期刊
FRONTIERS IN ONCOLOGY
卷 8, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2018.00357
关键词
TGF-beta; plasticity; liver; cancer biology; fibrosis; HCC; EMT; hepatic stellate cell
类别
资金
- Ministry of Science, Innovation and Universities, Spain [SAF2015-64149-R]
- FPI program, Ministry of Economy, Industry and Competitiveness, Spain [BES-2016 0077564]
- Instituto de Salud Carlos III, Spain
The Transforming Growth Factor-beta (TGF-beta) family plays relevant roles in the regulation of different cellular processes that are essential for tissue and organ homeostasis. In the case of the liver, TGF-beta signaling participates in different stages of disease progression, from initial liver injury toward fibrosis, cirrhosis and cancer. When a chronic injury takes place, mobilization of lymphocytes and other inflammatory cells occur, thus setting the stage for persistence of an inflammatory response. Macrophages produce profibrotic mediators, among them, TGF-beta, which is responsible for activation-transdifferentiation of quiescent hepatic stellate cells (HSC) to a myofibroblast (MFB) phenotype. MFBs are the principal source of extracellular matrix protein (ECM) accumulation and prominent mediators of fibrogenesis. TGF-beta also mediates an epithelial-mesenchymal transition (EMT) process in hepatocytes that may contribute, directly or indirectly, to increase the MFB population. In hepatocarcinogenesis, TGF-beta plays a dual role, behaving as a suppressor factor at early stages, but contributing to later tumor progression, once cells escape from its cytostatic effects. As part of its potential pro-tumorigenic actions, TGF-beta induces EMT in liver tumor cells, which increases its pro-migratory and invasive potential. In parallel, TGF-beta also induces changes in tumor cell plasticity, conferring properties of a migratory tumor initiating cell (TIC). The main aim of this review is to shed light about the pleiotropic actions of TGF-beta that explain its effects on the different liver cell populations. The cross-talk with other signaling pathways that contribute to TGF-beta effects, in particular the Epidermal Growth Factor Receptor (EGFR), will be presented. Finally, we will discuss the rationale for targeting the TGF-beta pathway in liver pathologies.
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