Evidence for an origin of ethyl-nitrosourea-induced rat central nervous system tumors from pluripotent germinal neuroepithelium

Brain tumors induced by transplacental application of ethyl-nitrosourea (ENU) in F344 rats were immunohistochemically demonstrated to consist of undifferentiated cells, astriocyte-like cells, oligodendroglia-like cells, and two distinct types of vimentin-expressing cell groupings termed as perivascular small cell nests (PSCNs) and large cell nests (LCNs). Co-distribution of vimentin and glial fibrillary acidic protein (GFAP) was sparsely ovserved in the astrocyte-like cells, which suggested an immature glial phenotype. PCSNs contained cells expressing GFAP, neuron-specific enolase (NSE), β-tubulin isotype III, and low-affinity nerve growth factor receptors (LNGFRs). LCNs contained cells showing a neuronal phenotype with expression of low- and middle-molecular mass neurofilament proteins (NF-L and-M) as well as NSE, β-tubulin isotype III and LNGFR. Double-labelling immunohistochemistry revealed the NF-L-expression in LNGFR-positive LCN-forming cells. Oligodendroglia-like cells and their intercellular neuropil-like structures expressed β-tubulin isotype III, synaptophysin and NSE, in addition to the expressions of vimentin and GFAP. Electron microscopically, synapse-like structures were formed between these oligodendroglia-like cells and their dendritic processes. Topographically, bidirectional cell transitions from PSCNs to astrocytes and LCNs were indicated. The present study strongly suggests that so-called ENU-induced "gliomas" originate from pluripotent germinal neuroepithelium. Furthermore, LNGFR expression may be responsible for acquisition of neuronal phenotype in these tumors.