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

• Published in: International journal of cancer 2010-03, Vol.126 (5), p.1095-1108
• Main Authors: Dagouassat, Maylis, Suffee, Nadine, Hlawaty, Hanna, Haddad, Oualid, Charni, Faten, Laguillier, Christelle, Vassy, Roger, Martin, Loïc, Schischmanoff, Pierre‐Olivier, Gattegno, Liliane, Oudar, Olivier, Sutton, Angela, Charnaux, Nathalie
• Format: Article
• Language: English
• Subjects: Biochemistry; Biochemistry, Molecular Biology; Biological and medical sciences; Cancer; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Cell Movement - physiology; chemokine; Chemokine CCL2 - metabolism; Enzyme-Linked Immunosorbent Assay; Fibroblasts - metabolism; Flow Cytometry; Gastroenterology. Liver. Pancreas. Abdomen; glycosaminoglycan; hepatoma; Humans; Life Sciences; Liver - cytology; Liver - metabolism; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; MCP‐1/CCL2; Medical sciences; Medication; myofibroblast; Neoplasm Invasiveness - physiopathology; Pharmaceutical sciences; RNA Interference; Surface Plasmon Resonance; Tumors
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.24800

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 β‐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.