Recombinant adenovirus expressing wild-type p53 is antiangiogenic: A proposed mechanism for bystander effect

Angiogenesis is required for the growth and progression of malignancies, Re cent studies have demonstrated that genetic alterations may accompany acqui sition of the angiogenic phenotype, The tumor suppressor gene p53 is most f requently mutated in human cancers and is also known to be a transcriptiona l 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 ce ll lung cancer cell line. Mutant p53-expressing H226Br non-small cell lung cancer cells were transduced with the wt-p53 gene using a recombinant adeno viral vector (Ad5CMVp53) and applied to semiquantitative reverse transcript ion-PCRs for the detection of altered mRNA expression of angiogenic and/or antiangiogenic factors. In vivo neovascularization assay of Ad5CMVp53-infec ted cells was then performed using a membrane-diffusion chamber system s.c. transplanted in nu/nu mice. We also evaluated the effect of Ad5CMVp53-infe cted H226Br cells on nontransduced tumor cells in vivo by s.c. inoculating mixture of cells into nu/nu mice. Ad5CMVp53 infection markedly inhibited th e expression of an angiogenic factor, vascular endothelial growth factor, a nd increased the expression of a novel antiangiogenic factor, brain-specifi c angiogenesis inhibitor 1, resulting in reduced neovascularization in vivo . Mixing experiments showed that tumor cells transduced with the wt-p53 gen e inhibited the in vivo tumor growth of adjacent nontransduced cells. Our d ata suggest that a recombinant adenovirus expressing the wt-p53 gene is ant iangiogenic, which may explain, in part, the mechanism of the bystander eff ect induced by the wt-p53 gene transfer on adjacent tumor cells.