Hepatic Stellate Cells in Hepatocellular Carcinoma Promote Tumor Growth Via Growth Differentiation Factor 15 Production

Background & AimsAlthough the tumor microenvironment plays an important role in growth, it is not fully understood what hepatic stellate cells (HSCs) play hepatocellular carcinoma (HCC) microenvironment.MethodsA 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 hepatoma cells.ResultsIn steatohepatitis-based tumorigenesis model, GFAP-Atg7KO mice formed fewer and smaller liver tumors than their wild-type littermates. Mixed culture of promoted autophagy proliferation, which attenuated by Atg7 KO cells. Hepatoma xenograft grew rapidly presence but abolished this growth. RNA-sequencing revealed that HepG2 highly expressed GDF15, GDF15 did show growth-promoting effect on either vitro model. deficiency HSCs reduced size caused GDF15-positive nonparenchymal more abundant HCC compared noncancerous parts. Single-cell RNA sequencing showed rates higher background liver. Serum levels high patients increased progression.ConclusionsIn microenvironment, increase produces autophagy-dependent manner may be involved progression. Although microenvironment. A In