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.

The deregulation of several transcription factors contribute to the aggressive course of mantle cell lymphoma. This study focuses on survival signals emanating from the tumor environment and involving the signal transducer and activator of transcription (STAT) 3 through cytokines or antigen recognition. Primary mantle cell lymphoma cells were isolated from 20 leukemic patients. The phosphorylation status of STAT3 was evaluated by immunoblottting and immunofluorescence, the levels of cytokine secretion by enzyme-linked immunosorbent assay and the cell survival signals by apoptosis and cell viability assays. STAT3 was constitutively phosphorylated in the Jeko-1 mantle cell lymphoma cell line and in 14 out of 20 (70%) cases of leukemic mantle cell lymphoma as the result of an autocrine secretion of interleukin-6 and/or interleukin-10. In addition, B-cell receptor engagement resulted in an increase of both in vitro cell survival and STAT3 phosphorylation in primary mantle cell lymphoma cells. Inhibition of the Janus-activated kinase/STAT3 pathway increased spontaneous apoptosis and suppressed B-cell receptor-induced cell survival in all cases analyzed. The impact of in vitro exposure to the proteasome inhibitor bortezomib was next evaluated in primary mantle cell lymphoma cells. Bortezomib induced apoptosis and a decrease of both interleukin-6/interleukin-10 secretion and STAT3 phosphorylation. In addition, bortezomib inhibited B-cell receptor-triggered STAT3 phosphorylation and cell survival. We demonstrated that STAT3 was activated in primary mantle cell lymphoma cells either constitutively through a cytokine autocrine loop or in response to B-cell receptor engagement, both processes leading to a survival signal inhibited by bortezomib. STAT3 appears, therefore, to play a pivotal role in mantle cell lymphoma and represents a promising therapeutic target.