The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Reduces but Does Not Prevent Tumorigenesis in Chemical and Hormonal Induced Hepatocarcinogenesis Rat Models

Int J Mol Sci. 2016 Sep 23;17(10):1618. doi: 10.3390/ijms17101618.

Abstract

Activation of the epidermal growth factor receptor (EGFR) signaling pathway promotes the development of hepatocellular adenoma (HCA) and carcinoma (HCC). The selective EGFR inhibitor Gefitinib was found to prevent hepatocarcinogenesis in rat cirrhotic livers. Thus, Gefitinib might reduce progression of pre-neoplastic liver lesions to HCC. In short- and long-term experiments, administration of N-Nitrosomorpholine (NNM) or intrahepatic transplantation of pancreatic islets in diabetic (PTx), thyroid follicles in thyroidectomized (TTx) and ovarian fragments in ovariectomized (OTx) rats was conducted for the induction of foci of altered hepatocytes (FAH). Gefitinib was administered for two weeks (20 mg/kg) or three and nine months (10 mg/kg). In NNM-treated rats, Gefitinib administration decreased the amount of FAH when compared to controls. The amount of HCA and HCC was decreased, but development was not prevented. Upon all transplantation models, proliferative activity of FAH was lower after administration of Gefitinib in short-term experiments. Nevertheless, the burden of HCA and HCC was not changed in later stages. Thus, EGFR inhibition by Gefitinib diminishes chemical and hormonal also induced hepatocarcinogenesis in the initiation stage in the non-cirrhotic liver. However, progression to malignant hepatocellular tumors was not prevented, indicating only a limited relevance of the EGFR signaling cascade in later stages of hepatocarcinogenesis.

Keywords: Gefitinib; epidermal growth factor receptor (EGFR); hepatocarcinogenesis; intraportal transplantation.

MeSH terms

  • Animals
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Drug Administration Schedule
  • ErbB Receptors / antagonists & inhibitors*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Gefitinib
  • Immunohistochemistry
  • Islets of Langerhans Transplantation
  • Liver Neoplasms, Experimental / chemically induced
  • Liver Neoplasms, Experimental / drug therapy*
  • Male
  • Nitrosamines / toxicity
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Quinazolines / pharmacology*
  • Quinazolines / therapeutic use
  • Rats
  • Rats, Inbred Lew
  • Sodium-Glucose Transporter 1 / metabolism
  • TOR Serine-Threonine Kinases / metabolism
  • Thyroid Epithelial Cells / transplantation
  • Transforming Growth Factor alpha / genetics
  • Transforming Growth Factor alpha / metabolism
  • ras Proteins / metabolism

Substances

  • Nitrosamines
  • Protein Kinase Inhibitors
  • Quinazolines
  • Sodium-Glucose Transporter 1
  • Transforming Growth Factor alpha
  • N-nitrosomorpholine
  • ErbB Receptors
  • TOR Serine-Threonine Kinases
  • ras Proteins
  • Gefitinib