TGF-β Signaling in Onset and Progression of Hepatocellular Carcinoma

Abstract

Transforming growth factor (TGF)-β 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-β 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-β activities resulting in hyperproliferative disorders and cancer. This concept is based on studies that describe a bipartite role of TGF-β with tumor suppressor functions at early stages of liver damage and regeneration, whereas during cancer progression TGF-β 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-β signaling pathway has been explored to inhibit liver disease progression. While interfering with TGF-β 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-β or its targeting may have both beneficial and adverse outcomes. We emphasize that, in order to achieve therapeutic effects, targeting TGF-β signaling in the right cell type at the right time is required.

Efficacy of ALK5 inhibition in myelofibrosis

“…TGF-β is a well-established fibrotic cytokine that plays a vital role in the pathophysiology of MF as well as other fibrotic diseases (15,17,(19)(20)(21)(37)(38)(39)(40)(41)(42). Elevated levels of the TGF-β1 isoform were detected in plasma and bone marrow serum in MF mouse models.…”

“…Among the abnormally expressed cytokines in MF, TGF-β1 has received attention due to its critical role in inducing fibrosis not only in bone marrow (15)(16)(17)(18), but other organs (19)(20)(21). TGF-β1 may be produced by abnormal megakaryocytes or monocytes, and this in turn may remodel the MSCs that promote the changes illustrated by MF (22)(23)(24)(25).…”

TGF-β signal shifting between tumor suppression and fibro-carcinogenesis in human chronic liver diseases

“…Several components of the TGF-b signaling pathway are lost or inactivated in various epithelial neoplasms [14]. However, only a fraction of liver tumors exhibit inactivating mutations [15,16], so other mechanisms perturbing hepatocytic TGF-b signaling appear critical in human hepatocarcinogenesis [17]. On the other hand, TGF-b as well as proinflammatory cytokines such as tumor necrosis factor (TNF)-a and interleukin-6 can synergistically promote fibrogenesis by stimulating ECM deposition in activated mesenchymal cells [18].…”

Relationship between the Pathogenesis of Glaucoma and miRNA

“…The TGF-β subfamily of cytokines includes a series of multifunctional proteins [25] and participates in many biological processes such as inflammation, wound healing, the generation and accumulation of extracellular matrix, and so on [26] . The relationship between TGF-β and fibrosis is reflected in many diseases [27] . Studies showed that trabecular meshwork cells synthesized and secreted TGF-β, and TGF-β influenced the synthesis of the extracellular matrix in primary open-angle glaucoma by regulating connective tissue growth factor [28] .…”