Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells

Katakam, Sampath Kumar; Pelucchi, Paride; Cocola, Cinzia; Reinbold, Rolland; Vlodavsky, Israël; Greve, Burkhard; Götte, Martin

doi:10.3389/fonc.2020.00774

Cited by 16 publications

(13 citation statements)

References 58 publications

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“…In the present study, colony and mammosphere formation – two important functional readouts of CSCs - were consistently upregulated in both model cell lines upon overexpression of both sulfotransferases, indicating a stemness-promoting function of these enzymes. At the molecular level, our data point at an upregulation of several components of the notch signaling pathway, which we previously linked to Sdc-1 function in breast and colon cancer ( Ibrahim et al, 2017 ; Katakam et al, 2020a ). For example, Sdc-1 expression in inflammatory breast cancer is correlated with CD44, Notch-1, and Notch-3 expression, and siRNA knockdown of Sdc-1 results in a weaker CSC phenotype and reduced expression of Notch-1-4 and Hey1 in inflammatory breast cancer cells ( Ibrahim et al, 2017 ).…”

Section: Discussionsupporting

confidence: 60%

The Heparan Sulfate Sulfotransferases HS2ST1 and HS3ST2 Are Novel Regulators of Breast Cancer Stem-Cell Properties

Teixeira

Kumar

Katakam

et al. 2020

Front. Cell Dev. Biol.

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Heparan sulfate (HS) is a glycosaminoglycan found mainly in its protein-conjugated form at the cell surface and the extracellular matrix. Its high sulfation degree mediates functional interactions with positively charged amino acids in proteins. 2-O sulfation of iduronic acid and 3-O sulfation of glucosamine in HS are mediated by the sulfotransferases HS2ST and HS3ST, respectively, which are dysregulated in several cancers. Both sulfotransferases regulate breast cancer cell viability and invasion, but their role in cancer stem cells (CSCs) is unknown. Breast CSCs express characteristic markers such as CD44 + /CD24 −/low , CD133 and ALDH1 and are involved in tumor initiation, formation, and recurrence. We studied the influence of HS2ST1 and HS3ST2 overexpression on the CSC phenotype in breast cancer cell lines representative of the triple-negative (MDA-MB-231) and hormone-receptor positive subtype (MCF-7). The CD44 + /CD24 −/low phenotype was significantly reduced in MDA-MB-231 cells after overexpression of both enzymes, remaining unaltered in MCF-7 cells. ALDH1 activity was increased after HS2ST1 and HS3ST2 overexpression in MDA-MB-231 cells and reduced after HS2ST1 overexpression in MCF-7 cells. Colony and spheroid formation were increased after HS2ST1 and HS3ST2 overexpression in MCF-7 cells. Moreover, MDA-MB-231 cells overexpressing HS2ST1 formed more colonies and could not generate spheres. The phenotypic changes were associated with complex changes in the expression of the stemness-associated notch and Wnt-signaling pathways constituents, syndecans, heparanase and Sulf1. The results improve our understanding of breast CSC function and mark a subtype-specific impact of HS modifications on the CSC phenotype of triple-negative and hormone receptor positive breast cancer model cell lines.

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Section: Discussionsupporting

confidence: 60%

The Heparan Sulfate Sulfotransferases HS2ST1 and HS3ST2 Are Novel Regulators of Breast Cancer Stem-Cell Properties

Teixeira

Kumar

Katakam

et al. 2020

Front. Cell Dev. Biol.

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“…Since we previously showed that heparan sulfate proteoglycans are capable of modulating breast and colon cancer stem cell properties, associated with therapeutic resistance [ 20 , 21 , 22 , 23 ], we evaluated the potential influence of SDC3 on the growth of three-dimensional spheroids as a readout of stem cell activity in a hanging drop assay [ 24 ]. Both SDC3-depleted and control siRNA-treated SKOV3 and CAOV3 cells formed dense spheroids after 4 days of culture that were surrounded by a margin of more loosely arranged cells ( Figure 2 A, left panel).…”

Section: Resultsmentioning

confidence: 99%

The Cell Surface Heparan Sulfate Proteoglycan Syndecan-3 Promotes Ovarian Cancer Pathogenesis

