Anti-angiogenesis triggers exosomes release from endothelial cells to promote tumor vasculogenesis

ABSTRACT

Although anti-angiogenic therapies (AATs) have some effects against multiple malignancies, they are limited by subsequent tumor vasculogenesis and progression. To investigate the mechanisms by which tumor vasculogenesis and progression following AATs, we transfected microRNA (miR)-9 into human umbilical vein endothelial cells (HUVECs) to mimic the tumor-associated endothelial cells in hepatocellular carcinoma and simulated the AATs in vitro and in vivo. We found that administration of the angiogenesis inhibitor vandetanib completely abolished miR-9-induced angiogenesis and promoted autophagy in HUVECs, but induced the release of vascular endothelial growth factor (VEGF)-enriched exosomes. These VEGF-enriched exosomes significantly promoted the formation of endothelial vessels and vasculogenic mimicry in hepatocellular carcinoma and its progression in mice. Anti-autophagic therapy is proposed to improve the efficacy of AATs. However, similar effects by AATs were observed with the application of anti-autophagy by 3-methyladenine. Our results revealed that tumor vasculogenesis and progression after AATs and anti-autophagic therapies were due to the cross-talk between endothelial and tumor cells via VEGF-enriched exosomes.

KEYWORDS:

• Exosomes
• vascular endothelial growth factor (VEGF)
• anti-angiogenesis
• anti-autophagy
• pre-metastatic niches

Acknowledgments

The authors would like to thank Bio-Gene Technology Ltd., Hong Kong for help with exosomes analysis using the Apogee A60 Micro Plus Flow Cytometer.

Author contributions

Y.Z. and B.M.F. designed the studies. Y.Z., X.H.Y., and Z.P.Y. performed and analyzed the experiments. Y.Z. and B.M.F. wrote the manuscript. X.H.Y. and B.M.F. assisted with the flow cytometry, data analysis and collection of the samples. X.L.H. and J.W. helped with tissue staining. X.H.L., L.L., and X.J.L. contributed to study design. Y.Z. and B.M.F. oversaw all data analysis.

Disclosure of interest

The authors report no conflicts of interest.

Additional information

Funding

National Natural Science Foundation of China (Grant no. 11402153), and the Excellent Young Scientist Foundation (No. 2015SCU04A38) and the Talent Introduction Scientific Research Projects Funded Start-Up Funds (No.2082204174089) of Sichuan University.