Abstract

Extracellular Vesicles From Prostate Cancer Cells Promote Angiogenesis Through alphavß6 Integrin

Shiv Ram Krishn, Post-doctoral Fellow, Thomas Jefferson University

Increased angiogenesis in prostate tumors has been shown to be promoted by cancer cells, but the underlying mechanisms are not completely understood.  Prostate cancer (PrCa) cells continuously release extracellular vesicles (EV) of endosomal origin, to mediate unique crosstalk with other cells in the tumor microenvironment by direct transfer of vesicular cargo.  Our group has shown expression of alphav-beta6 integrin (alphavß6), which is an epithelial-specific integrin, in human PrCa cell-derived EV.  We hypothesized that extracellular vesicles-associated alphavß6 (EV-alphavß6) shed by PrCa cells may impact the endothelial cells in the prostate tumor microenvironment and thus angiogenesis.  Here in, we demonstrate that EV-alphavß6 is efficiently transferred to alphavß6-negative recipient human microvascular endothelial cells (HMEC1).  We also demonstrate the intracellular localization of ß6-GFP transferred via PrCa cell-derived EVs.  De novo alphavß6 expression in HMEC1 is not a result of a change in mRNA levels but is a consequence of EV-mediated transfer of alphavß6 from PrCa cells to HMEC1.  Incubation of HMEC1 with purified EV from PC3 cells, transfected with shRNA to ß6, results in a significant reduction in viability and motility of HMEC1.  Our results also demonstrate that EV-alphavß6 significantly augments tube formation of HMEC1.  At the molecular level, our results demonstrate that transfer of PrCa cell-derived EV-alphavß6 to HMEC1 causes down-regulation of STAT1, a molecule known to negatively regulate angiogenesis.  Overall, our study suggests that EV-mediated transfer of alphavß6 from PrCa cells to endothelial cells may regulate angiogenesis during PrCa progression.