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Gefitinib, an EGFR inhibitor, prevents hepatocellular carcinoma development in the rat liver with cirrhosis
Author(s) -
Schiffer Eduardo,
Housset Chantal,
Cacheux Wulfran,
Wendum Dominique,
DesboisMouthon Christèle,
Rey Colette,
Clergue François,
Poupon Raoul,
Barbu Véronique,
Rosmorduc Olivier
Publication year - 2005
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.20538
Subject(s) - gefitinib , hepatocellular carcinoma , cirrhosis , medicine , epidermal growth factor receptor , hepatology , tyrosine kinase inhibitor , epidermal growth factor , endocrinology , transforming growth factor , cancer research , egfr inhibitors , cancer , receptor
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. (H EPATOLOGY 2005,41:307–314.)