Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis.
Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis.
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DOI：
10.3389/fonc.2018.00357
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发表时间：
2018
影响因子：
4.7
通讯作者：
Caballero-Díaz D
中科院分区：
文献类型：
--
作者：
Fabregat I;Caballero-Díaz D
转化生长因子-β (TGF-β) 家族在调节组织和器官稳态所必需的不同细胞过程中发挥着相关作用。就肝脏而言，TGF-β信号传导参与疾病进展的不同阶段，从最初的肝损伤到纤维化、肝硬化和癌症。当发生慢性损伤时，淋巴细胞和其他炎症细胞会动员起来，从而为炎症反应的持续存在奠定基础。巨噬细胞产生促纤维化介质，其中包括 TGF-β，它负责将静止的肝星状细胞 (HSC) 活化并转分化为肌成纤维细胞 (MFB) 表型。 MFB 是细胞外基质蛋白 (ECM) 积累的主要来源和纤维发生的重要介质。 TGF-β 还介导肝细胞中的上皮间质转化 (EMT) 过程，这可能直接或间接地促进 MFB 数量的增加。在肝癌发生过程中，TGF-β 发挥双重作用，在早期阶段充当抑制因子，但一旦细胞摆脱其细胞抑制作用，就会促进后期肿瘤进展。作为其潜在促肿瘤作用的一部分，TGF-β 会诱导肝肿瘤细胞发生 EMT，从而增加其促迁移和侵袭的潜力。与此同时，TGF-β 还诱导肿瘤细胞可塑性的变化，赋予迁移性肿瘤起始细胞 (TIC) 的特性。本综述的主要目的是阐明 TGF-β 的多效作用，解释其对不同肝细胞群的影响。将介绍与其他有助于 TGF-β 效应的信号通路（特别是表皮生长因子受体 (EGFR)）的交互作用。最后，我们将讨论针对肝脏病理学中的 TGF-β 通路的基本原理。
The Transforming Growth Factor-beta (TGF-β) 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-β 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-β, 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-β also mediates an epithelial-mesenchymal transition (EMT) process in hepatocytes that may contribute, directly or indirectly, to increase the MFB population. In hepatocarcinogenesis, TGF-β 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-β induces EMT in liver tumor cells, which increases its pro-migratory and invasive potential. In parallel, TGF-β 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-β that explain its effects on the different liver cell populations. The cross-talk with other signaling pathways that contribute to TGF-β effects, in particular the Epidermal Growth Factor Receptor (EGFR), will be presented. Finally, we will discuss the rationale for targeting the TGF-β pathway in liver pathologies.
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