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Targeting all transforming growth factor-? isoforms with an Fc chimeric receptor impairs tumor growth and angiogenesis of oral squamous cell cancer.

ABSTRACT: Tumor progression is governed by various growth factors and cytokines in the tumor microenvironment (TME). Among these, transforming growth factor-? (TGF-?) 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-? comprises three isoforms, TGF-?1, -?2, and -?3, and transduces intracellular signals via TGF-? type I receptor (T?RI) and TGF-? type II receptor (T?RII). 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 T?RII (T?RII-Fc) has been developed as an effective therapeutic strategy for targeting TGF-? ligands, but several lines of evidence indicate that T?RII-Fc more effectively traps TGF-?1 and TGF-?3 than TGF-?2, whose expression is elevated in multiple cancer types. In the present study, we developed a chimeric TGF-? receptor containing both T?RI and T?RII (T?RI-T?RII-Fc) and found that T?RI-T?RII-Fc trapped all TGF-? isoforms, leading to inhibition of both the TGF-? signal and TGF-?-induced EMT of oral cancer cells, whereas T?RII-Fc failed to trap TGF-?2. Furthermore, we found that T?RI-T?RII-Fc suppresses tumor growth and angiogenesis more effectively than T?RII-Fc in a subcutaneous xenograft model of oral cancer cells with high TGF-? expression. These results suggest that T?RI-T?RII-Fc may be a promising tool for targeting all TGF-? isoforms in the TME.

SUBMITTER: Takahashi K

PROVIDER: S-EPMC7476713 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Targeting all transforming growth factor-β isoforms with an Fc chimeric receptor impairs tumor growth and angiogenesis of oral squamous cell cancer.

Takahashi Kazuki K Akatsu Yuichi Y Podyma-Inoue Katarzyna A KA Matsumoto Takehisa T Takahashi Hitomi H Yoshimatsu Yasuhiro Y Koinuma Daizo D Shirouzu Mikako M Miyazono Kohei K Watabe Tetsuro T

The Journal of biological chemistry 20200706 36

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). ...[more]

PMID: 32631954

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Project description: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.

Dataset Information

Targeting all transforming growth factor-? isoforms with an Fc chimeric receptor impairs tumor growth and angiogenesis of oral squamous cell cancer.

Publications

Targeting all transforming growth factor-β isoforms with an Fc chimeric receptor impairs tumor growth and angiogenesis of oral squamous cell cancer.

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