Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer

George M. Philips, Isaac S. Chan, Marzena Swiderska, Vanessa T. Schroder, Cynthia Guy, Gamze F. Karaca, Cynthia Moylan, Talaignair Venkatraman, Sebastian Feuerlein, Wing Kin Syn, Youngmi Jung, Rafal P. Witek, Steve Choi, Gregory A. Michelotti, Fatima Rangwala, Elmar Merkle, Christopher Lascola, Anna Mae Diehl

Research output: Contribution to journalArticlepeer-review

127 Scopus citations

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.

Original languageEnglish (US)
Article numbere23943
JournalPloS one
Volume6
Issue number9
DOIs
StatePublished - Sep 2 2011
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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