title: Epidermal growth factor receptor inhibition attenuates liver fibrosis and development of hepatocellular carcinoma.
abstract: Hepatocellular carcinoma (HCC) is the most rapidly increasing cause of cancer-related mortality in the United States. Because of the lack of viable treatment options for HCC, prevention in high-risk patients has been proposed as an alternative strategy. The main risk factor for HCC is cirrhosis and several lines of evidence implicate epidermal growth factor (EGF) in the progression of cirrhosis and development of HCC. We therefore examined the effects of the EGF receptor (EGFR) inhibitor erlotinib on liver fibrogenesis and hepatocellular transformation in three different animal models of progressive cirrhosis: a rat model induced by repeated, low-dose injections of diethylnitrosamine (DEN), a mouse model induced by carbon tetrachloride (CCl4 ), and a rat model induced by bile duct ligation (BDL). Erlotinib reduced EGFR phosphorylation in hepatic stellate cells (HSC) and reduced the total number of activated HSC. Erlotinib also decreased hepatocyte proliferation and liver injury. Consistent with all these findings, pharmacological inhibition of EGFR signaling effectively prevented the progression of cirrhosis and regressed fibrosis in some animals. Moreover, by alleviating the underlying liver disease, erlotinib blocked the development of HCC and its therapeutic efficacy could be monitored with a previously reported gene expression signature predictive of HCC risk in human cirrhosis patients.
  
  
  CONCLUSIONS
  These data suggest that EGFR inhibition using Food and Drug Administration-approved inhibitors provides a promising therapeutic approach for reduction of fibrogenesis and prevention of HCC in high-risk cirrhosis patients who can be identified and monitored by gene expression signatures.
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Fuchs
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Fujii
authors.forename: Lan
authors.initials: L
authors.lastname: Wei
authors.forename: Suguru
authors.initials: S
authors.lastname: Yamada
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.forename: Christopher M
authors.initials: CM
authors.lastname: McGinn
authors.forename: Danielle K
authors.initials: DK
authors.lastname: DePeralta
authors.forename: Xintong
authors.initials: X
authors.lastname: Chen
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Kuroda
authors.forename: Michael
authors.initials: M
authors.lastname: Lanuti
authors.forename: Anthony D
authors.initials: AD
authors.lastname: Schmitt
authors.forename: Supriya
authors.initials: S
authors.lastname: Gupta
authors.forename: Andrew
authors.initials: A
authors.lastname: Crenshaw
authors.forename: Robert
authors.initials: R
authors.lastname: Onofrio
authors.forename: Bradley
authors.initials: B
authors.lastname: Taylor
authors.forename: Wendy
authors.initials: W
authors.lastname: Winckler
authors.forename: Nabeel
authors.initials: N
authors.lastname: Bardeesy
authors.forename: Peter
authors.initials: P
authors.lastname: Caravan
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Tanabe
mesh_terms: D000818:Animals; D001652:Bile Ducts / Q000503:physiopathology; D002251:Carbon Tetrachloride / Q000009:adverse effects; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000517:prevention & control*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004052:Diethylnitrosamine / Q000009:adverse effects; D004195:Disease Models, Animal; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000187:drug effects / Q000473:pathology; D006801:Humans; D008026:Ligation / Q000009:adverse effects; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics / Q000517:prevention & control*; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D059467:Transcriptome
chemical_list: D011799:Quinazolines; D004052:Diethylnitrosamine; D002251:Carbon Tetrachloride; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors