Cancer-derived exosomal miR-25-3p promotes pre-metastatic niche formation by inducing vascular permeability and angiogenesis

Zhicheng Zeng,Yangjian Pan,Xiaohui Zhu,Yuling Li,Xiaolong Liu,Feifei Wang,Yanqing Ding,Li Liang,Xiaoliang Lan,Guoxin Li,Xiaoli Ren,Fuyao Song,Wenting Liao,Wei Yang,Kun Zhou,Jingbo Sun,Jinlong Hu

doi:10.1038/s41467-018-07810-w

Abstract

Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear. Here, we show that miR-25-3p, a metastasis-promoting miRNA of colorectal cancer (CRC), can be transferred from CRC cells to endothelial cells via exosomes. Exosomal miR-25-3p regulates the expression of VEGFR2, ZO-1, occludin and Claudin5 in endothelial cells by targeting KLF2 and KLF4, consequently promotes vascular permeability and angiogenesis. In addition, exosomal miR-25-3p from CRC cells dramatically induces vascular leakiness and enhances CRC metastasis in liver and lung of mice. Moreover, the expression level of miR-25-3p from circulating exosomes is significantly higher in CRC patients with metastasis than those without metastasis. Our work suggests that exosomal miR-25-3p is involved in pre-metastatic niche formation and may be used as a blood-based biomarker for CRC metastasis.

Highlights

Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear
fluorescence in situ hybridization (FISH) analysis showed that miR-25-3p was expressed in both colorectal cancer (CRC) epithelium and stroma, which was consistent with the previous study[18]
We unveil that CRC-secreted miR-25-3p can be delivered to vascular endothelial cells via exosomes, disrupts the integrity of endothelial barriers and induces angiogenesis, contributes to CRC metastasis

Summary

Introduction

Cancer-derived exosomes are considered a major driver of cancer-induced pre-metastatic niche formation at foreign sites, but the mechanisms remain unclear. Exosomal miR-25-3p regulates the expression of VEGFR2, ZO-1, occludin and Claudin[5] in endothelial cells by targeting KLF2 and KLF4, promotes vascular permeability and angiogenesis. Guangzhou 510515 Guangdong Province, People’s Republic of China These authors contributed : Zhicheng Zeng, Yuling Li, Yangjian Pan. Formation of pre-metastatic niche provides a supportive microenvironment at foreign sites for disseminating tumor cells, which is characterized by inflammation, immunosuppression, angiogenesis, vascular permeability, lymphangiogenesis, organotropism, and reprogramming[1,2,3,4]. We identify that CRC-derived exosomal miR-25-3p can be transferred to vascular endothelial cells and thereby promotes vascular permeability and angiogenesis by targeting Krüppel-like factor 2 (KLF2) and Krüppel-like factor 4 (KLF4). We demonstrate that exosomal miR-25-3p mediates the formation of a pre-metastatic niche in nude mice by inducing vascular leakiness and promotes CRC metastasis. Our clinical data suggest that miR-25-3p from circulating exosomes of CRC patients may be used as a blood-based biomarker for prediction of metastasis

Methods

Results

Conclusion