title: Contribution of CD95 ligand-induced neutrophil infiltration to the bystander effect in p53 gene therapy for human cancer.
abstract: Clinical trials of adenoviral p53 gene therapy provide the evidence that the bystander effect induced by the wild-type p53 gene transfer on adjacent tumor cells contributes to tumor progression; its mechanism, however, remains uncharacterized. We report in this work that injection of adenovirus expressing the human wild-type p53 gene (Ad5CMVp53) into established human colorectal tumors in nu/nu mice resulted in CD95 ligand (CD95L) overexpression, followed by a massive neutrophil infiltration. Culture supernatants of human colorectal cancer cells infected with Ad5CMVp53 exhibited a potent chemotactic activity against murine polymorphonuclear neutrophils, which could be abolished by the anti-CD95L mAb (NOK-1). In vivo cell depletion experiments indicated that neutrophils were in part responsible for the antitumor effect of the Ad5CMVp53 infection. Our data directly suggest that overexpression of CD95L by the wild-type p53 gene transfer induces neutrophil infiltration into human colorectal tumors, which may play a critical role in the bystander effect of p53 gene therapy.
authors.affiliation: Section of Molecular Oncology, First Department of Surgery, Okayama University Medical School, Okayama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Waku
authors.forename: T
authors.initials: T
authors.lastname: Fujiwara
authors.forename: J
authors.initials: J
authors.lastname: Shao
authors.forename: T
authors.initials: T
authors.lastname: Itoshima
authors.forename: T
authors.initials: T
authors.lastname: Murakami
authors.forename: M
authors.initials: M
authors.lastname: Kataoka
authors.forename: S
authors.initials: S
authors.lastname: Gomi
authors.forename: J A
authors.initials: JA
authors.lastname: Roth
authors.forename: N
authors.initials: N
authors.lastname: Tanaka
mesh_terms: D000260:Adenoviruses, Human / Q000235:genetics / Q000276:immunology; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000276:immunology; D002461:Cell Line, Transformed; D002634:Chemotaxis, Leukocyte / Q000276:immunology; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology; D053222:Fas Ligand Protein; D005260:Female; D016158:Genes, p53 / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods; D005822:Genetic Vectors / Q000008:administration & dosage / Q000276:immunology; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D015552:Injections, Intralesional; D007279:Injections, Subcutaneous; D008024:Ligands; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology*; D014407:Tumor Cells, Cultured; D019014:fas Receptor / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C505661:FASLG protein, human; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006131:Growth Inhibitors; D008024:Ligands; D008562:Membrane Glycoproteins; D019014:fas Receptor