Skip to main content
Duke University Libraries
DukeSpace Scholarship by Duke Authors
  • Login
  • Ask
  • Menu
  • Login
  • Ask a Librarian
  • Search & Find
  • Using the Library
  • Research Support
  • Course Support
  • Libraries
  • About
View Item 
  •   DukeSpace
  • Duke Scholarly Works
  • Scholarly Articles
  • View Item
  •   DukeSpace
  • Duke Scholarly Works
  • Scholarly Articles
  • View Item
JavaScript is disabled for your browser. Some features of this site may not work without it.

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

Thumbnail
View / Download
2.4 Mb
Date
2011
Authors
Philips, George M
Chan, Isaac S
Swiderska, Marzena
Schroder, Vanessa T
Guy, Cynthia
Karaca, Gamze F
Moylan, Cynthia
Venkatraman, Talaignair
Feuerlein, Sebastian
Syn, Wing-Kin
Jung, Youngmi
Witek, Rafal P
Choi, Steve
Michelotti, Gregory A
Rangwala, Fatima
Merkle, Elmar
Lascola, Christopher
Diehl, Anna Mae
Show More
(18 total)
Repository Usage Stats
207
views
252
downloads
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 article
Subject
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
Permalink
https://hdl.handle.net/10161/11084
Published Version (Please cite this version)
10.1371/journal.pone.0023943
Publication 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.
Collections
  • Scholarly Articles
More Info
Show full item record

Scholars@Duke

Choi

Steven Sok Choi

Associate Professor of Medicine
Hepatic stellate cell biology; Hepatic Fibrogenesis; Liver regeneration
Diehl

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
Guy

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
Lascola

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 &#945;1aAR has been shown to mediate myocardial hypertrophy, culminating in both morphological and genetic cellular changes, however it is unknown if &#945;1ARs 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.
Moylan

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
Schroder

Vanessa Teaberry Schroder

Assistant Professor of Surgery
More Authors
Alphabetical list of authors with Scholars@Duke profiles.
Open Access

Articles written by Duke faculty are made available through the campus open access policy. For more information see: Duke Open Access Policy

Rights for Collection: Scholarly Articles

Make Your Work Available Here

How to Deposit

Browse

All of DukeSpaceCommunities & CollectionsAuthorsTitlesTypesBy Issue DateDepartmentsAffiliations of Duke Author(s)SubjectsBy Submit DateThis CollectionAuthorsTitlesTypesBy Issue DateDepartmentsAffiliations of Duke Author(s)SubjectsBy Submit Date

My Account

LoginRegister

Statistics

View Usage Statistics
Duke University Libraries

Contact Us

411 Chapel Drive
Durham, NC 27708
(919) 660-5870
Perkins Library Service Desk

Digital Repositories at Duke

  • Report a problem with the repositories
  • About digital repositories at Duke
  • Accessibility Policy
  • Deaccession and DMCA Takedown Policy

TwitterFacebookYouTubeFlickrInstagramBlogs

Sign Up for Our Newsletter
  • Re-use & Attribution / Privacy
  • Support the Libraries
Duke University