Hepatic myofibroblasts promote the progression of human cholangiocarcinoma through activation of epidermal growth factor receptor

Authors

  • Audrey Clapéron,

    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    2. UPMC, Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
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  • Martine Mergey,

    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    2. UPMC, Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
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  • Lynda Aoudjehane,

    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    2. UPMC, Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    3. Human HepCell, Hôpital Saint-Antoine, Paris, France
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  • Thanh Huong Nguyen Ho-Bouldoires,

    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    2. UPMC, Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
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  • Dominique Wendum,

    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    2. UPMC, Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    3. AP-HP, Hôpital Saint-Antoine, Service d'Anatomie et Cytologie Pathologiques, Paris, France
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  • Aurélie Prignon,

    1. UPMC, Univ Paris 06, IFR 65, Plateforme d'Imagerie Moléculaire Positonique, Paris, France
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  • Fatiha Merabtene,

    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Plateforme Morphologie du Petit Animal, Paris, France
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  • Delphine Firrincieli,

    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    2. UPMC, Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
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  • Christèle Desbois-Mouthon,

    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    2. UPMC, Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
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  • Olivier Scatton,

    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    2. UPMC, Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    3. AP-HP, Hôpital Saint-Antoine, Service de Chirurgie Hépato-Biliaire et Transplantation Hépatique, Paris, France
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  • Filomena Conti,

    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    2. UPMC, Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    3. AP-HP, Hôpital Saint-Antoine, Service de Chirurgie Hépato-Biliaire et Transplantation Hépatique, Paris, France
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  • Chantal Housset,

    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    2. UPMC, Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
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  • Laura Fouassier

    Corresponding author
    1. Inserm, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    2. UPMC, Univ Paris 06, UMRS 938, Centre de Recherche Saint-Antoine, Paris, France
    • Address reprint requests to: Laura Fouassier, Ph.D., Inserm UMRS 938, Centre de Recherche Saint-Antoine, Faculté de Médecine Pierre et Marie Curie, 27 rue Chaligny, 75571 Paris cedex 12, France. E-mail: laura.fouassier@inserm.fr; fax: +33 1 40 01 13 52.

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  • Potential conflict of interest: Nothing to report.

Abstract

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. (Hepatology 2013; 58:2001–2011)

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