title: Living T9 glioma cells expressing membrane macrophage colony-stimulating factor produce immediate tumor destruction by polymorphonuclear leukocytes and macrophages via a "paraptosis"-induced pathway that promotes systemic immunity against intracranial T9 gliomas.
abstract: Cloned T9-C2 glioma cells transfected with membrane macrophage colony-stimulating factor (mM-CSF) never formed subcutaneous tumors when implanted into Fischer rats, whereas control T9 cells did. The T9-C2 cells were completely killed within 1 day through a mechanism that resembled paraptosis. Vacuolization of the T9-C2 cell's mitochondria and endoplasmic reticulum started within 4 hours after implantation. By 24 hours, the dead tumor cells were swollen and terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL)-positive. Bcl2-transduced T9-C2 cells failed to form tumors in rats. Both T9 and T9-C2 cells produced cytokine-induced neutrophil chemoattractant that recruited the granulocytes into the tumor injection sites, where they interacted with the tumor cells. Freshly isolated macrophages killed the T9-C2 cells in vitro by a mechanism independent of phagocytosis. Nude athymic rats treated with antiasialo GM1 antibody formed T9-C2 tumors, whereas rats treated with a natural killer cell (NK)-specific antibody failed to form tumors. When treated with antipolymorphonuclear leukocyte (anti-PMN) and antimacrophage antibodies, 80% of nude rats formed tumors, whereas only 40% of the rats developed a tumor when a single antibody was used. This suggests that both PMNs and macrophages are involved in the killing of T9-C2 tumor cells. Immunocompetent rats that rejected the living T9-C2 cells were immune to the intracranial rechallenge with T9 cells. No vaccinating effect occurred if the T9-C2 cells were freeze-thawed, x-irradiated, or treated with mitomycin-C prior to injection. Optimal tumor immunization using mM-CSF-transduced T9 cells requires viable tumor cells. In this study optimal tumor immunization occurred when a strong inflammatory response at the injection of the tumor cells was induced.
authors.affiliation: Diagnostic and Molecular Health Care Group, Veterans Affairs Medical Center, Long Beach, CA 90822, USA.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Chen
authors.forename: Thomas
authors.initials: T
authors.lastname: Douglass
authors.forename: Edward W B
authors.initials: EW
authors.lastname: Jeffes
authors.forename: Qingcheng
authors.initials: Q
authors.lastname: Xu
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Williams
authors.forename: Neary
authors.initials: N
authors.lastname: Arpajirakul
authors.forename: Christina
authors.initials: C
authors.lastname: Delgado
authors.forename: Michael
authors.initials: M
authors.lastname: Kleinman
authors.forename: Ramon
authors.initials: R
authors.lastname: Sanchez
authors.forename: Qinghong
authors.initials: Q
authors.lastname: Dan
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Kim
authors.forename: H Terry
authors.initials: HT
authors.lastname: Wepsic
authors.forename: Martin R
authors.initials: MR
authors.lastname: Jadus
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001932:Brain Neoplasms / Q000276:immunology*; D016923:Cell Death; D019743:Chemokines, CXC; D002630:Chemotactic Factors / Q000502:physiology; D005260:Female; D005615:Freezing; D015870:Gene Expression; D005910:Glioma / Q000276:immunology* / Q000378:metabolism*; D006133:Growth Substances / Q000502:physiology; D006358:Hot Temperature; D007114:Immunization; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins; D007694:Killer Cells, Natural / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor / Q000235:genetics* / Q000502:physiology; D008264:Macrophages / Q000276:immunology*; D008854:Microscopy, Electron; D016685:Mitomycin / Q000494:pharmacology; D009504:Neutrophils / Q000276:immunology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D014162:Transfection; D014407:Tumor Cells, Cultured; D014965:X-Rays
chemical_list: D000906:Antibodies; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D016685:Mitomycin; D016173:Macrophage Colony-Stimulating Factor