Targeting all transforming growth factor-β isoforms with an Fc chimeric receptor impairs tumor growth and angiogenesis of oral squamous cell cancer.

Abstract

Tumor progression is governed by various growth factors and cytokines in the tumor microenvironment (TME). Among these, transforming growth factor-β (TGF-β) is secreted by various cell types residing in the TME and promotes tumor progression by inducing the epithelial-to-mesenchymal transition (EMT) of cancer cells and tumor angiogenesis. TGF-β comprises three isoforms, TGF-β1, -β2, and -β3, and transduces intracellular signals via TGF-β type I receptor (TβRI) and TGF-β type II receptor (TβRII). For the purpose of designing ligand traps that reduce oncogenic signaling in the TME, chimeric proteins comprising the ligand-interacting ectodomains of receptors fused with the Fc portion of immunoglobulin are often used. For example, chimeric soluble TβRII (TβRII-Fc) has been developed as an effective therapeutic strategy for targeting TGF-β ligands, but several lines of evidence indicate that TβRII-Fc more effectively traps TGF-β1 and TGF-β3 than TGF-β2, whose expression is elevated in multiple cancer types. In the present study, we developed a chimeric TGF-β receptor containing both TβRI and TβRII (TβRI-TβRII-Fc) and found that TβRI-TβRII-Fc trapped all TGF-β isoforms, leading to inhibition of both the TGF-β signal and TGF-β-induced EMT of oral cancer cells, whereas TβRII-Fc failed to trap TGF-β2. Furthermore, we found that TβRI-TβRII-Fc suppresses tumor growth and angiogenesis more effectively than TβRII-Fc in a subcutaneous xenograft model of oral cancer cells with high TGF-β expression. These results suggest that TβRI-TβRII-Fc may be a promising tool for targeting all TGF-β isoforms in the TME.

• Authors: Kazuki Takahashi, Yuichi Akatsu, Katarzyna A Podyma-Inoue, Takehisa Matsumoto, Hitomi Takahashi, Yasuhiro Yoshimatsu, Daizo Koinuma, Mikako Shirouzu, Kohei Miyazono, Tetsuro Watabe
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 295 Issue 36 Pg. 12559-12572 (09 04 2020) ISSN: 1083-351X [Electronic] United States
• PMID: 32631954 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 Takahashi et al.

Chemical References

• Antineoplastic Agents
• Protein Isoforms
• Receptors, Fc
• Receptors, Transforming Growth Factor beta
• Recombinant Proteins
• Transforming Growth Factor beta

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Carcinoma, Squamous Cell (drug therapy, metabolism)
• HEK293 Cells
• Humans
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Nude
• Mouth Neoplasms (drug therapy, metabolism)
• Neovascularization, Pathologic (drug therapy)
• Protein Isoforms (antagonists & inhibitors, metabolism)
• Receptors, Fc (genetics, metabolism)
• Receptors, Transforming Growth Factor beta (genetics, metabolism)
• Recombinant Proteins (genetics, metabolism, therapeutic use)
• Transforming Growth Factor beta (antagonists & inhibitors, metabolism)
• Tumor Microenvironment