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Cellular and molecular aspects of neurocarcinogenesis
P Kleihues1, A Aguzzi, O D Wiestler
1Department of Pathology, University of Zürich, Switzerland.
Abstract:
Although the morphology of neural tumors induced in rats by N-ethyl-N-nitrosourea (NEU) and related alkylating agents has been extensively investigated, their histogenesis and the molecular basis of malignant transformation are still largely unknown. This review gives an account of the interaction of neurocarcinogenic agents with cellular DNA, the possible role of promutagenic O6-alkyldeoxyguanine and their deficient repair by the cerebral O6-alkylguanine-DNA alkyltransferase. A new experimental model is described in which neural tumors are induced in fetal brain transplants. Pregnant rats received a single iv 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. After additional exposure to NEU of the host animals 8 days and 9 weeks post transplantation, all rats developed brain tumors within the neural graft. Histopathologically, all neoplasms were classified as olidogdendrogliomas. Other neoplasms typically induced by NEU transplacentally (astrocytomas, mixed gliomas, ependymomas) were absent. The selective induction of oligodendrogliomas indicates that neoplastic transformation in the nervous system can occur in a differentiated glial cell or a precursor cell committed to oligodendrocytic differentiation, and that transformation of a pluripotential stem cell is not necessary. Transplacental exposure of the donor fetuses to NEU alone, i.e., without additional postgrafting exposure, did not produce brain tumors in any of the experimental animals indicating that in the microenvironment of fetal brain transplants the multistep development of gliomas requires additional mutational events. Malignant schwanomas perinatally induced by NEU carry a point mutation in the transmembrane domain of the neu gene. The mode of oncogene activation in NEU-induced CNS gliomas has not yet been elucidated. We have used cerebral grafting techniques to study the effects of known oncogenes on the developing nervous system, taking advantage of efficient gene transfer by replication-defective retroviral vectors and of the extraordinary capacity of fetal CNS to differentiate in and fully integrate with the host brain. Rats carrying transplants exposed in vitro to the polyoma medium T-antigen developed endothelial hemangiomas in the graft which often led to fatal cerebral hemorrhage within 13-50 days after transplantation. Introduction of the viral src gene caused astrocytic and mesenchymal tumors after latency periods of 2-6 months. Following infection of fetal donor cells with a vector encoding the v-myc oncogene, only a single embryonal CNS tumor was observed whereas exposure to v-H-ras produced a low incidence of gliomas.(ABSTRACT TRUNCATED AT 400 WORDS)
Insights
N-ethyl-N-nitrosourea (NEU) induces oligodendrogliomas in rat brain transplants, suggesting specific glial cell transformation. This model highlights the multistep development of gliomas and the role of oncogenes in neural tumors.
Area of Science:
- Neuro-oncology
- Molecular carcinogenesis
- Experimental neuropathology
Background:
- The histogenesis and molecular mechanisms of N-ethyl-N-nitrosourea (NEU)-induced neural tumors remain largely unknown.
- Understanding these processes is crucial for developing targeted therapies for brain tumors.
Purpose of the Study:
- To investigate the histogenesis and molecular basis of NEU-induced neural tumors using a novel experimental model.
- To explore the role of specific oncogenes in neural tumor development within the central nervous system (CNS).
Main Methods:
- Induction of neural tumors in fetal rat brain transplants using NEU.
- Stereotactic injection of fetal brain cells into adult rat brains.
- In vitro exposure of transplants to oncogenes (polyoma medium T-antigen, v-src, v-myc, v-H-ras) using retroviral vectors.
Main Results:
- NEU-induced brain tumors in transplants were exclusively oligodendrogliomas, indicating transformation of differentiated glial cells or precursors.
- Transplacental NEU exposure alone did not induce tumors, suggesting a requirement for additional mutations in the transplant microenvironment.
- Viral oncogenes induced various tumors, including endothelial hemangiomas, astrocytic tumors, and gliomas, with varying latency periods.
Conclusions:
- Neoplastic transformation in the nervous system can occur in committed glial precursor cells.
- The development of NEU-induced gliomas is a multistep process requiring additional genetic events.
- Cerebral grafting combined with oncogene introduction provides a powerful model for studying CNS tumor development.