Journal Article

Inhibition of transforming growth factor‐β signals suppresses tumor formation by regulation of tumor microenvironment networks

Watabe, Tetsuro, Uchida, Shizuka, Shirouzu, Mikako, Podyma‐Inoue, Katarzyna A., Tokizaki, Shiori, Hashimoto, Shinichi, Takahashi, Kazuki, Miyazono, Kohei, Iwabuchi, Sadahiro, Kobayashi, Miho, Ibi, Haruka, Harada, Hiroyuki, Matsumoto, Takehisa

2024

Overview

The tumor microenvironment (TME) consists of cancer cells surrounded by stromal components including tumor vessels. Transforming growth factor‐β (TGF‐β) promotes tumor progression by inducing epithelial–mesenchymal transition (EMT) in cancer cells and stimulating tumor angiogenesis in the tumor stroma. We previously developed an Fc chimeric TGF‐β receptor containing both TGF‐β type I (TβRI) and type II (TβRII) receptors (TβRI‐TβRII‐Fc), which trapped all TGF‐β isoforms and suppressed tumor growth. However, the precise mechanisms underlying this action have not yet been elucidated. In the present study, we showed that the recombinant TβRI‐TβRII‐Fc protein effectively suppressed in vitro EMT of oral cancer cells and in vivo tumor growth in a human oral cancer cell xenograft mouse model. Tumor cell proliferation and angiogenesis were suppressed in tumors treated with TβRI‐TβRII‐Fc. Molecular profiling of human cancer cells and mouse stroma revealed that K‐Ras signaling and angiogenesis were suppressed. Administration of TβRI‐TβRII‐Fc protein decreased the expression of heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF), interleukin‐1β (IL‐1β) and epiregulin (EREG) in the TME of oral cancer tumor xenografts. HB‐EGF increased proliferation of human oral cancer cells and mouse endothelial cells by activating ERK1/2 phosphorylation. HB‐EGF also promoted oral cancer cell‐derived tumor formation by enhancing cancer cell proliferation and tumor angiogenesis. In addition, increased expressions of IL‐1β and EREG in oral cancer cells significantly enhanced tumor formation. These results suggest that TGF‐β signaling in the TME controls cancer cell proliferation and angiogenesis by activating HB‐EGF/IL‐1β/EREG pathways and that TβRI‐TβRII‐Fc protein is a promising tool for targeting the TME networks. In the present study, we show that inhibition of transforming growth factor‐β (TGF‐β) signals by recombinant Fc chimeric TGF‐β receptor containing both TGF‐β type I (TβRI) and type II (TβRII) receptors (TβRI‐TβRII‐Fc) suppresses tumor formation through inhibition of cancer cell proliferation and tumor angiogenesis. These results suggest that TβRI‐TβRII‐Fc protein is a promising tool for targeting the various components of tumor microenvironment.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Angiogenesis / Animals / Cell proliferation / Cells / Endothelial cells / Endothelial Cells - metabolism / Epidermal growth factor / epithelial–mesenchymal transition / Extracellular signal-regulated kinase / Fc receptors / Heparin / Heparin-binding EGF-like Growth Factor / Heparin-binding epidermal growth factor-like growth factor / Humans / IL-1β / interleukin‐1beta / Isoforms / K-Ras protein / Kinases / Ligands / Mice / Motility / Mouth Neoplasms - genetics / Oral cancer / Original / Penicillin / Phosphorylation / Protein Serine-Threonine Kinases - metabolism / Proteins / Receptors, Transforming Growth Factor beta - metabolism / Reporters / Smooth muscle / Stroma / Transforming Growth Factor beta - metabolism / Transforming Growth Factor beta1 / Transforming growth factor-b / Transforming Growth Factors / transforming growth factor‐beta / Tumor Microenvironment / Tumors / Xenografts