ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer

Abstract

For decades, metalloproteinase 17 (ADAM17) has been the goal of wide investigation. Since its discovery as the tumour necrosis factor-α convertase, it has been studied as the main drug target, especially in the context of inflammatory conditions and tumour. In fact, evidence is mounting to support a key role of ADAM17 in the induction of the proliferation, migration and progression of tumour cells and the trigger of the pro-fibrotic process during chronic inflammatory conditions; this occurs, probably, through the activation of epithelial-to-mesenchymal transition (EMT). EMT is a central morphologic conversion that occurs in adults during wound healing, tumour progression and organ fibrosis. EMT is characterised by the disassembly of cell–cell contacts, remodelling of the actin cytoskeleton and separation of cells, and generates fibroblast-like cells that express mesenchymal markers and have migratory properties. This transition is characterised by loss of epithelial proteins such as E-cadherin and the acquisition of new mesenchymal markers, including vimentin and a-smooth muscle actin. The present review discusses the current understanding of molecular mechanisms involved in ADAM17-dependent EMT in order to individuate innovative therapeutic strategies using ADAM17-related pathways.

Sjögren’s Syndrome-Related Organs Fibrosis: Hypotheses and Realities

“…Alterations in the cellular junction integrity lead to significant changes in salivary gland epithelial cells polarity and organization that may affect secretory functionality [ 19 ]. This scenario fits well with the inflammatory-related EMT activation program observed in SS, characterized by a loss of epithelial markers, such as E-cadherin and tight junction proteins [ 20 , 21 , 22 ]. All these phenomena, potentially implicated in the reduction of the normal quality and quantity of saliva in SS, resulted in accelerated development of SG inflammation [ 18 , 19 ].…”

Amphiregulin induces CCN2 and fibronectin expression by TGF-β through EGFR-dependent pathway in lung epithelial cells

“…In a previous study, profibrotic protein expression (e.g., TGF-β, CCN2) and airway fibrosis were suppressed in OVA-treated ADAM17 f/f /Cre + mice [ 51 ]. Moreover, TGF-β activates ADAM17, which in turn leads to the EMT via angiotensin-converting enzyme-2 ectodomain shedding or the RSK1/C/EBPβ pathway [ 50 , 52 ]. A Previous study found that AREG has a synergistic effect on TGF-β-induced EMT via Smad 2/3 pathway in fibroblasts [ 53 ].…”

Sophocarpine inhibits tumor progression by antagonizing the PI3K/AKT/mTOR signaling pathway in castration-resistant prostate cancer

“…EMT is a key process in tumor progression. During EMT, epithelial tumor cells lose the epithelial cell hallmarks and acquire mesenchymal characteristics ( Zeisberg & Neilson, 2009 ), such as increased expressions of extracellular matrix (ECM) proteins and migratory properties ( Sisto, Ribatti & Lisi, 2021 ). N-cadherin (a cell adhesion molecule) and α-SMA (one of the cytoskeletal proteins) are mesenchymal marker proteins, which are considered important mediators in the EMT process and tumor cell migration ( Huang et al, 2021 ; Janthamala et al, 2021 ).…”