CTGF Mediates Tumor-Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression
CTGF Mediates Tumor-Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression
复制标题
DOI：
10.1158/0008-5472.can-17-3844
复制
发表时间：
2018-09-01
期刊：
影响因子：
11.2
通讯作者：
Takehara, Tetsuo
中科院分区：
文献类型：
--
作者：
Makino, Yuki;Hikita, Hayato;Takehara, Tetsuo
结缔组织生长因子（CTGF）是一种与肝纤维化相关的基质细胞蛋白。本研究旨在阐明CTGF在肝细胞癌（HCC）中的作用，HCC通常由肝纤维化发展而来。与非肿瘤组织相比，CTGF在93例人类HCC中过表达，主要在肿瘤细胞中。CTGF表达升高与HCC的临床病理恶性相关。CTGF在肝细胞特异性Kras突变小鼠（Alb-Cre Kras(LSL-G12D/+)）的肝癌细胞中表达上调。在这些小鼠中，肝细胞特异性敲除CTGF(Alb-Cre Kras（LSL-G12D/+)CTGF(fl/fl)）可减少肝脏肿瘤的数量和大小。人和小鼠肝脏肿瘤中均存在肝星状细胞（Hepatic stellate cells， HSC），而作为肝星状细胞活化标志的α - sma的表达与CTGF的表达呈正相关。强制表达CTGF不影响CTGF表达较少的肝癌细胞系PLC/PRF/5细胞的生长，但在HSC细胞系LX-2细胞存在时促进其生长。与单独培养相比，与LX-2细胞共培养可促进表达高水平CTGF的HepG2细胞的生长。LX-2细胞的生长促进作用在培养和异种移植物中均被抗ctgf抗体否定。LX-2细胞与HepG2细胞共培养可驱动LX-2衍生的IL6产生，从而导致STAT-3活化和HepG2细胞增殖。抗ctgf抗体降低LX-2细胞中IL6的产生，抑制HepG2细胞中STAT-3的激活。总之，我们的数据确定肿瘤细胞来源的CTGF是HCC微环境中的一个基石，激活附近的HSC，将促生长信号传递给HCC细胞，这种相互作用容易被抗CTGF抗体抑制。
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 over-expressed 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 Kras(LSL-G12D/+)). Hepatocyte-specific knockout of CTGF in these mice (Alb-Cre Kras(LSL-G12D/+)CTGF(fl/fl)) decreased liver tumor number and size. Hepatic stellate cells (HSC) were present in both human and murine liver tumors, and alpha-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 identifytumor 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.