Targeting stromal cell Syndecan-2 reduces breast tumour growth, metastasis and limits immune evasion.

Autor: Loftus PG; Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland.; Orbsen Therapeutics, National University of Ireland, Galway, Ireland., Watson L; Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland., Deedigan LM; Orbsen Therapeutics, National University of Ireland, Galway, Ireland., Camarillo-Retamosa E; Orbsen Therapeutics, National University of Ireland, Galway, Ireland., Dwyer RM; Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland., O'Flynn L; Orbsen Therapeutics, National University of Ireland, Galway, Ireland.; Lisa O'Flynn, Avectas Ltd, Maynooth University, Co Kildare, Ireland., Alagesan S; Orbsen Therapeutics, National University of Ireland, Galway, Ireland., Griffin M; Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland., O'Brien T; Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland., Kerin MJ; Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland., Elliman SJ; Orbsen Therapeutics, National University of Ireland, Galway, Ireland., Barkley LR; Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland.
Jazyk: angličtina
Zdroj: International journal of cancer [Int J Cancer] 2021 Mar 01; Vol. 148 (5), pp. 1245-1259. Date of Electronic Publication: 2020 Dec 02.
DOI: 10.1002/ijc.33383
Abstrakt: Tumour stromal cells support tumourigenesis. We report that Syndecan-2 (SDC2) is expressed on a nonepithelial, nonhaematopoietic, nonendothelial stromal cell population within breast cancer tissue. In vitro, syndecan-2 modulated TGFβ signalling (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 TGFβ signalling (SMAD7, PAI-1), tumour growth and metastasis, whereas reducing levels of SDC2 in TASCs attenuated TGFβ signalling (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 TGFβ-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 TGFβ signalling and increased immune control.
(© 2020 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of Union for International Cancer Control.)
Databáze: MEDLINE
Externí odkaz: