Transforming growth factor beta 1 (TGF-β1) (TGF-β1)

Transforming growth factor beta 1 (TGF-β1) is a pleiotropic cytokine that acts as a master regulator of the tumor microenvironment, specifically driving the activation of resident fibroblasts into cancer-associated fibroblasts (CAFs) and promoting tumor cell invasion (Batlle & Massagué, 2019, Immunity). In the context of the TGF-β1-induced invasion and CAF activation pathway, the ligand binds to a heteromeric receptor complex consisting of TGF-beta receptor types 1 and 2 (TGFBR1/2), triggering Smad-dependent and Smad-independent signaling cascades (Derynck & Zhang, 2003, Nature). These signals induce an epithelial-mesenchymal transition (EMT) in cancer cells, enhancing their migratory and invasive capabilities, while simultaneously reprogramming the stroma to support tumor growth and immune evasion (Calon et al., 2015, Nature Genetics). Therapeutic interventions targeting this pathway include neutralizing antibodies against the TGF-β1 ligand, decoy receptors (traps), and small molecule inhibitors of the TGFBR1 (ALK5) kinase activity (Akhurst & Hata, 2012, Nature Reviews Drug Discovery). While these agents show promise in reversing immune exclusion and inhibiting metastasis, their clinical application is complicated by the dual role of TGF-β1 as a tumor suppressor in early-stage disease and its essential role in maintaining cardiovascular and immune homeostasis (Herbertz et al., 2015, Drug Design, Development and Therapy).

Other names

TGFB1Transforming growth factor beta-1LAPCEDTGF-beta-1TGF-beta signaling pathway

Inhibition of the TGF-β1 signaling axis is achieved by preventing ligand-receptor interaction using neutralizing antibodies or decoy receptors, or by blocking the intracellular kinase activity of the TGF-beta receptor type 1 (ALK5), thereby preventing the phosphorylation of Smad2 and Smad3 and the subsequent activation of pro-invasive and pro-fibrotic gene programs (Akhurst, 2017, Cold Spring Harbor Perspectives in Biology).