title: Recombinant adenovirus expressing wild-type p53 is antiangiogenic: a proposed mechanism for bystander effect.
abstract: Angiogenesis is required for the growth and progression of malignancies. Recent studies have demonstrated that genetic alterations may accompany acquisition of the angiogenic phenotype. The tumor suppressor gene p53 is most frequently mutated in human cancers and is also known to be a transcriptional regulator of a variety of genes. Here, we investigated the antiangiogenic effect of the wild-type p53 (wt-p53) gene transfer on a human non-small cell lung cancer cell line. Mutant p53-expressing H226Br non-small cell lung cancer cells were transduced with the wt-p53 gene using a recombinant adenoviral vector (Ad5CMVp53) and applied to semiquantitative reverse transcription-PCRs for the detection of altered mRNA expression of angiogenic and/or antiangiogenic factors. In vivo neovascularization assay of Ad5CMVp53-infected cells was then performed using a membrane-diffusion chamber system s.c. transplanted in nu/nu mice. We also evaluated the effect of Ad5CMVp53-infected H226Br cells on nontransduced tumor cells in vivo by s.c. inoculating mixture of cells into nu/nu mice. Ad5CMVp53 infection markedly inhibited the expression of an angiogenic factor, vascular endothelial growth factor, and increased the expression of a novel antiangiogenic factor, brain-specific angiogenesis inhibitor 1, resulting in reduced neovascularization in vivo. Mixing experiments showed that tumor cells transduced with the wt-p53 gene inhibited the in vivo tumor growth of adjacent nontransduced cells. Our data suggest that a recombinant adenovirus expressing the wt-p53 gene is antiangiogenic, which may explain, in part, the mechanism of the bystander effect induced by the wt-p53 gene transfer on adjacent tumor cells.
authors.affiliation: Section of Molecular Oncology, Okayama University Medical School, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Nishizaki
authors.forename: T
authors.initials: T
authors.lastname: Fujiwara
authors.forename: T
authors.initials: T
authors.lastname: Tanida
authors.forename: A
authors.initials: A
authors.lastname: Hizuta
authors.forename: H
authors.initials: H
authors.lastname: Nishimori
authors.forename: T
authors.initials: T
authors.lastname: Tokino
authors.forename: Y
authors.initials: Y
authors.lastname: Nakamura
authors.forename: M
authors.initials: M
authors.lastname: Bouvet
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*; D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000473:pathology*; D003587:Cytomegalovirus / Q000235:genetics; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D016158:Genes, p53; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000473:pathology*; D008222:Lymphokines / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000628:therapy*; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012334:RNA, Neoplasm / Q000096:biosynthesis; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
chemical_list: C468226:ADGRB1 protein, human; D020533:Angiogenesis Inhibitors; D042501:Angiogenic Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009363:Neoplasm Proteins; D011506:Proteins; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D043562:Receptors, G-Protein-Coupled; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors