Monocyte chemoattractant protein-1 (MCP-1)/CCL2 secreted by hepatic myofibroblasts promotes migration and invasion of human hepatoma cells.
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.
Dagouassat
Maylis
M
INSERM U698, Bioingénierie cardiovasculaire, Université Paris 13, Bobigny, France.
Suffee
Nadine
N
Hlawaty
Hanna
H
Haddad
Oualid
O
Charni
Faten
F
Laguillier
Christelle
C
Vassy
Roger
R
Martin
Loïc
L
Schischmanoff
Pierre-Olivier
PO
Gattegno
Liliane
L
Oudar
Olivier
O
Sutton
Angela
A
Charnaux
Nathalie
N
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
C111835:CCL2 protein, human; D018932:Chemokine CCL2