Selective Induction by N-Nitrosoethylurea of Oligodendrogliomas in Fetal Forebrain Transplants

Induction of neuroepithelial neoplasms by a single transplacental exposure to N-nitrosoethylurea (NEU) has been widely used as an experimental model for human brain tumors. NEU-induced gliomas are variably composed of neoplastic oligodendrocytes, astrocytes, and ependymal cells. It has remained controversial whether these neoplasms originate from differentiated glia or from pluripotent precursor cells of the subependymal matrix layer. We have taken a novel approach to define the histogenesis of these gliomas based on neural grafting techniques and the extraordinary difference in susceptibility between the fetal and adult brain to neoplastic transformation by alkylnitrosoureas. Pregnant rats received a single i.v. dose of NEU (50 mg/kg) on the 14th day of gestation. One day later, suspensions were prepared from the fetal forebrain and stereotactically injected into the caudoputamen of adult rats. These host animals received additional i.v. injections of NEU (50 mg/kg each) 8 days and 9 weeks posttransplantation. After a mean survival time of 316 days, all animals developed brain tumors within the neural graft. Histopathologically, these neoplasms were classified as oligodendrogliomas, ranging from early neoplastic foci to large, infiltrating malignant tumors. The selective induction of oligodendrogliomas indicates that neoplastic transformation in the nervous system can occur in a differentiated glial cell or in a precursor cell committed to oligodendrocytic differentiation, and that transformation of a pluripotential stem cell is not necessary. Omission of the first (prenatal) dose of NEU led to a much lower tumor incidence, whereas this dose in itself, i.e., without additional postgrafting exposure, did not produce brain tumors in any of the experimental animals. This differential effect of pre-and postgrafting exposure to NEU constitutes the first in vivo evidence of a multistep development of brain tumors.