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 potential specific target for anti-glioma therapy. However, little is known regarding the effects of Fas expression on glioma viability in vivo. The goal of this study was to clarify the relationships among Fas expression, apoptosis, and survival rates for high-grade astrocytomas.


METHODS
Fas expression was measured in several human glioblastoma multiforme cell lines and a malignant rat glioma cell line (36B10), before and after Fas up-regulation by gene transfer. Expression was correlated with the degree of Fas-mediated cytotoxicity and apoptosis induced after Fas activation. Subsequently, rats underwent intracranial implantation of either wild-type 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 multiforme were correlated with their limited susceptibility to Fas-mediated cytotoxicity. 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 ligand-producing cell line increased from 4% in the sham-transfected line (36B10-) to 27% in the Fas-transfected line (36B10-Fas). After intracranial implantation of these tumors into rats, the median survival time increased significantly from 14 days (36B10 and 36B10-) to 24.5 days (36B10-Fas), which represents a 75% increase in the survival time for the greater Fas-expressing group (P = 0.0005).


CONCLUSIONS
It seems that the overall low rate of apoptosis in high-grade astrocytomas is related to low levels of cell surface Fas expression. With increases in cellular Fas expression, rates of Fas-mediated apoptosis and survival rates were increased.
Frankel
B
B
Department of Neurosurgery, State University of New York Upstate Medical University, Syracuse 13210, USA. frankelb@mail.upstate.edu
Longo
S L
SL
Kyle
M
M
Canute
G W
GW
Ryken
T C
TC
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001932:Brain Neoplasms / Q000503:physiopathology*; D002462:Cell Membrane / Q000378:metabolism; D005910:Glioma / Q000503:physiopathology*; D006801:Humans; D008297:Male; D009368:Neoplasm Transplantation; D051381:Rats; D011916:Rats, Inbred F344; D016019:Survival Analysis; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism* / Q000502:physiology
D019014:fas Receptor