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Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of epidermal growth factor receptor
Author(s) -
Clapéron Audrey,
Mergey Martine,
Aoudjehane Lynda,
HoBouldoires Thanh Huong Nguyen,
Wendum Dominique,
Prig Aurélie,
Merabtene Fatiha,
Firrincieli Delphine,
DesboisMouthon Christèle,
Scatton Olivier,
Conti Filomena,
Housset Chantal,
Fouassier Laura
Publication year - 2013
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.26585
Subject(s) - gefitinib , cancer research , epidermal growth factor receptor , epidermal growth factor , myofibroblast , stromal cell , autocrine signalling , biology , hepatocyte growth factor , growth factor receptor , paracrine signalling , heparin binding egf like growth factor , pathology , cancer , medicine , receptor , signal transduction , fibrosis , microbiology and biotechnology
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 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. 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. (H epatology 2013; 58:2001–2011)