MECHANISM OF INDUCTION OF MALIGNANT GLIOMAS

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Presently, the management of gliomas consists principally of surgical resection and radiation that are effective in reducing tumor burden, but are usually not curative. The limitations of surgery and radiation are clearly related to the ability of glioma cells to infiltrate intact parenchyma, apparently, via migration from the tumor site. Thus, the development of therapies to target tumor cells within normal tissue without damaging functional neurons has considerable merit. The main obstacle to the development of such therapies is our lack of understanding of the infiltrating cell. The chemotherapeutic target in gliomas must include not only residual tumor cells left behind by surgery and radiation, but also the infiltrating cells that may be protected by an intact brain barrier and low mitotic activity thus making radiotherapy and chemotherapy less effective. Recent advances in brain tumor cell biology have given rise to the hypothesis that the cell of origin of glial tumors could be a mutated "progenitor" of glial cells which upon certain conditions gives rise to astrocytic and oligodendroglial tumors. This view is supported by the isolation of normal "progenitor" cells and the observation that most glial tumors are mixed, containing both astrocytic and oligodendrocytic components. It is further hypothesized that glioma cells may mimic their cells of origin by maintaining their migratory ability. In order to test this hypothesis the applicant has introduced the adult rat model which develops true glial tumors upon continuous exposure to N-methylnitrosourea (MNU). Multipotent progenitor cells from rats that can differentiate into either astrocytic or oligodendroglial like cells have been isolated and studied. The applicant has also isolated cells from the apparently normal brain parenchyma of MNU treated tumor free rats. These mutant cells can migrate, and differentiate into oligodendroglial or astrocytic morphologies upon stimulation with growth factors; they have some potential to induce tumors in athymic mice. Karyotyping of mutated progenitor (multipotent) cells shows various degrees of chromosomal abnormalities that correlate well with their respective tumorigenic potential. The applicant's aim is to characterize migrating gliomal cells from seemingly normal brain tissue before the development of MNU induced tumors and compare them with frank tumor cells infiltrating the eloquent parenchyma according to their potential to proliferate, transform into oligodendroglial and astrocytic morphology, expression of antigens and tumorigenic potency. Determination of genetic differences between tumorigenic and non-tumorigenic progenitor cells will be helpful in determining the mechanism(s) of glial tumor development. Genetic differences between tumor cells and those capable of infiltrating the normal parenchyma will also be identified and compared to those of initiated multipotent progenitor cells in order to understand their lineage.