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 selleck inhibitor mice. In these experiments, cotransplantation of CCA cells with human liver myofibroblasts (HLMFs) increased tumor incidence, size, and metastastic 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. selleck 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. (Hepatology 2013; 58:2001–2011) Intrahepatic cholangiocarcinoma (CCA) is a highly fatal tumor that arises from biliary epithelial cells. Worldwide, learn more it accounts for 3% of all primary gastrointestinal malignancies. CCA is the second-most common primary hepatic malignancy after hepatocellular carcinoma (HCC). Its incidence has increased drastically over the past few years, even though factors causing this increase are not clear.[1] CCA

has a very poor prognosis because of its late clinical presentation and lack of effective nonsurgical therapies. The tyrosine kinase receptor, epidermal growth factor receptor (EGFR), binds different ligands, including epidermal growth factor (EGF), heparin-binding epidermal growth factor (HB-EGF), and amphiregulin, which initiate intracellular signaling cascades leading to tumor development and progression. Among EGFR ligands, aberrant expression of HB-EGF has been involved in the development of various cancers, including liver carcinoma.[2-4] EGFR activation disturbs cell–cell adhesion by destabilizing the adherens junction complexes (i.e., E-cadherin/β-catenin) and thus contributes to acquisition of a motile, invasive phenotype.[5] EGFR plays a significant role in CCA malignancy. Activating mutations, sustained activation, and overexpression of EGFR (28%-68%) are associated with a poor prognosis in patients with CCA.[6-14] Recently, transcriptional profiling revealed a significant enrichment of the signature related to EGFR activation in a subclass of CCA that displays the most aggressive behavior.