Abstract
Transforming growth factor-β (TGF-β) signaling is essential in embryo development and maintaining normal homeostasis. Extensive evidence shows that TGF-β activation acts on several cell types, including epithelial cells, fibroblasts, and immune cells, to form a pro-fibrotic environment, ultimately leading to fibrotic diseases. TGF-β is stored in the matrix in a latent form; once activated, it promotes a fibroblast to myofibroblast transition and regulates extracellular matrix (ECM) formation and remodeling in fibrosis. TGF-β signaling can also promote cancer progression through its effects on the tumor microenvironment. In cancer, TGF-β contributes to the generation of cancer-associated fibroblasts (CAFs) that have different molecular and cellular properties from activated or fibrotic fibroblasts. CAFs promote tumor progression and chronic tumor fibrosis via TGF-β signaling. Fibrosis and CAF-mediated cancer progression share several common traits and are closely related. In this review, we consider how TGF-β promotes fibrosis and CAF-mediated cancer progression. We also discuss recent evidence suggesting TGF-β inhibition as a defense against fibrotic disorders or CAF-mediated cancer progression to highlight the potential implications of TGF-β-targeted therapies for fibrosis and cancer.
Highlights
Transforming growth factor-β (TGF-β) is known to participate in various cellular processes, including differentiation, proliferation, migration, extracellular matrix (ECM) remodeling, and apoptosis, all of which influence embryogenesis, wound healing, fibrosis, inflammation, and tumor progression [1]
TGF-β ligands consisting of TGF-β1, TGF-β2, and TGF-β3 are secreted by numerous cell types, including epithelial cells, fibroblasts, and immune cells [2,3], and stored in the tumor microenvironment (TME, the environment surrounding the tumor) in an inactive form [4]; activated TGF-β ligands exert their role through an autocrine or paracrine manner [5]
This study indicates that TGF-βRI, TGF-βRII, and SMAD3, but not SMAD2 are critical mediators of myofibroblast differentiation and fibrosis (Figure 1)
Summary
TGF-β is known to participate in various cellular processes, including differentiation, proliferation, migration, extracellular matrix (ECM) remodeling, and apoptosis, all of which influence embryogenesis, wound healing, fibrosis, inflammation, and tumor progression [1]. Activated TβRI phosphorylates small mothers against decapentaplegic homolog (SMAD) and SMAD3 (R-SMADs); phosphorylated SMAD2 and SMAD3 (p-SMAD2 and p-SMAD3) oligomerize with SMAD4 and translocate to the nucleus to regulate expression of TGF-β target genes (Figure 1). This R-SMADs dependent pathway is referred to as canonical TGF-β signaling. Fibroblasts are mesenchymal cells, a major cell type producing ECM proteins that are generally quiescent in non-pathological adult tissues They can become activated myofibroblasts via TGF-β signaling after an injury to produce a different set of ECM molecules during wound healing and tissue inflammation, playing a critical role in wound healing and resolution [15]. We elaborate on potential therapeutics targeting TGF-β signaling to more effectively treat patients with fibrotic disease and cancer
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