepithelial cell Neoplastic transformation of neuroepithelial pre- cursor cells is considered an initial event in the de- velopment of various CNS tumors. Although first proposed many years ago by Cushing [1], this hy- pothesis is still based on sparse experimental evi- dence. Experiments in this area have been ham- pered by the difficulties in identifying, isolating and manipulating neural precursor cells. Recently there has been considerable progress analysing the linea- ge of differentiated cells in the central nervous sys- tem. This work shows that the different cells in the brain are often derived from multipotential precur- sors. The plasticity of the system focusses attention on the cell-cell signals that control cell numbers and types in the nervous system. These signals act in a cellular context, to define the signals we need to identify the responding cell or cells. Identifying pre- cursor cells in the adult brain would have important consequences for understanding brain tumor gene- sis. The nestin intermediate filament - hallmark of neuroepithelial stem cells Cloning of the nestin gene greatly facilitated the identification of neuroepithelial stem cells [2]. Nes- tin represents a new class of intermediate filaments and is highly expressed in the developing CNS. Be- fore neurogenesis, up to 98% of the cells in devel- oping brain and spinal cord express nestin. During neuro- and gliogenesis, nestin expression is down- regulated [3]. Typically, the downregulation of nes- tin is followed by the expression of new cell type- specifc intermediate filaments, e.g., neurofila- ments and glial fibrillary acidic protein (GFAP). These changes in the intermediate filament profile have proved valuable in the precise developmental staging and isolation of precursors for neurons and glia [4-6]. Reexpression of nestin in neuroepithelial tumors With the exception of scattered tanycytes lining the ventricular system, the nestin protein is no longer expressed in mature glial or neuronal cells of the normal adult brain [6]. If one considers neoplastic transformation of neural precursors a major tumo- rigenic pathway, wouldn't one expect the tumor cells to retain some of their intermediate filament expression profile? Strong expression of nestin is found in biopsy specimens and cell lines derived from human primitive neuroectodermal tumors (PNET), astrocytomas and ependymomas [7, 8]. However, from these data it is not clear whether the nestin expression results from a precursor origin of the tumor or merely represents an aberrant gene expression in a neoplasm derived from a more ma- ture cell population. Neoplastic transformation of neural progenitors in medulloblastoma is empha- sized by the occurrence of the tumor in late devel- oping regions and the tumor architecture, which frequently features nestin-positive columnar epi- thelial cells.