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TGF-beta signaling in onset and progression of hepatocellular carcinoma

Meindl-Beinker, Nadja M. ; Matsuzaki, Koichi ; Dooley, Steven

In: Digestive diseases, 30 (2012), Nr. 5. pp. 514-523. ISSN 0257-2753

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Transforming growth factor (TGF)-beta is a central regulator in chronic liver disease, contributing to all stages of disease progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver damage-induced levels of active TGF-beta enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Further evidence points to a decisive role of cytostatic and apoptotic functions mediated on hepatocytes, which is critical for the control of liver mass, with loss of TGF-beta activities resulting in hyperproliferative disorders and cancer. This concept is based on studies that describe a bipartite role of TGF-beta with tumor suppressor functions at early stages of liver damage and regeneration, whereas during cancer progression TGF-beta may turn from a tumor suppressor into a tumor promoter that exacerbates invasive and metastatic behavior. We have delineated this molecular switch of the pathway from cytostatic to tumor promoting in further detail and identify activation of survival signaling pathways in hepatocytes as a most critical requirement. Targeting the TGF-beta signaling pathway has been explored to inhibit liver disease progression. While interfering with TGF-beta signaling in various short-term animal models has demonstrated promising results, liver disease progression in humans is a process of decades with different phases in which TGF-beta or its targeting may have both beneficial and adverse outcomes. We emphasize that, in order to achieve therapeutic effects, targeting TGF-beta signaling in the right cell type at the right time is required. Copyright © 2012 S. Karger AG, Basel

Item Type: Article
Journal or Publication Title: Digestive diseases
Volume: 30
Number: 5
Publisher: S. Karger AG
Date Deposited: 22 Dec 2014 08:49
Date: 2012
ISSN: 0257-2753
Page Range: pp. 514-523
Faculties / Institutes: Medizinische Fakultät Mannheim > Medizinische Klinik - Lehrstuhl für Innere Medizin II
Subjects: 610 Medical sciences Medicine
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