Inhibition of TGF-beta signals by a chimeric Fc receptor suppresses tumor formation by regulation of tumor microenvironment networks

The tumor microenvironment (TME) consists of cancer cells surrounded by stromal components including tumor vessels. Transforming growth factor-beta (TGF-beta) promotes tumor progression by inducing the epithelial-to-mesenchymal transition (EMT) of cancer cells and stimulating tumor angiogenesis. We previously developed a chimeric TGF-beta receptor containing both TGF-beta type I (TBRI) and type II (TBRII) receptors (TBRI-TBRII-Fc), which trapped all TGF-beta isoforms, leading to suppression of tumor growth. However, the precise mechanisms of its action have not been elucidated. In the present study, we show that recombinant TBRI-TBRII-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. In the tumors treated with TBRI-TBRII-Fc, both tumor cell proliferation and angiogenesis were suppressed. Molecular profiling of human cancer cells and mouse stroma revealed that KRAS signaling, and angiogenesis were decreased. We found that TBRI-TBRII decreased the expression of heparin-binding epidermal growth factor-like growth factor (HB-EGF) in vivo but not in vitro, suggesting that TGF-beta signaling in the TME promotes tumor growth by controlling cancer cell proliferation and angiogenesis. These results suggest that TBRI-TBRII-Fc may be a promising tool for targeting the TME network.