Hillemeyer

Espinoza-Sánchez

Greve

et al. 2022

IJMS

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Syndecans are transmembrane heparan sulfate proteoglycans that integrate signaling at the cell surface. By interacting with cytokines, signaling receptors, proteases, and extracellular matrix proteins, syndecans regulate cell proliferation, metastasis, angiogenesis, and inflammation. We analyzed public gene expression datasets to evaluate the dysregulation and potential prognostic impact of Syndecan-3 in ovarian cancer. Moreover, we performed functional in vitro analysis in syndecan-3-siRNA-treated SKOV3 and CAOV3 ovarian cancer cells. In silico analysis of public gene array datasets revealed that syndecan-3 mRNA expression was significantly increased 5.8-fold in ovarian cancer tissues (n = 744) and 3.4-fold in metastases (n = 44) compared with control tissue (n = 46), as independently confirmed in an RNAseq dataset on ovarian serous cystadenocarcinoma tissue (n = 374, controls: n = 133, 3.5-fold increase tumor vs. normal). Syndecan-3 siRNA knockdown impaired 3D spheroid growth and colony formation as stemness-related readouts in SKOV3 and CAOV3 cells. In SKOV3, but not in CAOV3 cells, syndecan-3 depletion reduced cell viability both under basal conditions and under chemotherapy with cisplatin, or cisplatin and paclitaxel. While analysis of the SIOVDB database did not reveal differences in Syndecan-3 expression between patients, sensitive, resistant or refractory to chemotherapy, KM Plotter analysis of 1435 ovarian cancer patients revealed that high syndecan-3 expression was associated with reduced survival in patients treated with taxol and platin. At the molecular level, a reduction in Stat3 activation and changes in the expression of Wnt and notch signaling constituents were observed. Our study suggests that up-regulation of syndecan-3 promotes the pathogenesis of ovarian cancer by modulating stemness-associated pathways.

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“…Gene silencing and overexpression in Caco-2 cells revealed that heparanase expression and activity were upregulated in syndecan-1-depleted cells likely due to upregulation of the transcription factor Egr1. 55 Syndecan-1 depletion also increased stemness and invasiveness of Caco-2 cells in heparanase-dependent manner. Upregulated expression of heparanase resulted in increased resistance to radiotherapy and chemotherapy.…”

Section: The Heparanase/shed Syndecan-1 Axis Regulates Cancer Progresmentioning

confidence: 91%

Heparanase-enhanced Shedding of Syndecan-1 and Its Role in Driving Disease Pathogenesis and Progression

Rangarajan¹,

Richter²,

Richter³

et al. 2020

J Histochem Cytochem.

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Both heparanase and syndecan-1 are known to be present and active in disease pathobiology. An important feature of syndecan-1 related to its role in pathologies is that it can be shed from the surface of cells as an intact ectodomain composed of the extracellular core protein and attached heparan sulfate and chondroitin sulfate chains. Shed syndecan-1 remains functional and impacts cell behavior both locally and distally from its cell of origin. Shedding of syndecan-1 is initiated by a variety of stimuli and accomplished predominantly by the action of matrix metalloproteinases. The accessibility of these proteases to the core protein of syndecan-1 is enhanced, and shedding facilitated, when the heparan sulfate chains of syndecan-1 have been shortened by the enzymatic activity of heparanase. Interestingly, heparanase also enhances shedding by upregulating the expression of matrix metalloproteinases. Recent studies have revealed that heparanase-induced syndecan-1 shedding contributes to the pathogenesis and progression of cancer and viral infection, as well as other septic and non-septic inflammatory states. This review discusses the heparanase/shed syndecan-1 axis in disease pathogenesis and progression, the potential of targeting this axis therapeutically, and the possibility that this axis is widespread and of influence in many diseases.

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Syndecan-1-Dependent Regulation of Heparanase Affects Invasiveness, Stem Cell Properties, and Therapeutic Resistance of Caco2 Colon Cancer Cells

Cited by 16 publications

References 58 publications

The Heparan Sulfate Sulfotransferases HS2ST1 and HS3ST2 Are Novel Regulators of Breast Cancer Stem-Cell Properties

The Heparan Sulfate Sulfotransferases HS2ST1 and HS3ST2 Are Novel Regulators of Breast Cancer Stem-Cell Properties

The Cell Surface Heparan Sulfate Proteoglycan Syndecan-3 Promotes Ovarian Cancer Pathogenesis

Heparanase-enhanced Shedding of Syndecan-1 and Its Role in Driving Disease Pathogenesis and Progression

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