Abstract
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.
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Abbreviations
- FGF-2:
-
fibroblast growth factor-2
- MEF:
-
mouse embryonic fibroblast
- REF:
-
rat embryonic fibroblast
- REFrm:
-
rat embryonic fibroblasts expressing the H-rasv12 and human c-myc genes
- LT:
-
large T
- REFrmpr:
-
rat embryonic fibroblasts transfected with ras, myc and the gene encoding puromycin resistance
- REFrmLTpr:
-
rat embryonic fibroblasts transfected with ras, myc and SV40LT and the gene encoding puromycin resistance
- SV40LT:
-
SV40 large T
- T-EC:
-
tumor-associated endothelial cell
- VEGF:
-
vascular endothelial growth factor
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Acknowledgements
We dedicate this paper to the memory of Judah Folkman. This study was supported by grants from the Swedish Research Council, Swedish Cancer Society, Karolinska Institutet, Cancerföreningen, Stockholm, Sweden, and EUCAAD FP7. We thank Dr. Raja Choudhury for proofreading the paper.
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Ehnfors, J., Kost-Alimova, M., Persson, N. et al. Horizontal transfer of tumor DNA to endothelial cells in vivo. Cell Death Differ 16, 749–757 (2009). https://doi.org/10.1038/cdd.2009.7
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DOI: https://doi.org/10.1038/cdd.2009.7
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