Cell-specific brain tumour induction in neural transplants: evidence for multistep carcinogenesis in the nervous system.

Using neural grafting techniques, an attempt was made to elucidate the histogenesis of gliomas induced transplacentally by N-ethyl-N-nitrosourea (ENU). Pregnant rats received a single intravenous dose of ENU (50 mg/kg body weight) on day 14 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 intravenous injections of ENU (50 mg/kg each) eight days and nine weeks after the neural graft. Histopathologically, these neoplasms were classified as oligodendrogliomas, ranging from early neoplastic foci to large, infiltrating malignant tumours. The selective induction of oligodendrogliomas indicates that neoplastic transformation in the nervous system can occur in oligodendrocytes or in precursor cells committed to oligodendrocytic differentiation and that transformation of a pluripotential stem cell is not necessary. Omission of the first (prenatal) dose of ENU led to a much lower tumour incidence, whereas this dose in itself, i.e., without additional postgrafting exposure, did not produce brain tumours in any of the experimental animals. This differential effect of pre- and postgrafting exposure to ENU constitutes the first evidence for a multistep development of brain tumours in vivo.