title: IFN-gamma-dependent delay of in vivo tumor progression by Fas overexpression on murine renal cancer cells.
abstract: The role of Fas in the regulation of solid tumor growth was investigated. Murine renal carcinoma (Renca) cells were constitutively resistant to Fas-mediated killing in vitro, but exhibited increased expression of Fas and sensitivity to Fas-mediated killing after exposure to IFN-gamma and TNF. Transfected Renca cells overexpressing Fas were efficiently killed in vitro upon exposure to anti-Fas Ab (Jo2). When Fas-overexpressing Renca cells were injected into syngenic BALB/c mice, there was a consistent and significant delay in tumor progression, reduced metastasis, and prolonged survival that was not observed for Renca cells that overexpressed a truncated nonfunctional Fas receptor. The delay of in vivo tumor growth induced by Fas overexpression was not observed in IFN-gamma-/- mice, indicating that IFN-gamma is required for the delay of in vivo tumor growth. However, there was a significant increase of infiltrated T cells and in vivo apoptosis in Fas-overexpressing Renca tumors, and Fas-overexpressing Renca cells were also efficiently killed in vitro by T cells. In addition, a strong therapeutic effect was observed on Fas-overexpressing tumor cells by in vivo administration of anti-Fas Ab, confirming that overexpressed Fas provides a functional target in vivo for Fas-specific ligands. Therefore, our findings demonstrate that Fas overexpression on solid tumor cells can delay tumor growth and provides a rationale for therapeutic manipulation of Fas expression as a means of inducing tumor regression in vivo.
authors.affiliation: Laboratory of Experimental Immunology, Division of Basic Sciences, National Cancer Institute-Frederick Cancer Research and Development Center, MD 21702-1201, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Lee
authors.forename: T J
authors.initials: TJ
authors.lastname: Sayers
authors.forename: A D
authors.initials: AD
authors.lastname: Brooks
authors.forename: T C
authors.initials: TC
authors.lastname: Back
authors.forename: H A
authors.initials: HA
authors.lastname: Young
authors.forename: K L
authors.initials: KL
authors.lastname: Komschlies
authors.forename: J M
authors.initials: JM
authors.lastname: Wigginton
authors.forename: R H
authors.initials: RH
authors.lastname: Wiltrout
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D004357:Drug Synergism; D007106:Immune Sera / Q000008:administration & dosage; D007113:Immunity, Innate; D015552:Injections, Intralesional; D007371:Interferon-gamma / Q000502:physiology*; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D011994:Recombinant Proteins / Q000096:biosynthesis; D017384:Sequence Deletion; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000502:physiology; D015854:Up-Regulation / Q000276:immunology; D019014:fas Receptor / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology / Q000502:physiology
chemical_list: D007106:Immune Sera; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D007371:Interferon-gamma