CTGF mediates tumor-stroma interactions between hepatoma cells and hepatic stellate cells to accelerate HCC progression.

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 non-tumorous tissues, primarily in tumor cells. Increased CTGF expression was associated with clinicopathological 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, a hepatic stellate cell line. The growth of HepG2 cells, which express high levels of CTGF, was promoted by co-culture 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. Co-culturing LX-2 cells with HepG2 cells drove LX-2-derived production of IL-6, which led to STAT-3 activation and proliferation of HepG2 cells. An anti-CTGF antibody reduced IL-6 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 which transmit pro-growth signals to HCC cells, this interaction is susceptible to inhibition by an anti-CTGF antibody.

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