CTGF Mediates Tumor–Stroma Interactions between Hepatoma Cells and Hepatic Stellate Cells to Accelerate HCC Progression

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 Kras). Hepatocyte-specific knockout of CTGF in these mice (Alb-Cre Kras CTGF) 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. Protumor cross-talk between cancer cells and hepatic stellate cells presents an opportunity for therapeutic intervention against HCC. http://cancerres.aacrjournals.org/content/canres/78/17/4902/F1.large.jpg .

Tspan15 Is a New Stemness‐Related Marker in Hepatocellular Carcinoma

“…However, we did not observe under our experimental conditions a constitutive increase amount of activated TGF‐beta in the medium of HepG2/TS15 nor higher level of smad2 phosphorylation into the cells. The study was further focused on the role of ERK since the Ras/Mek/Erk pathway has been recently suggested as regulating CTGF expression in hepatoma cells . Interestingly, the phosphorylation of ERK was observed significantly increased in HepG2/TS15 as compared to HepG2 cells (Figure C,D).…”

Extracellular Vesicles Enriched with Moonlighting Metalloproteinase Are Highly Transmissive, Pro-Tumorigenic, and Trans-Activates Cellular Communication Network Factor (CCN2/CTGF): CRISPR against Cancer

“…MSC-derived CCN2/CTGF promoted tongue squamous cell carcinoma progression [51]. Another study reported that tumor-derived CCN2/CTGF could mediate tumor-stromal interactions which accelerate hepatocellular carcinoma progression [52]. Notably, it has recently been postulated that CCN2/CTGF might contribute to colorectal cancer progression, especially in a fibrotic consensus molecular subtype [53].…”

Extracellular Oncosomes Rich in Moonlighting Metalloproteinase (MMP3) Are Transmissive, Pro-Tumorigenic, and Induces Cellular Communication Network Factor 2 (CCN2/CTGF): CRISPR against Cancer

“…MSC-derived CCN2/CTGF promoted tongue squamous cell carcinoma progression [45]. Another study reported that tumor-derived CCN2/CTGF could mediate tumor-stromal interactions which accelerate hepatocellular carcinoma progression [46]. Notably, it has been recently postulated that CCN2/CTGF might contribute to colorectal cancer progression, especially in a fibrotic consensus molecular subtype [47].…”