RESUMO
Tumor endothelial cells have long been regarded as genomically stable and therefore less likely to develop resistance to antiangiogenic therapies. However, recent findings have challenged this notion. We have shown that DNA can be transferred between cells through phagocytosis of apoptotic bodies by adjacent viable cells. Propagation of the ingested DNA is prevented by the activation of the p53-p21 pathway. In this study, we examined whether concomitant transfer of tumor DNA with genes that inactivate the p53 pathway could overcome the barrier to tumor DNA propagation. Our results demonstrate that fibroblasts and endothelial cells are capable of acquiring and replicating tumor DNA when the apoptotic tumor cells contain the SV40 large T antigen. Analysis of the tumor stroma of xenotransplanted tumors in severe combined immunodeficient mice revealed that a sub-population of the endothelial cells contained tumor DNA. These cells maintained the ability to form functional vessels in an in vivo assay and concurrently express tumor-encoded and endothelial-specific genes.
Assuntos
DNA de Neoplasias/metabolismo , Transferência Genética Horizontal , Animais , Antígenos Transformantes de Poliomavirus/genética , DNA de Neoplasias/genética , Células Endoteliais/metabolismo , Humanos , Camundongos , Fagocitose , Proteínas Proto-Oncogênicas c-myc/genética , Ratos , Transplante Heterólogo , Proteína Supressora de Tumor p53/metabolismoRESUMO
Tumor formation involves the accumulation of a series of genetic alterations that are required for malignant growth. In most malignancies, genetic changes can be observed at the chromosomal level as losses or gains of whole or large portions of chromosomes. Here we provide evidence that tumor DNA may be horizontally transferred by the uptake of apoptotic bodies. Phagocytosis of apoptotic bodies derived from H-ras(V12)- and human c-myc-transfected rat fibroblasts resulted in loss of contact inhibition in vitro and a tumorigenic phenotype in vivo. Fluorescence in situ hybridization analysis revealed the presence of rat chromosomes or of rat and mouse fusion chromosomes in the nuclei of the recipient murine cells. The transferred DNA was propagated, provided that the transferred DNA conferred a selective advantage to the cell and that the phagocytotic host cell was p53-negative. These results suggest that lateral transfer of DNA between eukaryotic cells may result in aneuploidy and the accumulation of genetic changes that are necessary for tumor formation.
