Distinct mRNAs in Cancer Extracellular Vesicles Activate Angiogenesis and Alter Transcriptome of Vascular Endothelial Cells

SIMPLE SUMMARY: Cancer extracellular vesicles (EVs) are implicated in various processes of cancer development, with most of the EV-induced changes attributed to EV proteins and microRNAs. However, the knowledge about the cancer EV-mRNAs remains limited. Here, we have assessed the mRNAs of 61 diverse oncogenes and found half of them, including VEGFA and SNAIL1/2, are abundant in cancer EVs while absent in non-tumorigenic cell-derived EVs. Fluorescent trafficking shows the EV VEGFA mRNAs are translatable after being internalized by the recipient cell. Concomitantly, the cancer EVs induced VEGFA-dependent angiogenesis and upregulated epithelial-mesenchymal transition-related genes. Our findings reveal that the EV-mRNA profile can reflect the cell malignancy, and the intercellular transfer of these mRNAs can contribute toward tumor angiogenesis. ABSTRACT: Cancer-derived extracellular vesicles (EVs) have been demonstrated to be implicated in various processes of cancer development, with most of the EV-induced changes attributed to EV-proteins and EV-microRNAs. However, the knowledge about the abundance of cancer EV-mRNAs and their contribution to cancer development remain elusive. Here, we show that mRNAs prevail in cancer EVs as compared with normal EVs, and cancer EVs that carry abundant angiogenic mRNAs activate angiogenesis in human umbilical vein endothelial cells (HUVECs). Specifically, of a gene panel comprising 61 hypoxia-targeted oncogenes, a larger proportion is harbored by cancer EVs (>40%) than normal EVs (14.8%). Fluorescent trafficking indicates cancer EVs deliver translatable mRNAs such as VEGFA to HUVECs, contributing to the activation of VEGFR-dependent angiogenesis and the upregulation of epithelial-mesenchymal transition-related and metabolism-related genes. Overall, our findings provide novel insights into EV-mRNAs and their role in angiogenesis, and has potential for diagnostic and therapeutic applications.