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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.

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  • Authors+Show Affiliations

    ,

    Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America.

    , , , , , , , , , , , , , , , ,

    Source

    PloS one 6:9 2011 pg e23943

    MeSH

    ATP Binding Cassette Transporter, Subfamily B
    Anilides
    Animals
    Carcinoma, Hepatocellular
    Cell Count
    Disease Models, Animal
    Gene Expression Regulation, Neoplastic
    Hedgehog Proteins
    Hyaluronan Receptors
    Liver Cirrhosis
    Liver Neoplasms
    Magnetic Resonance Imaging
    Mice
    Osteopontin
    Pyridines
    Recurrence
    Signal Transduction
    Stem Cells
    Tumor Burden

    Pub Type(s)

    Journal Article
    Research Support, N.I.H., Extramural

    Language

    eng

    PubMed ID

    21912653

    Citation

    Philips, George M., et al. "Hedgehog Signaling Antagonist Promotes Regression of Both Liver Fibrosis and Hepatocellular Carcinoma in a Murine Model of Primary Liver Cancer." PloS One, vol. 6, no. 9, 2011, pp. e23943.
    Philips GM, Chan IS, Swiderska M, et al. Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer. PLoS ONE. 2011;6(9):e23943.
    Philips, G. M., Chan, I. S., Swiderska, M., Schroder, V. T., Guy, C., Karaca, G. F., ... Diehl, A. M. (2011). Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer. PloS One, 6(9), pp. e23943. doi:10.1371/journal.pone.0023943.
    Philips GM, et al. Hedgehog Signaling Antagonist Promotes Regression of Both Liver Fibrosis and Hepatocellular Carcinoma in a Murine Model of Primary Liver Cancer. PLoS ONE. 2011;6(9):e23943. PubMed PMID: 21912653.
    * Article titles in AMA citation format should be in sentence-case
    TY - JOUR T1 - Hedgehog signaling antagonist promotes regression of both liver fibrosis and hepatocellular carcinoma in a murine model of primary liver cancer. AU - Philips,George M, AU - Chan,Isaac S, AU - Swiderska,Marzena, AU - Schroder,Vanessa T, AU - Guy,Cynthia, AU - Karaca,Gamze F, AU - Moylan,Cynthia, AU - Venkatraman,Talaignair, AU - Feuerlein,Sebastian, AU - Syn,Wing-Kin, AU - Jung,Youngmi, AU - Witek,Rafal P, AU - Choi,Steve, AU - Michelotti,Gregory A, AU - Rangwala,Fatima, AU - Merkle,Elmar, AU - Lascola,Christopher, AU - Diehl,Anna Mae, Y1 - 2011/09/02/ PY - 2011/06/13/received PY - 2011/07/27/accepted PY - 2011/9/14/entrez PY - 2011/9/14/pubmed PY - 2011/12/30/medline SP - e23943 EP - e23943 JF - PloS one JO - PLoS ONE VL - 6 IS - 9 N2 - 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. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/21912653/Hedgehog_signaling_antagonist_promotes_regression_of_both_liver_fibrosis_and_hepatocellular_carcinoma_in_a_murine_model_of_primary_liver_cancer_ L2 - http://dx.plos.org/10.1371/journal.pone.0023943 DB - PRIME DP - Unbound Medicine ER -