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靶向基质细胞 Syndecan-2 可减少乳腺肿瘤生长、转移并限制免疫逃逸。

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

机构信息

Lambe Institute for Translational Research, National University of Ireland, Galway, Ireland.

Orbsen Therapeutics, National University of Ireland, Galway, Ireland.

出版信息

Int J Cancer. 2021 Mar 1;148(5):1245-1259. doi: 10.1002/ijc.33383. Epub 2020 Dec 2.

DOI:10.1002/ijc.33383
PMID:33152121
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7839764/
Abstract

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.

摘要

肿瘤基质细胞支持肿瘤发生。我们报告称，Syndecan-2（SDC2）在乳腺癌组织中的一种非上皮细胞、非造血细胞、非内皮细胞基质细胞群体中表达。在体外，Syndecan-2 调节 TGFβ 信号（SMAD7、PAI-1）、患者来源的肿瘤相关基质细胞（TASCs）的迁移和免疫抑制。在原位免疫缺陷乳腺癌模型中，TASCs 中 Syndecan-2 的过表达显著增强 TGFβ 信号（SMAD7、PAI-1）、肿瘤生长和转移，而降低 TASCs 中的 SDC2 水平则减弱 TGFβ 信号（SMAD7、PAI-1、CXCR4）、肿瘤生长和转移。为了探索治疗应用的潜力，生成了一种 Syndecan-2 肽，该肽抑制了 TASCs 的迁移和免疫抑制特性，同时下调了 TGFβ 调节的免疫抑制基因，如 CXCR4 和 PD-L1 的表达。此外，在原位同源乳腺癌模型中，TASCs 中 Syndecan-2 肽的过表达减少了 TME 中的肿瘤生长和免疫抑制。这些数据提供了证据，表明靶向 TME 中的基质 Syndecan-2 可通过降低 TGFβ 信号和增强免疫控制来抑制肿瘤生长和转移。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73ee/7839764/472b8bc52b4f/IJC-148-1245-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73ee/7839764/6be2cc9c5884/IJC-148-1245-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73ee/7839764/81077e00d13d/IJC-148-1245-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73ee/7839764/dca0a0801779/IJC-148-1245-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73ee/7839764/359286cd1cb8/IJC-148-1245-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73ee/7839764/472b8bc52b4f/IJC-148-1245-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73ee/7839764/6be2cc9c5884/IJC-148-1245-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73ee/7839764/81077e00d13d/IJC-148-1245-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73ee/7839764/dca0a0801779/IJC-148-1245-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73ee/7839764/359286cd1cb8/IJC-148-1245-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/73ee/7839764/472b8bc52b4f/IJC-148-1245-g005.jpg

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