Monocyte chemoattractant protein‐1 (MCP‐1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells

Abstract

The aim of our study was to investigate whether myofibroblasts and the chemokine monocyte chemoattractant protein-1 (MCP-1)/CCL2 may play a role in hepatocellular carcinoma progression. We observed that hepatic myofibroblast LI90 cells express MCP-1/CCL2 mRNA and secrete this chemokine. Moreover, myofibroblast LI90 cell-conditioned medium (LI90-CM) induces human hepatoma Huh7 cell migration and invasion. These effects are strongly reduced when a MCP-1/CCL2-depleted LI90-CM was used. We showed that MCP-1/CCL2 induces Huh7 cell migration and invasion through its G-protein-coupled receptor CCR2 and, to a lesser extent, through CCR1 only at high MCP-1/CCL2 concentrations. MCP-1/CCL2's chemotactic activities rely on tyrosine phosphorylation of focal adhesion components and depend on matrix metalloproteinase (MMP)-2 and MMP-9. Furthermore, we observed that Huh7 cell migration and invasion induced by the chemokine are strongly inhibited by heparin, by b-D-xyloside treatment of cells and by anti-syndecan-1 and -4 antibodies. Finally, we developed a 3-dimensional coculture model of myofibroblast LI90 and Huh7 cells and demonstrated that MCP-1/CCL2 and its membrane partners, CCR1 and CCR2, may be involved in the formation of mixed hepatoma-myofibroblast spheroids. In conclusion, our data show that human liver myofibroblasts act on hepatoma cells in a paracrine manner to increase their invasiveness and suggest that myofibroblast-derived MCP-1/CCL2 could be involved in the pathogenesis of hepatocellular carcinoma.

Targeting Galectin-1 in Carcinoma-Associated Fibroblasts Inhibits Oral Squamous Cell Carcinoma Metastasis by Downregulating MCP-1/CCL2 Expression

“…We found that MCP-1 secreted by CAFs promoted OSCC cell invasion and migration by binding to its receptor, CCR2, indicating a direct effect of MCP-1 on tumor malignancy. Recent studies (38,39) showing that MCP-1 directly induces prostate and hepatic tumor cell invasion and migration support our findings. Our results imply a critical role for MCP-1/CCR2 signaling in cell invasion and migration; therefore, blocking MCP-1/ CCR2 signals may attenuate OSCC metastasis.…”

Evaluation of Taline-1, MCP-1 and IGF-1 in Prediction the Risk of Developing Hepatocellular Carcinoma in Patients With Liver Cirrhosis

“…MCP-1 is a member of the small inducible gene family, and plays a role in the recruitment of monocytes to sites of injury and infection, its expression may plausibly be associated with HCC development (18).The current study showed a highly significant increase in the serum level of MCP-1 in HCC patients in comparison with other groups. The results are similar to that of Wang et al, (19) who found that serum MCP-1 levels were significantly higher in the HCC group than in the cirrhotic group or the controls.…”

The role of chemokines in acute and chronic hepatitis C infection

“…152 Moreover, CCL2 treatment enhances the migration and invasion of Huh7 hepatoma cells in vitro. 153 Macrophageand biliary epithelial cell-produced CCL3 is also upregulated in the fibrotic liver and expression of CCR1 and CCR5 has been detected on effector T cells within lymphoid-like follicles. 53 CCL3 appears to be an important mediator of injuryinduced liver fibrosis as demonstrated by the reduction in immune cell infiltration and attenuation of fibrosis in CCL3-deficient mice.…”