Biomechanics of TGFβ‐induced epithelial‐mesenchymal transition: implications for fibrosis and cancer

Abstract

Fibrosis, a disease that results in loss of organ function, contributes to a significant number of deaths worldwide and sustained fibrotic activation has been suggested to increase the risk of developing cancer in a variety of tissues. Fibrogenesis and tumor progression are regulated in part through the activation and activity of myofibroblasts. Increasing evidence links myofibroblasts found within fibrotic lesions and the tumor microenvironment to a process termed epithelial‐mesenchymal transition (EMT), a phenotypic change in which epithelial cells acquire mesenchymal characteristics. EMT can be stimulated by soluble signals, including transforming growth factor (TGF)‐β, and recent studies have identified a role for mechanical cues in directing EMT. In this review, we describe the role that EMT plays in fibrogenesis and in the progression of cancer, with particular emphasis placed on biophysical signaling mechanisms that control the EMT program. We further describe specific TGFβ‐induced intracellular signaling cascades that are affected by cell‐ and tissue‐level mechanics. Finally, we highlight the implications of mechanical induction of EMT on the development of treatments and targeted intervention strategies for fibrosis and cancer.

Targeting roles of inflammatory microenvironment in lung cancer and metastasis

“…TGFβ1-associated signaling cascade in cancer becomes dysfunctional and contributes to the evasion of immune surveillance, apoptosis resistance, or increased cell proliferation and invasion [36]. Activated TGFβ can bind type I and type II receptors (TβRI and TβRII) and activate serine/threonine kinases and phosphorylation of Smad2 and Smad3 which can further bind with Smad4, enter the nucleus, and act with other transcription factors to initiate the activation of TGFβ target genes [37]. TGFβ can also signal via Smad-independent pathways through various MAP kinases, Rho-like GTPases, or phosphatidylinositol-3-kinase/AKT (PI3K/AKT) signaling pathways [38].…”

A new role for the PI3K/Akt signaling pathway in the epithelial-mesenchymal transition

“…In the early stage of the neoplastic process, TGF-b is an important factor inhibiting the primary tumor; however, in the late stage of the neoplastic process, it promotes the release of cytokines, induces the EMT, stimulates angiogenesis and inhibits immune surveillance. 54,55 Bakin et al 9 reported that P13K/Akt activation was essential to the EMT process induced by TGF-b1 in tumor cell lines. The addition of LY294002, a P13K inhibitor, suppresses this process.…”

Shenqi detoxification granule combined with P311 inhibits epithelial-mesenchymal transition in renal fibrosis <i>via</i> TGF-β1-Smad-ILK pathway

“…The TGF-β1/Smad signaling pathway plays a key role in initiating and completing the entire EMT course in fibrotic disease pathogenesis (34). Currently, eight different Smad proteins have been found in vertebrates.…”