Glial ontogeny and glial neoplasia: the search for closure

The last ten years have seen rapid progress in both our understanding of the normal progression and control of gliogenesis and in the laboratory techniques necessary to sustain and study most glial cell types, including progenitor cells of both type-1 astrocyte (T1A) and oligodendrocyte-type-2 astrocyte (T2A) lineage. These studies have direct relevance for the lineage analysis of human gliomas, optimizing in vitro glioma models, and suggesting potentially fertile new grounds for glioma biology research. We do not yet known whether malignant transformation occurs only in mature glia that then 'de-differentiate' into cells with glial precursor phenotypes and behavior characteristics, whether neoplastic transformation occurs in O-2A progenitor cells, or whether both mechanisms may occur in different patients. However, preliminary results suggest that astrocytomas can arise from two different glial lineages, that oligodendrogliomas and mixed oligo-astrocytomas arise exclusively from the O-2A lineage, and that medulloblastomas may also have a connection with the O-2A lineage. An ontogeny-based glioma classification system may lead to better prognostic patient data and better predict patient response to treatment than currently available classification systems. Available data from the study of developmental glial biology raises serious doubts about the fidelity and relevance of in vitro glioma models that rely on culture media supplemented with animal serum and suggest that relying on chemically-defined media conditioned by astrocytes may be the better research strategy. Findings from the study of normal gliogenesis also suggest that growth factors are likely to act as much more than simple mitogens in glioma biology. Potentially fertile areas of research for glioma biology include studying the cooperative effect of multiple growth factors, potential growth factor effects as survival factors, inhibitors of differentiation, and differentiation inducers, and studying potential positive humoral feedback loops between glioma cells and normal glial cells, as well as normal non-glial cells, within and surrounding each glioma.