Journal
ANGIOGENESIS
Volume 19, Issue 1, Pages 25-38Publisher
SPRINGER
DOI: 10.1007/s10456-015-9486-1
Keywords
Acute promyelocytic leukemia; PML-RARa; Oncogene; Extracellular vesicles; Exosomes; Angiogenesis; Tissue factor; Endothelial cells; ATRA; Targeted agents; Angiogenic signature; Extracellular; RNA; Cancer biomarker
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Funding
- Canadian Institutes of Health Research (CIHR Foundation) [MOP 111119, 133424]
- Cole Foundation
- National Natural Science Foundation of China [30801062]
- China Scholarship Council [2009831055]
- Renji Hospital
- Michael Whitehead Fellowship Endowment to Montreal Children's Hospital Foundation
- FRSQ
- Piccoli Research Fund
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Oncogenic transformation is believed to impact the vascular phenotype and microenvironment in cancer, at least in part, through mechanisms involving extracellular vesicles (EVs). We explored these questions in the context of acute promyelocytic leukemia cells (NB4) expressing oncogenic fusion protein, PML-RARa and exquisitely sensitive to its clinically used antagonist, the all-trans retinoic acid (ATRA). We report that NB4 cells produce considerable numbers of EVs, which are readily taken up by cultured endothelial cells triggering their increased survival. NB4 EVs contain PML-RARa transcript, but no detectable protein, which is also absent in endothelial cells upon the vesicle uptake, thereby precluding an active intercellular trafficking of this oncogene in this setting. ATRA treatment changes the emission profile of NB4-related EVs resulting in preponderance of smaller vesicles, an effect that occurs in parallel with the onset of cellular differentiation. ATRA also increases IL-8 mRNA and protein content in NB4 cells and their EVs, while decreasing the levels of VEGF and tissue factor (TF). Endothelial cell uptake of NB4-derived EVs renders these cells more TF-positive and procoagulant, and this effect is diminished by pre-treatment of EV donor cells with ATRA. Profiling angiogenesis-related transcripts in intact and ATRA-treated APL cells and their EVs reveals multiple differences attributable to cellular responses and EV molecular packaging. These observations point to the potential significance of changes in the angiogenic signature and activity associated with EVs released from tumor cells subjected to targeted therapy.
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