Contribution of CD95 ligand-induced neutrophil infiltration to the bystander effect in p53 gene therapy for human cancer.
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.
Waku
T
T
Section of Molecular Oncology, First Department of Surgery, Okayama University Medical School, Okayama, Japan.
Fujiwara
T
T
Shao
J
J
Itoshima
T
T
Murakami
T
T
Kataoka
M
M
Gomi
S
S
Roth
J A
JA
Tanaka
N
N
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*
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