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Ex vivo malignant glioma cells are sensitive to Fas (CD95/APO-1) ligand-mediated apoptosis
1Department of Neurosurgery, University Hospital Zürich, Switzerland. kfrei@nch.unizh.ch
Abstract:
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.
Insights
Targeting the Fas receptor with Fas ligand (FasL) effectively induced apoptosis and inhibited tumor growth in high-grade gliomas. Alpha-Fas antibodies showed limited efficacy, suggesting FasL is a promising therapeutic target for glioma treatment.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Fas (CD95/APO-1) is a tumor necrosis factor receptor superfamily member mediating apoptosis.
- Human glioma cell lines are susceptible to Fas-mediated apoptosis via alpha-Fas antibodies.
- The efficacy of Fas targeting in ex vivo high-grade gliomas remains unknown.
Purpose of the Study:
- To investigate the potential of targeting the Fas system in ex vivo high-grade gliomas.
- To compare the efficacy of alpha-Fas antibodies and Fas ligand (FasL) in inducing glioma cell apoptosis and inhibiting tumor growth.
Main Methods:
- Short-term monolayer cultures and colony-forming assays were established from patient-derived anaplastic astrocytomas and glioblastoma multiforme.
- Cultures were treated with alpha-Fas antibodies or FasL.
- Cytotoxicity and tumor colony formation inhibition were assessed.
- Effects of pre-treatment with recombinant human interferon-gamma (rhuIFN-gamma) and tumor necrosis factor-alpha (rhuTNF-alpha) were evaluated.
Main Results:
- Alpha-Fas antibodies induced moderate apoptosis in 4/19 glioma cultures (9.6% cytotoxicity).
- FasL induced apoptosis in all 19 cultures (44.3% cytotoxicity) and >90% inhibition of clonal growth in 8/8 high-grade gliomas.
- Pretreatment with rhuIFN-gamma and rhuTNF-alpha did not enhance Fas-mediated cytotoxicity.
Conclusions:
- FasL demonstrates significant potential for targeting high-grade gliomas by inducing apoptosis and inhibiting tumor growth.
- Alpha-Fas antibodies show limited efficacy in this context.
- FasL represents a promising candidate for locoregional glioma therapy.