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

Philips, GM

Chan, IS

Swiderska, M

Schroder, VT

Guy, C

Karaca, GF

Moylan, C

Venkatraman, T

Feuerlein, S

Syn, WK

Jung, Y

Witek, RP

Choi, S

Michelotti, GA

Rangwala, F

Merkle, E

Lascola, C

Diehl, AM

Rameshwar, Pranela

United States

2015-12-04T03:03:01Z

2011

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.

http://www.ncbi.nlm.nih.gov/pubmed/21912653

PONE-D-11-10240

1932-6203

https://hdl.handle.net/10161/11084

eng

Public Library of Science (PLoS)

PLoS One

10.1371/journal.pone.0023943

Anilides

Animals

Antigens, CD44

Carcinoma, Hepatocellular

Cell Count

Disease Models, Animal

Gene Expression Regulation, Neoplastic

Hedgehog Proteins

Liver Cirrhosis

Liver Neoplasms

Magnetic Resonance Imaging

Mice

Osteopontin

P-Glycoproteins

Pyridines

Recurrence

Signal Transduction

Stem Cells

Tumor Burden

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

Journal article

Moylan, C|0000-0001-8454-7086

Choi, S|0000-0001-9228-4060

Lascola, C|0000-0002-8031-782X

http://www.ncbi.nlm.nih.gov/pubmed/21912653

e23943

9

Basic Science Departments

Clinical Science Departments

Duke

Duke Cancer Institute

Duke-UNC Center for Brain Imaging and Analysis

Faculty

Institutes and Centers

Medicine

Medicine, Gastroenterology

Molecular Genetics and Microbiology

Neurobiology

Pathology

Radiology

Radiology, Neuroradiology

School of Medicine

Surgery

Surgery, Trauma and Critical Care Surgery

Published

6