Department of Gastroenterology and Hepatology, Osaka University Graduate School of Medicine, Suita, Japan.
Genome Medical Sciences Project, National Center for Global Health and Medicine, Ichikawa, Japan.
Gastroenterology. 2021 Apr;160(5):1741-1754.e16. doi: 10.1053/j.gastro.2020.12.015. Epub 2020 Dec 17.
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.
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.
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.
In the HCC microenvironment, an increase of HSCs that produces GDF15 in an autophagy-dependent manner may be involved in tumor progression.
尽管肿瘤微环境在肿瘤生长中起着重要作用，但肝星状细胞（HSCs）在肝癌（HCC）微环境中所起的作用仍不完全清楚。
给予链脲佐菌素后，采用高脂肪饮食处理 HSC 特异性 Atg7 缺陷（GFAP-Atg7 敲除[KO]）或生长分化因子 15（GDF15）缺陷（GFAP-GDF15KO）小鼠。培养人 HSC 细胞系 LX-2 细胞与肝癌细胞共培养。
在脂肪性肝炎相关的肿瘤发生模型中，GFAP-Atg7KO 小鼠形成的肝肿瘤数量较少且体积较小。LX-2 细胞与肝癌细胞的混合培养促进了 LX-2 细胞自噬和肝癌细胞增殖，而 LX-2 细胞中的 Atg7KO 则减弱了这种作用。在 LX-2 细胞存在的情况下，肝癌细胞异种移植瘤生长迅速，但 LX-2 细胞中的 Atg7KO 则消除了这种生长。RNA 测序显示，与 HepG2 细胞共培养的 LX-2 细胞高度表达 GDF15，而 LX-2 细胞中的 Atg7KO 则消除了这种表达。在体外和异种移植模型中，GDF15 缺陷的 LX-2 细胞对肝癌细胞也没有促进生长的作用。HSCs 中的 GDF15 缺陷减少了由脂肪性肝炎相关肿瘤发生模型引起的肝肿瘤体积。与非癌组织相比，人 HCC 中 GDF15 表达水平较高，且 GDF15 阳性非实质细胞更为丰富。单细胞 RNA 测序显示，HCC 中 GDF15 阳性率高于背景肝。HCC 患者的血清 GDF15 水平较高，并随肿瘤进展而升高。
在 HCC 微环境中，依赖自噬产生 GDF15 的 HSCs 增加可能与肿瘤进展有关。
