Malignant glioma-derived soluble factors regulate proliferation of normal adult human astrocytes

Malignant gliomas are characteristically surrounded by marked gliosis. To assess whether glioma-derived products contribute to the proliferation of astrocytes, a feature of the gliosis response, we evaluated the influence of culture supernatants from malignant human glioma lines and tumor cyst fluids collected from two patients with glioblastoma multiforme on the proliferation of non-transformed adult human astrocytes. Both the culture supernatants and cyst fluids significantly increased DNA synthesis in astrocytes as assessed by a double immunofluorescence glial fibrillary acidic protein-bromodeoxyuridine technique. The net proliferative effect mediated by glioma cell line supernatants was tumor growth phase-dependent, being preferentially expressed during the logarithmic phase of glioma cell growth. Specific growth factor molecules and cytokines known to be secreted by gliomas (epidermal growth factor, fibroblast growth factor, platelet-derived growth factor, transforming growth factor-beta, interleukin-6, and tumor necrosis factor-alpha) could not reproduce the mitogenic effects of the glioma-derived soluble factors. Cytokines which can induce DNA synthesis by adult human astrocytes in vitro, gamma-interferon and interleukin-1, were not detected in the culture supernatant of glioma lines used in this study. In conjunction with the documented effects of glioma products on endothelial and lymphoid cells, the current study suggests that soluble glioma products can contribute to the production of surrounding gliosis observed in vivo.