The Epidermal Growth Factor Receptor (EGFR) Inhibitor Gefitinib Reduces but Does Not Prevent Tumorigenesis in Chemical and Hormonal Induced Hepatocarcinogenesis Rat Models.
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.
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. silvia.ribback@uni-greifswald.de.
Silvia
S
Ribback
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. verena.sailer@ukb.uni-bonn.de.|Englander Institut for Precision Medicine, Weill Cornell University of Medicine, New York, NY 10065, USA. verena.sailer@ukb.uni-bonn.de.
Verena
V
Sailer
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. e.boehning@yahoo.de.
Enrico
E
Böhning
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. guenther.julia@hotmail.de.
Julia
J
Günther
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. jacqueline.merz@gmx.de.
Jaqueline
J
Merz
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. f.steinmueller@diako-online.de.|Pathologisches Institut Diakonie-Krankenhaus, 27356 Rotenburg (Wümme), Germany. f.steinmueller@diako-online.de.
Frauke
F
Steinmüller
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. kirsten.utpatel@klinik.uni-regensburg.de.|Institut für Pathologie, Universitätsklinikum Regensburg, 93053 Regensburg, Germany. kirsten.utpatel@klinik.uni-regensburg.de.
Kirsten
K
Utpatel
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. a.cyglius@gmail.com.
Antonio
A
Cigliano
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. tp905@web.de.
Kristin
K
Peters
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. giuliapilo1983@gmail.com.
Maria G
MG
Pilo
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. matthias.evert@uni-greifswald.de.|Institut für Pathologie, Universitätsklinikum Regensburg, 93053 Regensburg, Germany. matthias.evert@uni-greifswald.de.
Matthias
M
Evert
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. dcalvisi@uni-greifswald.de.
Diego F
DF
Calvisi
Institut für Pathologie, Universitätsmedizin Greifswald, 17489 Greifswald, Germany. frank.dombrowski@uni-geifswald.de.
Frank
F
Dombrowski
D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D007150:Immunohistochemistry; D016381:Islets of Langerhans Transplantation; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000188:drug therapy*; D008297:Male; D009602:Nitrosamines / Q000633:toxicity; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D011799:Quinazolines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D011917:Rats, Inbred Lew; D051269:Sodium-Glucose Transporter 1 / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D000072637:Thyroid Epithelial Cells / Q000637:transplantation; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D009602:Nitrosamines; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D051269:Sodium-Glucose Transporter 1; D016211:Transforming Growth Factor alpha; C002741:N-nitrosomorpholine; D066246:ErbB Receptors; D058570:TOR Serine-Threonine Kinases; D018631:ras Proteins; D000077156:Gefitinib
Gefitinib; epidermal growth factor receptor (EGFR); hepatocarcinogenesis; intraportal transplantation
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