CD95 LIGAND - LETHAL WEAPON AGAINST MALIGNANT GLIOMA

CD95 (Fas/APO-1) and its ligand (CD95L) belong to a growing cytokine a nd cytokine receptor family that includes nerve growth factor (NGF) an d tumor necrosis factor (TNF) and their corresponding receptors. CD95 expression increases during malignant progression from low-grade to an aplastic astrocytoma and is most prominent in perinecrotic areas of gl ioblastoma, There is, however, no evidence that CD95 expression in mal ignant gliomas is triggered by hypoxia or ischemia. Agonistic antibodi es to CD95, or the natural ligand, CD95L, induce apoptosis in human ma lignant glioma cells in vitro, Glioma cell sensitivity to CD95-mediate d apoptosis is regulated by CD95 expression at the cell surface and by the revels 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 coexpr ess CD95 and CD95L in vitro without undergoing suicide or fratricide. Yet, they kill T cells via CD95/CD95L interactions and are sensitive t o exogenously added CD95L, Since CD95L is expressed in gliomas in vivo , too, forced induction of CD95 expression might promote therapeutic a poptosis 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 antit umor 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 re garding glioma cell sensitivity to CD95L/CD95-mediated apoptosis await elucidation, CD95 is a promising target for the treatment of malignan t glioma.