A targeted transforming growth factor-beta (TGF-ß) blocker,TTB, inhibits tumor growth and metastasis

Abstract

Transforming growth factor beta (TGF-ß) promotes cancer growth in late stage cancers. To inhibit the TGF-ß pathway, we investigated a tumor-targeting TGF-ß receptor blocker, TTB, and its role in tumor progress. The targeted TTB comprised of the extracellular domain of the TGF-ß receptor II, the endoglin domain of TGF-ß 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-ß 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-ß1- induced Smad2 phosphorylation and epithelial to mesenchymal transformation (EMT), and suppressed breast cancer metastasis. Thus, the TTB is an effective TGF-ß blocker with a potential for blocking excessive TGF-ß induced pathogenesis in vivo.