title: 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 beta-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.
authors.affiliation: INSERM U698, Bioingénierie cardiovasculaire, Université Paris 13, Bobigny, France.
authors.forename: Maylis
authors.initials: M
authors.lastname: Dagouassat
authors.forename: Nadine
authors.initials: N
authors.lastname: Suffee
authors.forename: Hanna
authors.initials: H
authors.lastname: Hlawaty
authors.forename: Oualid
authors.initials: O
authors.lastname: Haddad
authors.forename: Faten
authors.initials: F
authors.lastname: Charni
authors.forename: Christelle
authors.initials: C
authors.lastname: Laguillier
authors.forename: Roger
authors.initials: R
authors.lastname: Vassy
authors.forename: Loïc
authors.initials: L
authors.lastname: Martin
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Schischmanoff
authors.forename: Liliane
authors.initials: L
authors.lastname: Gattegno
authors.forename: Olivier
authors.initials: O
authors.lastname: Oudar
authors.forename: Angela
authors.initials: A
authors.lastname: Sutton
authors.forename: Nathalie
authors.initials: N
authors.lastname: Charnaux
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement / Q000502:physiology*; D018932:Chemokine CCL2 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness / Q000503:physiopathology; D034622:RNA Interference; D020349:Surface Plasmon Resonance
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2