TY - JOUR
T1 - Nidogen 1-Enriched Extracellular Vesicles Facilitate Extrahepatic Metastasis of Liver Cancer by Activating Pulmonary Fibroblasts to Secrete Tumor Necrosis Factor Receptor 1
AU - Mao, Xiaowen
AU - Tey, Sze Keong
AU - Yeung, Cherlie Lot Sum
AU - Kwong, Ernest Man Lok
AU - Fung, Yi Man Eva
AU - Chung, Clive Yik Sham
AU - Mak, Lung Yi
AU - Wong, Danny Ka Ho
AU - Yuen, Man Fung
AU - Ho, James Chung Man
AU - Pang, Herbert
AU - Wong, Maria Pik
AU - Leung, Carmen Oi Ning
AU - Lee, Terence Kin Wah
AU - Ma, Victor
AU - Cho, William Chi Shing
AU - Cao, Peihua
AU - Xu, Xiaoping
AU - Gao, Yi
AU - Yam, Judy Wai Ping
N1 - Funding Information:
The work was supported by Hong Kong Research Grants Council General Research Fund (Project no. 17117519), Health and Medical Research Fund (Project no. 07182096), the Seed Funding for Strategic Interdisciplinary Research Scheme (Project no. 102009863 and 007000142), and the Collaborative Research Support Scheme of State Key Laboratory of Liver Research (The University of Hong Kong) (Project no. SKLLR/CRSS/2019). The authors thank the Centre for PanorOmic Sciences, LKS Faculty of Medicine for providing equipment needed for animal imaging and confocal microscopy, and the Laboratory Animal Unit for providing animals and facility for animal experimentation. The authors also thank the Electron Microscope Unit, The University of Hong Kong for providing service and support needed for experiments involving electron microscope.
Publisher Copyright:
© 2020 The Authors. Published by Wiley-VCH GmbH
PY - 2020/11/1
Y1 - 2020/11/1
N2 - 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.
AB - 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.
KW - extracellular vesicles
KW - hepatocellular carcinoma
KW - nidogen 1
KW - pre-metastatic niche
KW - tumor necrosis factor receptor 1
UR - http://www.scopus.com/inward/record.url?scp=85089533361&partnerID=8YFLogxK
U2 - 10.1002/advs.202002157
DO - 10.1002/advs.202002157
M3 - Journal article
AN - SCOPUS:85089533361
SN - 2198-3844
VL - 7
JO - Advanced Science
JF - Advanced Science
IS - 21
M1 - 2002157
ER -
