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Loftus P;Watson L;Deedigan LM;Camarillo-Retamosa E;Dwyer RM;O'Flynn L;Griffin M;O'Brien T;Kerin M;Elliman SJ;Barkley LR;
International Journal Of Cancer
Targeting stromal cell Syndecan-2 reduces breast tumour growth, metastasis and limits immune evasion.
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Tumour stromal cells support tumourigenesis. We report that Syndecan-2 (SDC2) is expressed on a non-epithelial, non-haematopoietic, non-endothelial stromal cell population within breast cancer tissue. In-vitro, syndecan-2 modulated TGFß signaling (SMAD7, PAI-1), migration and immunosuppression of patient-derived tumour-associated stromal cells (TASCs). In an orthotopic immunocompromised breast cancer model overexpression of syndecan-2 in TASCs significantly enhanced TGFß signaling (SMAD7, PAI-1), tumour growth and metastasis, whereas reducing levels of SDC2 in TASCs attenuated TGFß signaling (SMAD7, PAI-1, CXCR4), tumour growth and metastasis. To explore the potential for therapeutic application, a syndecan-2-peptide was generated that inhibited the migratory and immunosuppressive properties of TASCs in association with reduced expression of TGFß-regulated immunosuppressive genes, such as CXCR4 and PD-L1. Moreover, using an orthotopic syngeneic breast cancer model overexpression of syndecan-2-peptide in TASCs reduced tumour growth and immunosuppression within the TME. These data provide evidence that targeting stromal syndecan-2 within the TME inhibits tumour growth and metastasis due to decreased TGFß signaling and increased immune control. This article is protected by copyright. All rights reserved.
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