Progression of melanoma is suppressed by targeting all transforming growth factor‑β isoforms with an Fc chimeric receptor
| Autor: | Toshihiro Inubushi, Hitomi Takahashi, Shingo Kodama, Kazuki Takahashi, Akinari Sugauchi, Mikihiko Kogo, Kyoko Kurioka, Tetsuro Watabe, Toshihiro Uchihashi, Susumu Tanaka, Katarzyna Α. Podyma‑Inoue |
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| Rok vydání: | 2021 |
| Předmět: |
TGF-β
Cancer Research Epithelial-Mesenchymal Transition Skin Neoplasms Melanoma Experimental Smad Proteins Receptors Fc SMAD Transforming Growth Factor beta1 Mice melanoma Tumor Microenvironment medicine Animals Humans Protein Isoforms Receptor Cell Proliferation Tumor microenvironment Receptors Chimeric Antigen Chemistry Melanoma EMT Fc chimeric receptor Articles General Medicine medicine.disease Fusion protein HEK293 Cells Oncology Tumor progression Immunoglobulin G Disease Progression Cancer research Cytokines Signal transduction Protein Binding Signal Transduction Transforming growth factor |
| Zdroj: | Oncology Reports |
| ISSN: | 1791-2431 1021-335X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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