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.

中文翻译：

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用Fc嵌合受体靶向所有转化生长因子-β同工型会损害口腔鳞状细胞癌的肿瘤生长和血管生成。

肿瘤的进展受肿瘤微环境（TME）中各种生长因子和细胞因子的控制。其中，转化生长因子-β（TGF-β）由驻留在TME中的各种细胞分泌，并通过诱导癌细胞的上皮-间质转化（EMT）和肿瘤血管生成来促进肿瘤进展。TGF-β包含三种同工型，TGF-β1，-β2和-β3，并通过TGF-βI型受体（TβRI）和TGF-βII型受体（TβRII）转导细胞内信号。为了设计减少TME中致癌信号转导的配体陷阱，经常使用包含与免疫球蛋白的Fc部分融合的受体的配体相互作用胞外域的嵌合蛋白。例如，已开发出嵌合可溶性TβRII（TβRII-Fc）作为靶向TGF-β配体的有效治疗策略，但是有几条证据表明，TβRII-Fc比TGF-β2更有效地捕获TGF-β1和TGF-β3，TGF-β2在多种癌症类型中的表达均升高。在本研究中，我们开发了一种同时包含TβRI和TβRII的嵌合TGF-β受体（TβRI-TβRII-Fc），发现TβRI-TβRII-Fc捕获了所有TGF-β亚型，从而抑制了TGF-β信号和TGF-β诱导的口腔癌细胞EMT，而TβRII-Fc无法捕获TGF-β2。此外，我们发现在高TGF-β表达的口腔癌细胞的皮下异种移植模型中，TβRI-TβRII-Fc比TβRII-Fc更有效地抑制了肿瘤生长和血管生成。这些结果表明，TβRI-TβRII-Fc可能是靶向TME中所有TGF-β亚型的有前途的工具。