Tumor Fas (APO-1/CD95) up-regulation results in increased apoptosis and survival times for rats with intracranial malignant gliomas

OBJECTIVE: The cellular "death" receptor Fas has been proposed to be a pote ntial specific target for anti-glioma therapy. However, little is known reg arding the effects of Fas expression on glioma viability in vivo. The goal of this study was to clarify the relationships among Fas expression, apopto sis, and survival rates for high-grade astrocytomas. METHODS: Fas expression was measured in several human glioblastoma multifor me cell lines and a malignant rat glioma cell line (36B10), before and afte r Fas up-regulation by gene transfer. Expression was correlated with the de gree of Fas-mediated cytotoxicity and apoptosis induced after Fas activatio n. Subsequently, rats underwent intracranial implantation of either wild-ty pe or genetically altered 36B10 cell lines, for study of the effects of Fas up-regulation on survival rates. RESULTS: Low levels of cell surface Fas expression in glioblastomas multifo rme were correlated with their limited susceptibility to Fas-mediated cytot oxicity. Through Fas receptor up-regulation, relationships among increased Fas expression, Fas-mediated cytotoxicity, and apoptosis were demonstrated. The percentage of cells undergoing apoptosis after exposure to a Fas ligan d-producing cell line increased from 4% in the sham-transfected line (36B10 -) to 27% in the Fas-transfected line (36B10-Fas). After intracranial impla ntation of these tumors into rats, the median survival time increased signi ficantly from 14 days (36B10 and 36B10-) to 24.5 days (36B10-Fas), which re presents a 75% increase in the survival time for the greater Fas-expressing group (P = 0.0005). ONCLUSION: It seems that the overall low rate of apoptosis in high-grade as trocytomas is related to low levels of cell surface Fas expression. With in creases in cellular Fas expression, rates of Fas-mediated apoptosis and sur vival rates were increased.