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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoviruses, Human / genetics
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Adenoviruses, Human / immunology
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / immunology
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Cell Line, Transformed
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Chemotaxis, Leukocyte / immunology
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Colorectal Neoplasms / genetics*
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Colorectal Neoplasms / immunology
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Colorectal Neoplasms / pathology
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Colorectal Neoplasms / therapy*
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Cytomegalovirus / genetics
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Cytomegalovirus / immunology
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Fas Ligand Protein
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Female
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Genes, p53 / immunology*
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Genetic Therapy* / methods
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Genetic Vectors / administration & dosage
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Genetic Vectors / immunology
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Growth Inhibitors / administration & dosage
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Growth Inhibitors / genetics
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Growth Inhibitors / immunology
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Humans
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Immunohistochemistry
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Injections, Intralesional
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Injections, Subcutaneous
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Ligands
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Membrane Glycoproteins / physiology*
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Transplantation
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Neutrophil Infiltration / genetics
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Neutrophil Infiltration / immunology*
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Tumor Cells, Cultured
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fas Receptor / metabolism*
Substances
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Antineoplastic Agents
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FASLG protein, human
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Fas Ligand Protein
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Fasl protein, mouse
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Growth Inhibitors
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Ligands
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Membrane Glycoproteins
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fas Receptor