Nidogen 1‐Enriched Extracellular Vesicles Facilitate Extrahepatic Metastasis of Liver Cancer by Activating Pulmonary Fibroblasts to Secrete Tumor Necrosis Factor Receptor 1

Advanced Science

Terence Kin Wah Lee¹  Carmen Oi‐Ning Leung¹  Yi Man Eva Fung²  Victor Ma³  William Chi‐Shing Cho³  Yi Gao⁴  Peihua Cao⁴  Xiaoping Xu⁴  Lung‐Yi Mak⁵  Man‐Fung Yuen⁵  Danny Ka Ho Wong⁵  James Chung Man Ho⁵  Sze Keong Tey⁶  Ernest Man Lok Kwong⁶  Xiaowen Mao⁶  Judy Wai Ping Yam⁶  Cherlie Lot Sum Yeung⁶  Maria Pik Wong⁶  Clive Yik Sham Chung⁷  Herbert Pang⁸ 

[1] Department of Applied Biology and Chemical Technology The Hong Kong Polytechnic University Kowloon Hong Kong;Department of Chemistry, State Key Laboratory of Synthetic Chemistry The University of Hong Kong Pokfulam Hong Kong;Department of Clinical Oncology Queen Elizabeth Hospital Kowloon Hong Kong;Department of Hepatobiliary Surgery II, Zhujiang Hospital Southern Medical University Guangzhou 510280 China;Department of Medicine, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong;Department of Pathology, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong;School of Biomedical Sciences, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong;School of Public Health, Li Ka Shing Faculty of Medicine The University of Hong Kong Hong Kong;

关键词: extracellular vesicles;    hepatocellular carcinoma;    nidogen 1;    pre‐metastatic niche;    tumor necrosis factor receptor 1;   

DOI  :  10.1002/advs.202002157

来源: DOAJ

【 摘 要 】

Abstract In hepatocellular carcinoma (HCC) patients with extrahepatic metastasis, the lung is the most frequent site of metastasis. However, how the lung microenvironment favors disseminated cells remains unclear. Here, it is found that nidogen 1 (NID1) in metastatic HCC cell‐derived extracellular vesicles (EVs) promotes pre‐metastatic niche formation in the lung by enhancing angiogenesis and pulmonary endothelial permeability to facilitate colonization of tumor cells and extrahepatic metastasis. EV‐NID1 also activates fibroblasts, which secrete tumor necrosis factor receptor 1 (TNFR1), facilitate lung colonization of tumor cells, and augment HCC cell growth and motility. Administration of anti‐TNFR1 antibody effectively diminishes lung metastasis induced by the metastatic HCC cell‐derived EVs in mice. In the clinical perspective, analysis of serum EV‐NID1 and TNFR1 in HCC patients reveals their positive correlation and association with tumor stages suggesting the potential of these molecules as noninvasive biomarkers for the early detection of HCC. In conclusion, these results demonstrate the interplay of HCC EVs and activated fibroblasts in pre‐metastatic niche formation and how blockage of their functions inhibits distant metastasis to the lungs. This study offers promise for the new direction of HCC treatment by targeting oncogenic EV components and their mediated pathways.

【 授权许可】

Unknown