1. Hedgehog Signaling Antagonist Promotes Regression of Both Liver Fibrosis and Hepatocellular Carcinoma in a Murine Model of Primary Liver Cancer
- Author
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Sebastian Feuerlein, Youngmi Jung, Christopher D. Lascola, Cynthia A. Moylan, Elmar M. Merkle, George Philips, Gamze Karaca, Talaignair N. Venkatraman, Gregory A. Michelotti, Rafal P. Witek, Fatima A. Rangwala, Marzena Swiderska, Cynthia D. Guy, Anna Mae Diehl, Steve S. Choi, Wing-Kin Syn, Vanessa T. Schroder, and Isaac S. Chan
- Subjects
Liver Cirrhosis ,Pathology ,Mouse ,Pyridines ,lcsh:Medicine ,Cell Count ,Mice ,0302 clinical medicine ,Recurrence ,Fibrosis ,Molecular Cell Biology ,Gastrointestinal Cancers ,Anilides ,Osteopontin ,lcsh:Science ,Liver injury ,0303 health sciences ,Multidisciplinary ,Stem Cells ,Liver Diseases ,Liver Neoplasms ,Animal Models ,Signaling in Selected Disciplines ,Magnetic Resonance Imaging ,Hedgehog signaling pathway ,Tumor Burden ,3. Good health ,Gene Expression Regulation, Neoplastic ,Hyaluronan Receptors ,Cirrhosis ,Oncology ,030220 oncology & carcinogenesis ,Hepatocellular carcinoma ,Medicine ,Immunohistochemistry ,Oncology Agents ,Genetic Engineering ,Signal Transduction ,Research Article ,Biotechnology ,medicine.medical_specialty ,ATP Binding Cassette Transporter, Subfamily B ,Carcinoma, Hepatocellular ,Gastroenterology and Hepatology ,Biology ,03 medical and health sciences ,Model Organisms ,Gastrointestinal Tumors ,medicine ,Animals ,Hedgehog Proteins ,Progenitor cell ,Hedgehog ,030304 developmental biology ,Oncogenic Signaling ,lcsh:R ,Cancers and Neoplasms ,Hepatocellular Carcinoma ,Molecular Development ,medicine.disease ,Signaling ,Disease Models, Animal ,biology.protein ,lcsh:Q ,Transgenics ,Developmental Biology - 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 2/2 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 2/2 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 resonanceimaging. Results: Unlike controls, Mdr2 2/2 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 intrahepatic 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.
- Published
- 2011
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