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.
Type
Journal articleSubject
AnilidesAnimals
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
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https://hdl.handle.net/10161/11084Published Version (Please cite this version)
10.1371/journal.pone.0023943Publication Info
Philips, George M; Chan, Isaac S; Swiderska, Marzena; Schroder, Vanessa T; Guy, Cynthia;
Karaca, Gamze F; ... Diehl, Anna Mae (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. 10.1371/journal.pone.0023943. Retrieved from https://hdl.handle.net/10161/11084.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Steven Sok Choi
Associate Professor of Medicine
Hepatic stellate cell biology; Hepatic Fibrogenesis; Liver regeneration
Anna Mae Diehl
Florence McAlister Distinguished Professor of Medicine
Our lab has a long standing interest in liver injury and repair. To learn more about
the mechanisms that regulate this process, we study cultured cells, animal models
of acute and chronic liver damage and samples from patients with various types of
liver disease. Our group also conducts clinical trials in patients with chronic liver
disease. We are particularly interested in fatty liver diseases, such as alcoholic
fatty liver disease and nonalcoholic fatty liver disease (NAFLD). <br
Cynthia Dianne Guy
Professor of Pathology
My research interests include: Fine Needle Aspiration of Liver, Gastrointestinal Tract,
and Pancreatic Lesions Biliary Duct Brushings Nonalcoholic Fatty Liver Disease/NASH
Liver Fibrogenesis
Christopher David Lascola
Associate Professor of Radiology
Gregory Alexander Michelotti
Associate Professor in Medicine
The goal of my research is to elucidate mechanisms underlying catecholamine-induced
myocardial hypertrophy and identify unique pathways directing adaptive (physiologic)
versus maladaptive (pathologic) responses. Stimulation of α1aAR has been shown
to mediate myocardial hypertrophy, culminating in both morphological and genetic cellular
changes, however it is unknown if α1ARs simply trigger initial hypertrophic events
or rather preferentially activate adaptive
This author no longer has a Scholars@Duke profile, so the information shown here reflects
their Duke status at the time this item was deposited.
Cynthia Ann Moylan
Associate Professor of Medicine
My research interests focus on the study of chronic liver disease and primary liver
cancer, particularly from nonalcoholic fatty liver disease (NAFLD). As part of the
NAFLD Research Team at Duke, I am investigating the role of epigenetics and genetics
on the development of advanced fibrosis from NAFLD. The long term goal of our research
is to develop non-invasive biomarkers to identify those patients at increased risk
for cirrhosis and end stage liver disease in order to risk stratif
Vanessa Teaberry Schroder
Assistant Professor of Surgery
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