Melanoma is an aggressive type of cancer originating from the skin that arises from neoplastic changes in melanocytes. Transforming growth factor‑β (TGF‑β) is a pleiotropic cytokine and is known to contribute to melanoma progression by inducing the epithelial‑mesenchymal transition (EMT) program and creating an environment that favors tumor progression. There are three TGF‑β isoforms, TGF‑β1, TGF‑β2 and TGF‑β3, all of which engage in pro‑tumorigenic activities by activating SMAD signaling pathways. All TGF‑β isoforms activate signaling pathways by binding to their TGF‑β type I (TβRI) and type II (TβRII) receptors. Thus, effective targeting of all TGF‑β isoforms is of great importance. In the present study, chimeric proteins comprising the extracellular domains of TβRI and/or TβRII fused with the Fc portion of human immunoglobulin (IgG) were validated in the melanoma context. The Fc chimeric receptor comprising both TβRI and TβRII (TβRI‑TβRII‑Fc) effectively trapped all TGF‑β isoforms. Conversely, TβRII‑Fc chimeric receptor, that comprises TβRII only, was able to interact with TGF‑β1 and TGF‑β3 isoforms, but not with TGF‑β2, which is a poor prognostic factor for melanoma patients. Accordingly, it was revealed that TβRI‑TβRII‑Fc chimeric receptor suppressed the EMT program in melanoma cells in vitro induced by any of the three TGF‑β isoforms, as revealed by decreased expression of mesenchymal markers. Conversely, TβRII‑Fc chimeric receptor inhibited the EMT program induced by TGF‑β1 and TGF‑β3. In addition, it was established that tumor growth in subcutaneous mouse melanoma was inhibited by TβRI‑TβRII‑Fc chimeric receptor indicating that Fc chimeric receptor could be applied to modify the tumor microenvironment (TME) of melanoma. Therefore, designing of Fc chimeric receptors targeting TGF‑β signals that affect various components of the TME may result in the development of effective anti‑melanoma agents.

中文翻译：

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通过使用 Fc 嵌合受体靶向所有转化生长因子 β 同种型，可以抑制黑色素瘤的进展。

黑色素瘤是一种侵袭性癌症，起源于皮肤，由黑色素细胞的肿瘤变化引起。转化生长因子-β (TGF-β) 是一种多效细胞因子，已知通过诱导上皮间质转化 (EMT) 程序和创造有利于肿瘤进展的环境来促进黑色素瘤进展。存在三种 TGF-β 亚型，TGF-β1、TGF-β2 和 TGF-β3，它们都通过激活 SMAD 信号通路参与促肿瘤发生活动。所有 TGF-β 同工型都通过与其 TGF-β I 型 (TβRI) 和 II 型 (TβRII) 受体结合来激活信号通路。因此，有效靶向所有 TGF-β 异构体非常重要。在目前的研究中，在黑色素瘤背景下验证了包含与人免疫球蛋白 (IgG) 的 Fc 部分融合的 TβRI 和/或 TβRII 的细胞外结构域的嵌合蛋白。包含 TβRI 和 TβRII（TβRI-TβRII-Fc）的 Fc 嵌合受体有效地捕获了所有 TGF-β 同工型。相反，仅包含 TβRII 的 TβRII-Fc 嵌合受体能够与 TGF-β1 和 TGF-β3 异构体相互作用，但不能与 TGF-β2 相互作用，后者是黑色素瘤患者的不良预后因素。因此，揭示了 TβRI-TβRII-Fc 嵌合受体抑制黑色素瘤细胞中的 EMT 程序 但不是 TGF-β2，这是黑色素瘤患者的不良预后因素。因此，揭示了 TβRI-TβRII-Fc 嵌合受体抑制黑色素瘤细胞中的 EMT 程序 但不是 TGF-β2，这是黑色素瘤患者的不良预后因素。因此，揭示了 TβRI-TβRII-Fc 嵌合受体抑制黑色素瘤细胞中的 EMT 程序由三种 TGF-β 同种型中的任何一种在体外诱导，如间充质标志物表达降低所揭示。相反，TβRII-Fc 嵌合受体抑制 TGF-β1 和 TGF-β3 诱导的 EMT 程序。此外，已确定 TβRI-TβRII-Fc 嵌合受体抑制皮下小鼠黑色素瘤的肿瘤生长，表明 Fc 嵌合受体可用于改变黑色素瘤的肿瘤微环境 (TME)。因此，设计针对影响 TME 各种成分的 TGF-β 信号的 Fc 嵌合受体可能会导致开发有效的抗黑色素瘤药物。