CTGF公司
肝星状细胞
癌症研究
生长因子
细胞培养
生物
肝细胞生长因子
间质细胞
化学
内科学
内分泌学
医学
遗传学
受体
作者
Yuki Makino,Hayato Hikita,Tatsuhiko Kodama,Minoru Shigekawa,Ryotaro Yamada,Ryotaro Sakamori,Hidetoshi Eguchi,Eiichi Morii,Hideki Yokoi,Masashi Mukoyama,Hiroshi Suemizu,Tomohide Tatsumi,Tetsuo Takehara
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2018-09-01
卷期号:78 (17): 4902-4914
被引量:80
标识
DOI:10.1158/0008-5472.can-17-3844
摘要
Abstract Connective tissue growth factor (CTGF) is a matricellular protein related to hepatic fibrosis. This study aims to clarify the roles of CTGF in hepatocellular carcinoma (HCC), which usually develops from fibrotic liver. CTGF was overexpressed in 93 human HCC compared with nontumorous tissues, primarily in tumor cells. Increased CTGF expression was associated with clinicopathologic malignancy of HCC. CTGF was upregulated in hepatoma cells in hepatocyte-specific Kras-mutated mice (Alb-Cre KrasLSL-G12D/+). Hepatocyte-specific knockout of CTGF in these mice (Alb-Cre KrasLSL-G12D/+ CTGFfl/fl) decreased liver tumor number and size. Hepatic stellate cells (HSC) were present in both human and murine liver tumors, and α-SMA expression, a marker of HSC activation, positively correlated with CTGF expression. Forced expression of CTGF did not affect growth of PLC/PRF/5 cells, a hepatoma cell line with little CTGF expression, but facilitated their growth in the presence of LX-2 cells, an HSC line. The growth of HepG2 cells, which express high levels of CTGF, was promoted by coculture with LX-2 cells compared with monoculture. Growth promotion by LX-2 cells was negated by an anti-CTGF antibody in both culture and xenografts. Coculturing LX-2 cells with HepG2 cells drove LX-2-derived production of IL6, which led to STAT-3 activation and proliferation of HepG2 cells. An anti-CTGF antibody reduced IL6 production in LX-2 cells and suppressed STAT-3 activation in HepG2 cells. In conclusion, our data identify tumor cell–derived CTGF as a keystone in the HCC microenvironment, activating nearby HSC that transmit progrowth signals to HCC cells, and this interaction is susceptible to inhibition by an anti-CTGF antibody. Significance: Protumor cross-talk between cancer cells and hepatic stellate cells presents an opportunity for therapeutic intervention against HCC. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/17/4902/F1.large.jpg. Cancer Res; 78(17); 4902–14. ©2018 AACR.
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