Ex vivo malignant glioma cells are sensitive to Fas (CD95/APO-1) ligand-mediated apoptosis.
Fas (also known as CD95/APO-1) is a cell surface receptor and member of the tumor necrosis factor receptor superfamily which mediates apoptosis in sensitive cells upon oligomerization by specific antibodies or by its ligand (FasL). Recently, human glioma cell lines were found to be susceptible to Fas-mediated apoptosis triggered by alpha-Fas antibodies. However, whether the Fas system can also be targeted in ex vivo high grade gliomas is at present unknown. In the present investigation, alpha-Fas antibodies and FasL were tested in short-term monolayer cultures or in colony forming assays established from freshly resected tumors of patients with anaplastic astrocytomas (WHO grade III) and glioblastoma multiforme (WHO grade IV). Anti-Fas antibodies induced only moderate apoptosis in four of the 19 tested glioma cell cultures. This contrasts FasL which induced apoptosis in all of the 19 tumor cell cultures analyzed. Mean cytotoxicity of glioma cell cultures treated for 48 h with alpha-Fas antibodies or FasL was 9.6% and 44.3%, respectively. Irrespective of whether alpha-Fas antibodies or FasL were used, pretreatment with recombinant hu (rhu) IFN-gamma and rhuTNF-alpha for 48 h did not sensitize glioma cells to Fas-mediated cytotoxicity. The long-term effect by FasL on tumor colony formation was more striking. FasL treatment resulted in more than 90% inhibition of clonal tumor cell growth of all the eight high grade gliomas analyzed. These results suggest that Fas targeting by FasL but not by alpha-Fas antibodies may provide a promising approach for locoregional glioma treatment.
Department of Neurosurgery, University Hospital Zürich, Switzerland. kfrei@nch.unizh.ch
K
K
Frei
B
B
Ambar
N
N
Adachi
Y
Y
Yonekawa
A
A
Fontana
D000906:Antibodies / Q000276:immunology; D017209:Apoptosis / Q000502:physiology*; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D008562:Membrane Glycoproteins / Q000494:pharmacology / Q000502:physiology*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000473:pathology; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000276:immunology / Q000378:metabolism
D000906:Antibodies; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D019014:fas Receptor