Inhibition of TGF-  Signaling for the Treatment of Tumor Metastasis and Fibrotic Diseases

Ota      Fuchs

Abstract

Transforming growth factor-β (TGF-β) is a cytokine involved in cell proliferation, apoptosis, differentiation, angiogenesis, cell adhesion, migration, extracellular matrix deposition, wound healing and immune regulation. The cellular response to TGF-β depends on the cell type and cell microenvironment. TGF-β supresses tumor growth in the early phase of neoplasia, while promotes tumor progression and metastasis in later phases. Thus, many malignant cells produce large amounts of TGF-β, but are resistant to its growth inhibitory effects. TGF-β produced by tumors depresses antitumor immune responses and diminishes cancer immunotherapy. TGF-β initiates the epithelial-to-mesenchymal transition (EMT) associated specifically with tumor invasiveness and metastasis and also with the generation of fibroblasts associated with accumulation of extracellular matrix in chronic fibrotic disorders. There are several possibilities for the disruption of TGF-β signaling: 1) targeting the expression and function of TGF-β by a small interfering RNA strategy, by a neutralizing TGF-β monoclonal antibody or by decreasing the enzymatic activity of furin, a TGF-β activating protease, 2) inhibiting TGF-β receptor kinase 1, named also activin receptor-like kinase (ALK5), activity by pyridinylimidazoles (SB- 431542, SB-505124, SB-525334, A-83-01), by 2,4-disubstituted pteridine (SD-208) or by a quinazoline-derived inhibitor (SD-093) which all interact with the ATP-binding site of ALK5; 3) inhibiting of Smad 2 and Smad 3 signaling by overexpression of their physiological inhibitor (Smad 7) or by using thioredoxin as an Smad anchor disambling Smad from activation; 4) inducing an immune response by administration of TGF-β-resistant cytotoxic T-lymphocytes or by the treatment with a small-molecule ALK5 inhibitor.

Keywords: Inhibitory Smad, receptor-regulated Smads, small interfering RNA, TGF-β monoclonal antibody, TGF-β receptor kinase 1 inhibitors, TGF-β signaling, transforming growth factor-β, epithelial, –, to-mesenchymal transition (EMT), Smad1, Smad2, Smad3, Smad5, Smad4, C.elegans, Drosophila melanogaster, Xenopus, bone morphogenetic protein (BMP), Smad8, TRI, ALK5, ALK1, phosphatidylinositol-3 kinase/ Akt /protein kinase B, chromosome 10, Hedgehog, Notch, polyethylenimine, Cy-clodextrin nanoparticles, adeno-associated virus (AAV), lentiviral vectors, SNALPs, TGFDE, TGFSCR, scleroderma, trabeculectomy, GC-1008 (Fresolimumab), MDA-MB-231 tumors, MCF7 breast cancer, P144, P17, doxorubicin, urokinase-type plasminogen activator receptor, A549 alveolar epithelial and T98G glioblas-toma cell lines, furin-like protease (FLP), Decorin, Fetuin, hepatic stellate cells, PDGF, SalI restriction, 3 NotI restriction site, pEAG347, SV40, pSV2, pAA002, Chinese hamster ovary cells, A-Sepharose, TRII:Fc, FKHRL1 Forkhead, p38, SB-431542, ALK4-, ALK2, ALK3, ALK6-, NMuMG, Mv1Lu, EMT, Halofuginone, Tempostatin, RU 19110, simvastatin