Intrahepatic cholangiocarcinoma (CCA) is characterized by an abundant 
desmoplastic environment. Poor prognosis of CCA has been associated with the 
presence of alpha-smooth muscle actin (α-SMA)-positive myofibroblasts (MFs) in 
the stroma and with the sustained activation of the epidermal growth factor 
receptor (EGFR) in tumor cells. Among EGFR ligands, heparin-binding epidermal 
growth factor (HB-EGF) has emerged as a paracrine factor that contributes to 
intercellular communications between MFs and tumor cells in several cancers. 
This study was designed to test whether hepatic MFs contributed to CCA 
progression through EGFR signaling. The interplay between CCA cells and hepatic 
MFs was examined first in vivo, using subcutaneous xenografts into 
immunocompromised mice. In these experiments, cotransplantation of CCA cells 
with human liver myofibroblasts (HLMFs) increased tumor incidence, size, and 
metastatic dissemination of tumors. These effects were abolished by gefitinib, 
an EGFR tyrosine kinase inhibitor. Immunohistochemical analyses of human CCA 
tissues showed that stromal MFs expressed HB-EGF, whereas EGFR was detected in 
cancer cells. In vitro, HLMFs produced HB-EGF and their conditioned media 
induced EGFR activation and promoted disruption of adherens junctions, migratory 
and invasive properties in CCA cells. These effects were abolished in the 
presence of gefitinib or HB-EGF-neutralizing antibody. We also showed that CCA 
cells produced transforming growth factor beta 1, which, in turn, induced HB-EGF 
expression in HLMFs.
CONCLUSION: A reciprocal cross-talk between CCA cells and myofibroblasts through 
the HB-EGF/EGFR axis contributes to CCA progression.