title: Metformin prevents hepatocellular carcinoma development by suppressing hepatic progenitor cell activation in a rat model of cirrhosis.
abstract: BACKGROUND
  Hepatocellular carcinoma (HCC)-associated mortality is increasing at an alarming rate, and there is a readily identifiable cohort of at-risk patients with cirrhosis, viral hepatitis, nonalcoholic fatty liver disease, and diabetes. These patients are candidates for chemoprevention. Metformin is an attractive agent for chemoprevention because it is inexpensive, has a favorable safety profile, and is well tolerated over long time periods.
  
  
  METHODS
  The authors studied the efficacy of metformin as a prevention agent in a clinically relevant rat model of HCC, in which tumors develop in the setting of chronic inflammation and cirrhosis. Repeated injections of diethylnitrosamine were used to induce sequential cirrhosis and HCC, and metformin was administered at the first signs of either fibrosis or cirrhosis.
  
  
  RESULTS
  Prolonged metformin exposure was safe and was associated with decreases in fibrotic and inflammatory markers, especially when administered early at the first signs of fibrosis. In addition, early metformin treatment led to a 44% decrease in HCC incidence, whereas tumor burden was unchanged when metformin was administered at the first signs of cirrhosis. It is noteworthy that activation of the hepatic progenitor/stem cell compartment was first observed at the onset of cirrhosis; therefore, only early metformin treatment suppressed receptor for advanced glycation end products and inhibited the activation of hepatic progenitor cells.
  
  
  CONCLUSIONS
  The current results are the first to demonstrate an effect on progenitor/stem cells in the setting of chemoprevention and provide further rationale to explore metformin as an early intervention in clinical trials of patients with chronic liver disease at high risk for HCC.
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Danielle K
authors.initials: DK
authors.lastname: DePeralta
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Lan
authors.initials: L
authors.lastname: Wei
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Sarani
authors.initials: S
authors.lastname: Ghoshal
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Schmidt
authors.affiliation: Department of Pathology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Gregory Y
authors.initials: GY
authors.lastname: Lauwers
authors.affiliation: Division of Thoracic Surgery, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Michael
authors.initials: M
authors.lastname: Lanuti
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Tanabe
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, Massachusetts.
authors.forename: Bryan C
authors.initials: BC
authors.lastname: Fuchs
mesh_terms: D000818:Animals; D001707:Biopsy, Needle; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000473:pathology / Q000517:prevention & control*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology; D008113:Liver Neoplasms / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D016133:Polymerase Chain Reaction / Q000379:methods; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D012016:Reference Values; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects*; D016896:Treatment Outcome
chemical_list: D008687:Metformin
keywords: hepatocellular carcinoma (HCC); liver; oval cells; prevention; receptor for advanced glycation end products (RAGE)