TGF-β and the Tissue Microenvironment: Relevance in Fibrosis and Cancer

Abstract

Transforming growth factor-β (TGF-β) is a cytokine essential for the induction of the fibrotic response and for the activation of the cancer stroma. Strong evidence suggests that a strong cross-talk exists among TGF-β and the tissue extracellular matrix components. TGF-β is stored in the matrix as part of a large latent complex bound to the latent TGF-β binding protein (LTBP) and matrix binding of latent TGF-β complexes, which is required for an adequate TGF-β function. Once TGF-β is activated, it regulates extracellular matrix remodelling and promotes a fibroblast to myofibroblast transition, which is essential in fibrotic processes. This cytokine also acts on other cell types present in the fibrotic and tumour microenvironment, such as epithelial, endothelial cells or macrophages and it contributes to the cancer-associated fibroblast (CAF) phenotype. Furthermore, TGF-β exerts anti-tumour activity by inhibiting the host tumour immunosurveillance. Aim of this review is to update how TGF-β and the tissue microenvironment cooperate to promote the pleiotropic actions that regulate cell responses of different cell types, essential for the development of fibrosis and tumour progression. We discuss recent evidences suggesting the use of TGF-β chemical inhibitors as a new line of defence against fibrotic disorders or cancer.

Keywords: CAF; HCC; TGF-β; cancer; extracellular matrix; fibrosis; galunisertib; hepatic stellate cells; microenvironment.

Figure 1

FoxP3 expression in 4 hepatocellular carcinoma (HCC) samples. FoxP3-positive cells belong principally to the CD4⁺ Treg subset, the presence of which is widely variable in different HCC tissues. The distribution pattern of FoxP3 does not show an apparent preference for any tumour sub-localization, as Tregs are found in parenchymal as well as stromal areas of HCC (upper right and lower right images, respectively). Representative images at 10×. The small images are a 200× of the selected area.

Figure 2

Staining of α-smooth muscle actin (αSMA) in 4 HCC samples. The differentiated myofibroblasts within the tumour are the main cells expressing this actin isoform and are located in the stromal septa or around the blood vessels. Representative images at 10×. The small images are a 200× of the selected area.

Figure 3

Expression of transforming growth factor-β (TGF-β) in 4 HCC samples. Overall staining is evident, with a preferential sub-endothelial localization, possibly perisinusoidal, especially in tissues with lower expression. The cytokine delivery sites appear to be closely associated to parenchymal cells in HCC nodules. Representative images at 10×.

Figure 4

Graphical abstract highlighting the pleiotropic actions of TGF-β on different cell types, which explain how TGF-β influences the microenvironment, contributing to the development and progression of fibrosis and cancer. Red lines indicate inhibition of the indicated cell type activity. Black arrows indicate activation of the indicated cell type. Green arrows indicate that Endothelial cells upon TGF-β stimulation can undergo either Angiogenesis or EndMT. Blue Arrows indicate that epithelial cells after TGF-β stimulation can undergo apoptosis or EMT.