Abstract
Transforming growth factor beta (TGF-β) promotes cancer growth in late stage cancers. To inhibit the TGF-β pathway, we investigated a tumor-targeting TGF-β receptor blocker, TTB, and its role in tumor progress. The targeted TTB comprised of the extracellular domain of the TGF-β receptor II, the endoglin domain of TGF-β receptor III, and the human immuno-globin IgG1 constant fragment (Fc). To enhance tumor microenvironment targeting, a RGD peptide was fused at the N-terminal of TTB. The targeted TTB exhibited potent TGF-β neutralization activities, and inhibited cancer cell migration and invasion as well as colony formation. In xenograft models, the TTB had potent tumor inhibition activities. The TTB also attenuated the TGF-β1-induced Smad2 phosphorylation and epithelial to mesenchymal transformation (EMT), and suppressed breast cancer metastasis. Thus, the TTB is an effective TGF-β blocker with a potential for blocking excessive TGF-β induced pathogenesis in vivo.
Highlights
Transforming growth factor beta (TGF-β) is a multifunctional cytokine including three different isoforms, TGF-β1, TGF-β2 and TGF-β3
To inhibit the TGF-β pathway, we investigated a tumor-targeting TGF-β receptor blocker, targeted TGF-β blocker (TTB), and its role in tumor progress
These isoforms differ in their binding affinity to three main cell surface TGF-β receptors (TGF-βR), TGF-β RI, RII and RIII, that regulate a diverse of cellular processes
Summary
Transforming growth factor beta (TGF-β) is a multifunctional cytokine including three different isoforms, TGF-β1, TGF-β2 and TGF-β3. These isoforms differ in their binding affinity to three main cell surface TGF-β receptors (TGF-βR), TGF-β RI, RII and RIII, that regulate a diverse of cellular processes. TGF-β RI and RII belong to serine/threonine kinase receptors, whereas RIII, known as beta-glycan (BG), binds and enhances the binding of TGF-β, especially TGF-β2, to RII [1]. After TGF-β RII is activated by TGF-β binding, it binds and transphosphorylates TGF-β RI to stimulate kinase activity. The phosphorylated Smad or 3 bind to Smad, and regulate the transcription of many downstream genes [3, 4]
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