title: Glioma apoptosis induced by macrophages involves both death receptor-dependent and independent pathways.
abstract: Apoptosis of glioma may represent a promising intervention for tumor treatment. Macrophages are able to induce apoptosis in a number of tumor cells, including glioma. It is known that apoptosis of cells is executed on either a death receptor-dependent or independent pathway. Whether and how apoptosis of glioma cells induced by activated macrophages is involved in these two pathways simultaneously are not known. Using in vitro and in vivo experimental models, we investigated Bcl-2 system and Fas/FasL channel, representing the death receptor-dependent and independent pathways, respectively, in glioma cells treated with the supernatant from the activated macrophages, which was rich in tumor necrosis factor-alpha and interferon-gamma. We found that levels of Fas and FasL were up-regulated both in vitro and in vivo, accompanying an increase in the expression of caspase-8. The number of apoptotic cells was also increased significantly, although the percentage of death cells exceeded the number of tumor cells positive for Fas or FasL. It was also evident that the expression of Bax was increased, whereas the level of Bcl-2 was decreased, in glioma cells treated with the supernatant from the activated macrophages. The alteration of molecules related to both death pathways led to apoptosis of glioma and the inhibition of xenograft glioma growth in mice. Apoptosis of glioma induced by the activated macrophage is executed by way of both death receptor-dependent and independent pathways, and such an apoptosis-induced approach can effectively inhibit the growth of glioma in vivo.
authors.affiliation: Department of Surgery, the Sir Y. K. Pao Center for Cancer at Prince of Wales Hospital, and the Chinese University of Hong Kong, Shatin, NT. gchen@cuhk.edu.hk
authors.forename: George G
authors.initials: GG
authors.lastname: Chen
authors.forename: Ernest C W
authors.initials: EC
authors.lastname: Chak
authors.forename: Ying S
authors.initials: YS
authors.lastname: Chun
authors.forename: Isa K Y
authors.initials: IK
authors.lastname: Lam
authors.forename: Fanny L F
authors.initials: FL
authors.lastname: Sin
authors.forename: Billy C S
authors.initials: BC
authors.lastname: Leung
authors.forename: Ho K
authors.initials: HK
authors.lastname: Ng
authors.forename: Wai S
authors.initials: WS
authors.lastname: Poon
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000096:biosynthesis; D002452:Cell Count; D017077:Culture Media, Conditioned / Q000494:pharmacology; D003602:Cytotoxicity, Immunologic; D053222:Fas Ligand Protein; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism / Q000494:pharmacology; D007728:Kupffer Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008262:Macrophage Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000096:biosynthesis* / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis* / Q000276:immunology; D051381:Rats; D011916:Rats, Inbred F344; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000494:pharmacology; D019014:fas Receptor / Q000096:biosynthesis* / Q000276:immunology
chemical_list: D017077:Culture Media, Conditioned; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; C505662:Faslg protein, rat; D008562:Membrane Glycoproteins; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505526:Casp8 protein, mouse; C505528:Casp8 protein, rat; C506434:Casp9 protein, mouse; C506435:Casp9 protein, rat; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases