Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production.
Gastroenterology
; 160(5): 1741-1754.e16, 2021 04.
Article
em En
| MEDLINE
| ID: mdl-33346004
ABSTRACT
BACKGROUND & AIMS:
Although the tumor microenvironment plays an important role in tumor growth, it is not fully understood what role hepatic stellate cells (HSCs) play in the hepatocellular carcinoma (HCC) microenvironment.METHODS:
A high-fat diet after streptozotocin was administered to HSC-specific Atg7-deficient (GFAP-Atg7 knockout [KO]) or growth differentiation factor 15 (GDF15)-deficient (GFAP-GDF15KO) mice. LX-2 cells, a human HSC cell line, were cultured with human hepatoma cells.RESULTS:
In the steatohepatitis-based tumorigenesis model, GFAP-Atg7KO mice formed fewer and smaller liver tumors than their wild-type littermates. Mixed culture of LX-2 cells and hepatoma cells promoted LX-2 cell autophagy and hepatoma cell proliferation, which were attenuated by Atg7 KO in LX-2 cells. Hepatoma cell xenograft tumors grew rapidly in the presence of LX-2 cells, but Atg7 KO in LX-2 cells abolished this growth. RNA-sequencing revealed that LX-2 cells cultured with HepG2 cells highly expressed GDF15, which was abolished by Atg7 KO in LX-2 cells. GDF15 KO LX-2 cells did not show a growth-promoting effect on hepatoma cells either in vitro or in the xenograft model. GDF15 deficiency in HSCs reduced liver tumor size caused by the steatohepatitis-based tumorigenesis model. GDF15 was highly expressed and GDF15-positive nonparenchymal cells were more abundant in human HCC compared with noncancerous parts. Single-cell RNA sequencing showed that GDF15-positive rates in HSCs were higher in HCC than in background liver. Serum GDF15 levels were high in HCC patients and increased with tumor progression.CONCLUSIONS:
In the HCC microenvironment, an increase of HSCs that produces GDF15 in an autophagy-dependent manner may be involved in tumor progression.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
/
Comunicação Parácrina
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Proliferação de Células
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Células Estreladas do Fígado
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Fator 15 de Diferenciação de Crescimento
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Hepatopatia Gordurosa não Alcoólica
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Neoplasias Hepáticas
Tipo de estudo:
Prognostic_studies
Limite:
Animals
/
Humans
/
Male
Idioma:
En
Revista:
Gastroenterology
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Japão