Transforming Growth Factor-β-Induced Cell Plasticity in Liver Fibrosis and Hepatocarcinogenesis

Abstract

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.

Keywords: EMT; HCC; TGF-β; cancer biology; fibrosis; hepatic stellate cell; liver; plasticity.

Figure 1

Canonical (Smad-dependent) and non-canonical (Smad-independent) TGF-β signaling pathways. Both converge in transcriptional-dependent and independent effects on cell proliferation, differentiation, apoptosis/survival, migration, etc., in a cell and context-dependent manner.

Figure 2

Role of TGF-β in the cell plasticity of hepatic stellate cells and macrophages during liver fibrosis. Different routes followed by TGF-β signals to mediate activation of HSC into MFB (left) or polarization of macrophages to a M2 state (right), which contribute to sustain a fibrotic and immunosuppressive environment, favorable to the initiation of a hepatocarcinogenic process.

Figure 3

Role of TGF-β in regulating EMT of liver tumor cells. Cross-talk between the TGF-β and the EGFR pathways in liver tumor cells, which rescues cells from TGF-β-induced apoptosis and allows them to respond to it undergoing a partial or full EMT, which increase their migratory/invasive and stemness properties.