Exosomes derived from HeLa cells break down vascular integrity by triggering endoplasmic reticulum stress in endothelial cells

Abstract

Exosomes play a critical role in intercellular communication since they contain signalling molecules and genetic materials. During tumorigenesis, tumour-derived exosomes have been demonstrated to promote tumour angiogenesis and metastasis. However, how the exosomes facilitate tumour metastasis is not clear. Here we explored the effect of HeLa cell-derived exosomes (Exo^HeLa) on endothelial tight junctions (TJ) and the related mechanisms. After human umbilical vein endothelial cells (HUVEC) were treated with Exo^HeLa, TJ proteins zonula occludens-1 (ZO-1) and Claudin-5 in HUVEC were significantly reduced as compared with that treated with exosomes from human cervical epithelial cells, while mRNA levels of ZO-1 and Claudin-5 remained unchanged. Consequently, permeability of endothelial monolayer was increased after the treatment with Exo^HeLa. Injection of Exo^HeLa into mice also increased vascular permeability and tumour metastasis <i>in vivo</i>. Neither knocking down of Dicer nor use of inhibitors of microRNAs targeting at mRNAs of ZO-1 and Claudin-5 could block the inhibitory effect of Exo^HeLa on ZO-1 and Claudin-5. The expression of genes involved in endoplasmic reticulum (ER) stress was significantly increased in HUVECs after treated with Exo^HeLa. Inhibition of ER stress by knocking down protein kinase RNA-like endoplasmic reticulum kinase prevented the down-regulation of ZO-1 and Claudin-5 by Exo^HeLa. Our study found that HeLa cell-derived exosomes promote metastasis by triggering ER stress in endothelial cells and break down endothelial integrity. Such effect of exosomes is microRNA-independent.