title: Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer.
abstract: OBJECTIVE
  Chronic fibrosing liver injury is a major risk factor for hepatocarcinogenesis in humans. Mice with targeted deletion of Mdr2 (the murine ortholog of MDR3) develop chronic fibrosing liver injury. Hepatocellular carcinoma (HCC) emerges spontaneously in such mice by 50-60 weeks of age, providing a model of fibrosis-associated hepatocarcinogenesis. We used Mdr2(-/-) mice to investigate the hypothesis that activation of the hedgehog (Hh) signaling pathway promotes development of both liver fibrosis and HCC.
  
  
  METHODS
  Hepatic injury and fibrosis, Hh pathway activation, and liver progenitor populations were compared in Mdr2(-/-) mice and age-matched wild type controls. A dose finding experiment with the Hh signaling antagonist GDC-0449 was performed to optimize Hh pathway inhibition. Mice were then treated with GDC-0449 or vehicle for 9 days, and effects on liver fibrosis and tumor burden were assessed by immunohistochemistry, qRT-PCR, Western blot, and magnetic resonance imaging.
  
  
  RESULTS
  Unlike controls, Mdr2(-/-) mice consistently expressed Hh ligands and progressively accumulated Hh-responsive liver myofibroblasts and progenitors with age. Treatment of aged Mdr2-deficient mice with GDC-0449 significantly inhibited hepatic Hh activity, decreased liver myofibroblasts and progenitors, reduced liver fibrosis, promoted regression of intra-hepatic HCCs, and decreased the number of metastatic HCC without increasing mortality.
  
  
  CONCLUSIONS
  Hh pathway activation promotes liver fibrosis and hepatocarcinogenesis, and inhibiting Hh signaling safely reverses both processes even when fibrosis and HCC are advanced.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.
authors.forename: George M
authors.initials: GM
authors.lastname: Philips
authors.forename: Isaac S
authors.initials: IS
authors.lastname: Chan
authors.forename: Marzena
authors.initials: M
authors.lastname: Swiderska
authors.forename: Vanessa T
authors.initials: VT
authors.lastname: Schroder
authors.forename: Cynthia
authors.initials: C
authors.lastname: Guy
authors.forename: Gamze F
authors.initials: GF
authors.lastname: Karaca
authors.forename: Cynthia
authors.initials: C
authors.lastname: Moylan
authors.forename: Talaignair
authors.initials: T
authors.lastname: Venkatraman
authors.forename: Sebastian
authors.initials: S
authors.lastname: Feuerlein
authors.forename: Wing-Kin
authors.initials: WK
authors.lastname: Syn
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Jung
authors.forename: Rafal P
authors.initials: RP
authors.lastname: Witek
authors.forename: Steve
authors.initials: S
authors.lastname: Choi
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Michelotti
authors.forename: Fatima
authors.initials: F
authors.lastname: Rangwala
authors.forename: Elmar
authors.initials: E
authors.lastname: Merkle
authors.forename: Christopher
authors.initials: C
authors.lastname: Lascola
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / Q000172:deficiency; D000813:Anilides / Q000009:adverse effects / Q000494:pharmacology*; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000150:complications / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D002452:Cell Count; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053823:Hedgehog Proteins / Q000378:metabolism*; D018960:Hyaluronan Receptors / Q000235:genetics / Q000378:metabolism; D008103:Liver Cirrhosis / Q000150:complications / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D008113:Liver Neoplasms / Q000150:complications / Q000175:diagnosis / Q000378:metabolism / Q000473:pathology*; D008279:Magnetic Resonance Imaging; D051379:Mice; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000009:adverse effects / Q000494:pharmacology*; D012008:Recurrence; D015398:Signal Transduction / Q000187:drug effects*; D013234:Stem Cells / Q000187:drug effects / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D018435:ATP Binding Cassette Transporter, Subfamily B; D000813:Anilides; D053823:Hedgehog Proteins; D018960:Hyaluronan Receptors; D053495:Osteopontin; D011725:Pyridines; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C538724:HhAntag691