Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis

Authors

  • Eduardo Schiffer,

    1. INSERM Unit 402, Faculté de Médecine Saint-Antoine et Université Pierre et Marie Curie, Paris, France
    2. Département d'Anesthésiologie, Hôpital Universitaire, Geneva, Switzerland
    Search for more papers by this author
  • Chantal Housset,

    1. INSERM Unit 402, Faculté de Médecine Saint-Antoine et Université Pierre et Marie Curie, Paris, France
    2. Service de Biochimie et d'Hormonologie, Hôpital Tenon, Paris, France
    Search for more papers by this author
  • Wulfran Cacheux,

    1. INSERM Unit 402, Faculté de Médecine Saint-Antoine et Université Pierre et Marie Curie, Paris, France
    2. Service d'Hépatologie, Hôpital Saint-Antoine, Paris, France
    Search for more papers by this author
  • Dominique Wendum,

    1. Service d'Anatomie et de Cytologie Pathologiques, Hôpital Saint-Antoine, Paris, France
    Search for more papers by this author
  • Christèle Desbois-Mouthon,

    1. INSERM Unit 402, Faculté de Médecine Saint-Antoine et Université Pierre et Marie Curie, Paris, France
    Search for more papers by this author
  • Colette Rey,

    1. INSERM Unit 402, Faculté de Médecine Saint-Antoine et Université Pierre et Marie Curie, Paris, France
    Search for more papers by this author
  • François Clergue,

    1. Département d'Anesthésiologie, Hôpital Universitaire, Geneva, Switzerland
    Search for more papers by this author
  • Raoul Poupon,

    1. INSERM Unit 402, Faculté de Médecine Saint-Antoine et Université Pierre et Marie Curie, Paris, France
    2. Service d'Hépatologie, Hôpital Saint-Antoine, Paris, France
    Search for more papers by this author
  • Véronique Barbu,

    1. INSERM Unit 402, Faculté de Médecine Saint-Antoine et Université Pierre et Marie Curie, Paris, France
    2. Fédération des Services de Biochimie, Hôpital Saint-Antoine, Paris, France
    Search for more papers by this author
  • Olivier Rosmorduc

    Corresponding author
    1. INSERM Unit 402, Faculté de Médecine Saint-Antoine et Université Pierre et Marie Curie, Paris, France
    2. Service d'Hépatologie, Hôpital Saint-Antoine, Paris, France
    • INSERM Unit 402 and Service d'Hépatologie, Faculté de Médecine Saint-Antoine, 27 rue de Chaligny, 75012 Paris, France
    Search for more papers by this author
    • fax: (33) 1-49282107


  • Conflict of interest: Nothing to report.

Abstract

Epidermal growth factor receptor (EGFR) binds transforming growth factor α (TGF-α) which is mitogenic for hepatocytes. Diverse lines of evidence suggest that activation of the TGF-α /EGFR pathway contributes to hepatocellular carcinoma (HCC) formation. Herein, we developed an experimental model of cirrhosis giving rise to HCC and tested the antitumoral effect of gefitinib, a selective EGFR tyrosine kinase inhibitor, in this model. Rats received weekly intraperitoneal injections of diethylnitrosamine (DEN) followed by a 2-week wash-out period that caused cirrhosis in 14 weeks and multifocal HCC in 18 weeks. Hepatocyte proliferation was increased in diseased tissue at 14 weeks compared with control liver and at even higher levels in HCC nodules compared with surrounding diseased tissues at 18 weeks. Increased proliferation was paralleled by upregulation of TGF-α messenger RNA expression. A group of DEN-treated rats received daily intraperitoneal injections of gefitinib between weeks 12 and 18. In rats treated with gefitinib, the number of HCC nodules was significantly lower than in untreated rats (18.1 ± 2.4 vs. 3.7 ± 0.45; P < .05), while EGFR was activated to a lesser extent in the diseased and tumoral tissues of these animals compared with untreated rats. HCC nodules from both untreated and gefitinib-treated animals displayed insulin-like growth factor 2 overexpression that contributed to tumor formation in treated animals. In conclusion, the blockade of EGFR activity by gefitinib has an antitumoral effect on the development of HCC in DEN-exposed rats, suggesting that it may provide benefit for the chemoprevention of HCC. (HEPATOLOGY 2005,41:307–314.)

Ancillary