CD95 (Fas/APO-1) and its
ligand (
CD95L) belong to a growing
cytokine and
cytokine receptor family that includes
nerve growth factor (
NGF) and
tumor necrosis factor (TNF) and their corresponding receptors. CD95 expression increases during malignant progression from low-grade to
anaplastic astrocytoma and is most prominent in perinecrotic areas of
glioblastoma. There is, however, no evidence that CD95 expression in
malignant gliomas is triggered by
hypoxia or
ischemia. Agonistic
antibodies to CD95, or the natural
ligand,
CD95L, induce apoptosis in human
malignant glioma cells in vitro.
Glioma cell sensitivity to CD95-mediated apoptosis is regulated by CD95 expression at the cell surface and by the levels of intracellular
apoptosis-regulatory proteins, including bcl-2 family members. Several cytotoxic drugs synergize with
CD95L to kill
glioma cells. For as yet unknown reasons,
glioma cells may co-express CD95 and
CD95L in vitro without undergoing suicide or fratricide. Yet, they kill T cells via CD95/
CD95L interactions and are sensitive to exogenously added
CD95L. Since
CD95L is expressed in
gliomas in vivo, too, forced induction of CD95 expression might promote therapeutic apoptosis in these
tumors. That
glioma cells differ from nontransformed T cells in their sensitivity to CD95
antibodies or recombinant
ligand, may allow the development of selective CD95 agonists with high antitumor activity that spare normal brain tissue. A family of death
ligand/receptor pairs related to
CD95L/CD95, including APO2L (TRAIL) and its multiple receptors is beginning to emerge. Although several issues regarding
glioma cell sensitivity to
CD95L/CD95-mediated apoptosis await elucidation, CD95 is a promising target for the treatment of
malignant glioma.