TGF-beta signal transduction: biology, function and therapy for diseases

Abstract

The transforming growth factor beta (TGF-β) is a crucial cytokine that get increasing concern in recent years to treat human diseases. This signal controls multiple cellular responses during embryonic development and tissue homeostasis through canonical and/or noncanonical signaling pathways. Dysregulated TGF-β signal plays an essential role in contributing to fibrosis via promoting the extracellular matrix deposition, and tumor progression via inducing the epithelial-to-mesenchymal transition, immunosuppression, and neovascularization at the advanced stage of cancer. Besides, the dysregulation of TGF-beta signal also involves in other human diseases including anemia, inflammatory disease, wound healing and cardiovascular disease et al. Therefore, this signal is proposed to be a promising therapeutic target in these diseases. Recently, multiple strategies targeting TGF-β signals including neutralizing antibodies, ligand traps, small-molecule receptor kinase inhibitors targeting ligand–receptor signaling pathways, antisense oligonucleotides to disrupt the production of TGF-β at the transcriptional level, and vaccine are under evaluation of safety and efficacy for the forementioned diseases in clinical trials. Here, in this review, we firstly summarized the biology and function of TGF-β in physiological and pathological conditions, elaborated TGF-β associated signal transduction. And then, we analyzed the current advances in preclinical studies and clinical strategies targeting TGF-β signal transduction to treat diseases.

Inhibition of discoidin domain receptor (DDR)-1 with nilotinib alters CSF miRNAs and is associated with reduced inflammation and vascular fibrosis in Alzheimer’s disease

“…Interestingly, DDR1 activation is required for Collagen IV synthesis [ 48 ] and DDR1 regulates collagen transcription and MMP production [ 49 ]; we observed alterations in subtypes of tissue TIMP3 and TIMP4 as key regulators of MMP expression [ 50 ] in the nilotinib group. We also observed reduction of TGF, which is the master regulator of fibrosis [ 51 ], as well as attenuation of inflammatory markers, including chemokines, cytokines and TNF-alpha, in the nilotinib-treated group in agreement with reduced collagen and fibrosis, in association with cytokines [ 52 ] and chemokine production [ 53 ]. COL6 genes encode the ECM protein collagen VI, and mutations in these genes are associated with muscular dystrophies [ 54 ].…”

Cancer-associated Fibroblast Spatial Heterogeneity andEMILIN1Expression in Cancer Stroma Modulate TGF-β Activity and CD8+T-Cell Infiltration in Breast Cancer

“…Both processes showed a clear tissue compartmentalization, suggesting that such interactions may be enriched in specific BC tissue regions ( Figure 1d ). TGF-β signaling was particularly interesting due to its capacity to suppress tumor immune response 28 . The T-cell and macrophage activation processes showed a distinct compartmentalization, but with a spatial pattern opposite to that of TGF-β signaling.…”

Type I and II interferons, transcription factors and major histocompatibility complexes were enhanced by knocking down the PRRSV-induced transforming growth factor beta in monocytes co-cultured with peripheral blood lymphocytes

“…Transforming growth factor beta (TGFβ) has three isoforms in mammals, with TGFβ1 being the most abundant isoform and responsible for a wide range of specific responses ( 33 ). In pigs, the impact of PRRSV-induced TGFβ1 overexpression on immune protection against PRRSV has not been investigated to date.…”