Tumour extracellular vesicle-derived Complement Factor H promotes tumorigenesis and metastasis by inhibiting complement-dependent cytotoxicity of tumour cells.
Animals
Carcinogenesis
/ metabolism
Carcinoma, Hepatocellular
/ metabolism
Cell Line, Tumor
Complement Factor H
/ metabolism
Extracellular Vesicles
/ metabolism
Humans
Liver Neoplasms, Experimental
/ metabolism
Male
Mice
Mice, Inbred BALB C
Mice, Nude
Neoplasm Metastasis
Neoplasm Proteins
/ metabolism
Complement Factor H
complement‐mediated cytotoxicity
extracellular vesicles
hepatocellular carcinoma
Journal
Journal of extracellular vesicles
ISSN: 2001-3078
Titre abrégé: J Extracell Vesicles
Pays: United States
ID NLM: 101610479
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
23
05
2020
revised:
02
10
2020
accepted:
07
11
2020
entrez:
12
3
2021
pubmed:
13
3
2021
medline:
13
3
2021
Statut:
ppublish
Résumé
The complement system is involved in the immunosurveillance of pathogens and tumour cells. Proteomic profiling revealed that extracellular vesicles (EVs) released by metastatic hepatocellular carcinoma (HCC) cells contained a significant number of complement proteins. Complement Factor H (CFH), an abundant soluble serum protein that inhibits the alternative complement pathway, was found to be highly expressed in EVs of metastatic HCC cell lines. Here, we investigated the functional role of EV-CFH and explored the therapeutic efficacy of targeting EV-CFH with an anti-CFH antibody in HCC. The results showed that EVs that are enriched in CFH promoted HCC cell growth, migration, invasiveness and enhanced liver tumour formation in mice. EV-CFH also promoted metastasis, which was significantly abrogated when treated with an anti-CFH antibody. These findings demonstrate an unexplored function of EV-CFH in protecting HCC cells by evading complement attack, thereby facilitating tumorigenesis and metastasis. Lastly, we demonstrated the therapeutic efficacy of an anti-CFH antibody in suppressing tumour formation in a syngeneic mouse model. This study suggests a new therapeutic strategy for HCC, by inhibiting EV-CFH with a tumour specific anti-CFH antibody.
Identifiants
pubmed: 33708358
doi: 10.1002/jev2.12031
pii: JEV212031
pmc: PMC7890557
doi:
Substances chimiques
CFH protein, human
0
Neoplasm Proteins
0
Complement Factor H
80295-65-4
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Pagination
e12031Informations de copyright
© 2020 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.
Déclaration de conflit d'intérêts
The authors report no conflict of interest. E.F.P. is a co‐founder and CEO of Grid Therapeutics.
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