Syndecan-1 Promotes Angiogenesis in Triple-Negative Breast Cancer through the Prognostically Relevant Tissue Factor Pathway and Additional Angiogenic Routes

被引：22

作者：

Nassar, Eyyad ^{[1
]}

Hassan, Nourhan ^{[1
,2
]}

El-Ghonaimy, Eslam A. ^{[1
,3
]}

Hassan, Hebatallah ^{[3
]}

Abdullah, Mahmoud Salah ^{[2
]}

Rottke, Theresa V. ^{[1
]}

Kiesel, Ludwig ^{[1
]}

Greve, Burkhard ^{[4
]}

Ibrahim, Sherif Abdelaziz ^{[3
]}

Goette, Martin ^{[1
]}

机构：

[1] Munster Univ Hosp, Dept Gynecol & Obstet, Albert Schweitzer Campus 1,D11, D-48149 Munster, Germany

[2] Cairo Univ, Biotechnol Biomol Chem Program, Fac Sci, Giza 12613, Egypt

[3] Cairo Univ, Dept Zool, Fac Sci, Giza 12613, Egypt

[4] Univ Hosp Munster, Dept Radiotherapy & Radiooncol, D-48149 Munster, Germany

来源：

CANCERS | 2021年 / 13卷 / 10期

基金：

欧盟地平线“2020”;

关键词：

triple-negative breast cancer; prognosis; Syndecan-1; CD138; angiogenesis; tissue factor; endothelin-1; PAR1; PAR2; 3D co-culture; ENDOTHELIAL GROWTH-FACTOR; FACTOR EXPRESSION; NUCLEAR TRANSLOCATION; RECEPTOR EXPRESSION; SOLUBLE SYNDECAN-1; E-CADHERIN; IN-VITRO; PROGNOSIS; CELLS; PAR1;

D O I：

10.3390/cancers13102318

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Simple Summary Triple-negative breast cancer is an aggressive subtype of breast cancer characterized by tumor angiogenesis and poor patient survival. Here, we analyzed the function of the cell surface molecule Syndecan-1 in tumor angiogenesis in a 3D cell culture system. As a novel finding, we demonstrate that downregulation of Syndecan-1 reduces angiogenesis by decreasing the amount of angiogenesis factors of the tissue factor pathway. Furthermore, we show that the components of this pathway are associated with the prognosis of breast cancer patients. Our study identifies Syndecan-1 and the tissue factor pathway as novel potential therapeutic targets in the aggressive triple-negative subtype of breast cancer, for which no targeted therapies are currently available. Triple-negative breast cancer (TNBC) is characterized by increased angiogenesis, metastasis, and poor survival. Dysregulation of the cell surface heparan sulfate proteoglycan and signaling co-receptor Syndecan-1 is linked to poor prognosis. To study its role in angiogenesis, we silenced Syndecan-1 in TNBC cell lines using a 3D human umbilical vein endothelial cell (HUVEC) co-culture system. Syndecan-1 siRNA depletion in SUM-149, MDA-MB-468, and MDA-MB-231 cells decreased HUVEC tubule network formation. Angiogenesis array revealed reduced VEGF-A and tissue factor (TF) in the Syndecan-1-silenced secretome. qPCR independently confirmed altered expression of F3, F7, F2R/PAR1, F2RL1/PAR2, VEGF-A, EDN1, IGFBP1, and IGFBP2 in SUM-149, MDA-MB-231, and MDA-MB-468 cells. ELISA revealed reduced secreted endothelin-1 (SUM-149, MDA-MB-468) and TF (all cell lines) upon Syndecan-1 depletion, while TF pathway inhibitor treatment impaired angiogenesis. Survival analysis of 3951 patients demonstrated that high expression of F3 and F7 are associated with better relapse-free survival, whereas poor survival was observed in TNBC and p53 mutant basal breast cancer (F3) and in ER-negative and HER2-positive breast cancer (F2R, F2RL1). STRING protein network analysis revealed associations of Syndecan-1 with VEGF-A and IGFBP1, further associated with the TF and ET-1 pathways. Our study suggests that TNBC Syndecan-1 regulates angiogenesis via the TF and additional angiogenic pathways and marks its constituents as novel prognostic markers and therapeutic targets.

引用

页数：21

共 80 条

[1] Endostatin's antiangiogenic signaling network [J].