Involvement of Syndecan-1 and Heparanase in Cancer and Inflammation

Teixeira, Felipe Charbel; Götte, Martin

doi:10.1007/978-3-030-34521-1_4

Cited by 35 publications

(41 citation statements)

References 240 publications

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“…Of particular relevance in this context is syndecan-1 (Sdc-1, CD138), the most highly expressed transmembrane HSPG on the surface of epithelial cells among the four members of the Sdc family [9]. Sdc-1 can bind several growth factors, chemokines, cell adhesion molecules, and ECM components, allowing for the regulation of virtually all steps of tumor progression as defined in the Hallmarks of Cancer [10]. Although some subtype-specific differences have been reported, the majority of studies on Sdc-1 expression have assigned a negative prognostic and predictive value for high Sdc-1 expression in breast cancer, suggesting that the inhibition of Sdc-1 expression and/or function could be a therapeutic approach to impair breast tumor progression [6,8,[11][12][13][14].…”

Section: Introductionmentioning

confidence: 99%

“…Further functional studies have demonstrated an impact of Sdc-1 on breast cancer cell motility that could be linked to the regulation of E-cadherin, Rho GTPases, and focal adhesion kinase [17], a differential regulatory impact of membrane-bound and soluble forms of Sdc-1 on breast cancer cell invasion that affected the expression of protease inhibitors [18], and a novel immunomodulatory role of tumor Sdc-1, inducing CD4+ T-cell polarization in the breast cancer microenvironment [19]. Considering that the Sdc-1 molecule is part of a complex glycocalyx and that its function is dependent on other molecules ranging from microRNAs to heparanase [10,17], alterations in its expression could also affect the function and expression of other PGs or GAGs. For example, the HA receptor CD44 is misexpressed in Sdc-1-depleted breast cancer cells [16], and MDA-MB-231 breast cancer cells depleted of beta4GalT-7, a biosynthetic enzyme generating the HS GAG attachment site, respond with a reduced expression of Sdc-1 and an upregulation of HA biosynthesis.…”

Section: Introductionmentioning

confidence: 99%

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Syndecan-1 Depletion Has a Differential Impact on Hyaluronic Acid Metabolism and Tumor Cell Behavior in Luminal and Triple-Negative Breast Cancer Cells

Valla

Hassan

Vitale

et al. 2021

IJMS

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Glycosaminoglycans (GAGs) and proteoglycans (PGs) are major components of the glycocalyx. The secreted GAG and CD44 ligand hyaluronic acid (HA), and the cell surface PG syndecan-1 (Sdc-1) modulate the expression and activity of cytokines, chemokines, growth factors, and adhesion molecules, acting as critical regulators of tumor cell behavior. Here, we studied the effect of Sdc-1 siRNA depletion and HA treatment on hallmark processes of cancer in breast cancer cell lines of different levels of aggressiveness. We analyzed HA synthesis, and parameters relevant to tumor progression, including the stem cell phenotype, Wnt signaling constituents, cell cycle progression and apoptosis, and angiogenic markers in luminal MCF-7 and triple-negative MDA-MB-231 cells. Sdc-1 knockdown enhanced HAS-2 synthesis and HA binding in MCF-7, but not in MDA-MB-231 cells. Sdc-1-depleted MDA-MB-231 cells showed a reduced CD24-/CD44+ population. Furthermore, Sdc-1 depletion was associated with survival signals in both cell lines, affecting cell cycle progression and apoptosis evasion. These changes were linked to the altered expression of KLF4, MSI2, and miR-10b and differential changes in Erk, Akt, and PTEN signaling. We conclude that Sdc-1 knockdown differentially affects HA metabolism in luminal and triple-negative breast cancer model cell lines and impacts the stem phenotype, cell survival, and angiogenic factors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Syndecan-1 Depletion Has a Differential Impact on Hyaluronic Acid Metabolism and Tumor Cell Behavior in Luminal and Triple-Negative Breast Cancer Cells

Valla

Hassan

Vitale

et al. 2021

IJMS

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“…The regulatory role of Sdc-1 in angiogenesis network formation was also assigned in another study, where Sdc-1 was shown to be a prerequisite for the activation of αvβ3 and αvβ5 integrins during angiogenesis and breast tumorigenesis in vivo [ 19 , 35 ]. These data suggest that Sdc-1 is able to modulate angiogenesis via several different pathways, which is in accordance with its pleiotropic role in physiology and tumor progression [ 36 ]. Apart from the central angiogenesis regulator VEGF-A, our study extends these findings to the tissue factor pathway, which apparently plays an important Sdc-1-dependent role in the communication of TNBC and endothelial cells during angiogenesis.…”

Section: Discussionmentioning

confidence: 57%

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

Nassar

Hassan

El-Ghonaimy

et al. 2021

Cancers

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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.

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“…There are two isoforms in the human, but only heparanase-1 has enzymatic activity [6]. This enzyme is notably upregulated in a number of cancer types and is the focus of trials to determine if its inhibition can ameliorate tumor aggressiveness [74,75]. Heparanase selectively cleaves HS chains, liberating oligosaccharides that may be biologically active [76].…”

Section: Regulation Of Syndecan-1 Expressionmentioning

confidence: 99%

Syndecan-1 (CD138), Carcinomas and EMT

Couchman

2021

IJMS

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Cell surface proteoglycans are known to be important regulators of many aspects of cell behavior. The principle family of transmembrane proteoglycans is the syndecans, of which there are four in mammals. Syndecan-1 is mostly restricted to epithelia, and bears heparan sulfate chains that are capable of interacting with a large array of polypeptides, including extracellular matrix components and potent mediators of proliferation, adhesion and migration. For this reason, it has been studied extensively with respect to carcinomas and tumor progression. Frequently, but not always, syndecan-1 levels decrease as tumor grade, stage and invasiveness and dedifferentiation increase. This parallels experiments that show depletion of syndecan-1 can be accompanied by loss of cadherin-mediated adhesion. However, in some tumors, levels of syndecan-1 increase, but the characterization of its distribution is relevant. There can be loss of membrane staining, but acquisition of cytoplasmic and/or nuclear staining that is abnormal. Moreover, the appearance of syndecan-1 in the tumor stroma, either associated with its cellular component or the collagenous matrix, is nearly always a sign of poor prognosis. Given its relevance to myeloma progression, syndecan-1-directed antibody—toxin conjugates are being tested in clinical and preclinical trials, and may have future relevance to some carcinomas.

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Involvement of Syndecan-1 and Heparanase in Cancer and Inflammation

Cited by 35 publications

References 240 publications

Syndecan-1 Depletion Has a Differential Impact on Hyaluronic Acid Metabolism and Tumor Cell Behavior in Luminal and Triple-Negative Breast Cancer Cells

Syndecan-1 Depletion Has a Differential Impact on Hyaluronic Acid Metabolism and Tumor Cell Behavior in Luminal and Triple-Negative Breast Cancer Cells

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

Syndecan-1 (CD138), Carcinomas and EMT

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