Progression of melanoma is suppressed by targeting all transforming growth factorß isoforms with an Fc chimeric receptor.
Oncol Rep
; 46(3)2021 Sep.
Article
em En
| MEDLINE
| ID: mdl-34296292
ABSTRACT
Melanoma is an aggressive type of cancer originating from the skin that arises from neoplastic changes in melanocytes. Transforming growth factorß (TGFß) is a pleiotropic cytokine and is known to contribute to melanoma progression by inducing the epithelialmesenchymal transition (EMT) program and creating an environment that favors tumor progression. There are three TGFß isoforms, TGFß1, TGFß2 and TGFß3, all of which engage in protumorigenic activities by activating SMAD signaling pathways. All TGFß isoforms activate signaling pathways by binding to their TGFß type I (TßRI) and type II (TßRII) receptors. Thus, effective targeting of all TGFß isoforms is of great importance. In the present study, chimeric proteins comprising the extracellular domains of TßRI and/or TßRII fused with the Fc portion of human immunoglobulin (IgG) were validated in the melanoma context. The Fc chimeric receptor comprising both TßRI and TßRII (TßRITßRIIFc) effectively trapped all TGFß isoforms. Conversely, TßRIIFc chimeric receptor, that comprises TßRII only, was able to interact with TGFß1 and TGFß3 isoforms, but not with TGFß2, which is a poor prognostic factor for melanoma patients. Accordingly, it was revealed that TßRITßRIIFc chimeric receptor suppressed the EMT program in melanoma cells in vitro induced by any of the three TGFß isoforms, as revealed by decreased expression of mesenchymal markers. Conversely, TßRIIFc chimeric receptor inhibited the EMT program induced by TGFß1 and TGFß3. In addition, it was established that tumor growth in subcutaneous mouse melanoma was inhibited by TßRITßRIIFc 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 TGFß signals that affect various components of the TME may result in the development of effective antimelanoma agents.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Cutâneas
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Receptores Fc
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Fator de Crescimento Transformador beta1
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Melanoma
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article