CELL BIOLOGY OF GLIOMAS AND PERSPECTIVES FOR MOLECULAR THERAPIES

Gliomas are a very heterogenous group of neoplasms and accordingly dif ferent etiological mechanisms have been worked out. Depending on the g enetic event or events, these tumors arise de novo as a very aggressiv e biological entity or they may progress slowly over many years, start ing with a lowgrade lesion which aquires more genetic defects due to g enomic instability. Two pathways are implemented in the development an d progression of a glioma, one of which is the aquisition or amplifica tion or advantageous genes which activate cell proliferation most of w hich belong to the so called proto-oncogenes. Otherwise, the tumor-cel ls may have lost the function of genes which are directly or indirectl y associated with the control of the cell cycle, the so called tumor s uppressor genes. Among the first group, growth factors and their respe ctive receptors may form autocrine loops such as the PDGF/PDGF-R syste m or the EGF/EGF-R complex together with a steadily expanding group of other factors. Among the suppressor genes, the p53 gene and the very recently discovered p16 gene seem to be relevant in a high proportion of cases. The RB gene appears to be relevant in a smaller percentage o f high grade tumors. Currently developed therapeutic concepts aim at t he interference with the autocrine pathways through either antagonists , antibodies or anti-sense strategies. In a parallel development, the substitution of defective suppressor genes via retroviral gene transfe r or using adeno-virus based vectors are explored in the first animal studies. Any therapy, however, will have to include application strate gies which in the future address the phenomenon of single tumorcell mi gration through the brain parenchyma sometimes far away from the origi nal tumor site.