期刊
INTERNATIONAL JOURNAL OF CANCER
卷 148, 期 5, 页码 1245-1259出版社
WILEY
DOI: 10.1002/ijc.33383
关键词
breast cancer; Fc‐ peptide; immunosuppression; syndecan‐ 2; TGFβ signalling; tumour‐ associated stromal cells
类别
资金
- Breast Cancer Now [2015NovSP676]
- Flight Attendant Medical Research Institute [072101]
- Irish Research Council [EBPPG/2014/109, EBPPG/2015/215]
- Science Foundation Ireland [15/IFA/3039]
- National Breast Cancer Research Institute [20025175]
- Irish Research Council (IRC) [EBPPG/2014/109] Funding Source: Irish Research Council (IRC)
- Science Foundation Ireland (SFI) [15/IFA/3039] Funding Source: Science Foundation Ireland (SFI)
The study revealed that syndecan-2 expressed on a specific stromal cell population within tumors plays a crucial role in regulating tumor growth and metastasis through modulation of TGF beta signaling. Inhibiting the migratory and immunosuppressive properties of tumor-associated stromal cells (TASCs) can effectively suppress tumor growth and spread.
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 TGF beta 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 TGF beta signalling (SMAD7, PAI-1), tumour growth and metastasis, whereas reducing levels of SDC2 in TASCs attenuated TGF beta 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 TGF beta-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 TGF beta signalling and increased immune control.
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