Hypoxia Promotes Syndecan-3 Expression in the Tumor Microenvironment

Prieto-Fernández, Endika; Egia-Mendikute, Leire; Bosch, Alexandre; Río, Ana García del; Jiménez-Lasheras, Borja; Antoñana-Vildosola, Asier; Lee, So Young; Palazón, Asís

doi:10.3389/fimmu.2020.586977

Cited by 14 publications

(8 citation statements)

References 49 publications

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“…for the ECM organization, are involved in the dysregulation of the TME. CAFs exhibited an elevated level of syndecan-4, while high expression of syndecan-3 was detected in melanoma cells, epithelial cells, and tumor-associated macrophages, which also correlated with hypoxia gene signature [ 91 ]. Finally, hypoxia is known to upregulate LOX (lysyl oxidase), one of the enzymes responsible for collagen crosslinking.…”

Section: Hypoxiamentioning

confidence: 99%

Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance

Dratkiewicz

Simiczyjew

Mazurkiewicz

et al. 2021

Cells

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Hypoxia and elevated extracellular acidification are prevalent features of solid tumors and they are often shown to facilitate cancer progression and drug resistance. In this review, we have compiled recent and most relevant research pertaining to the role of hypoxia and acidification in melanoma growth, invasiveness, and response to therapy. Melanoma represents a highly aggressive and heterogeneous type of skin cancer. Currently employed treatments, including BRAF V600E inhibitors and immune therapy, often are not effective due to a rapidly developing drug resistance. A variety of intracellular mechanisms impeding the treatment were discovered. However, the tumor microenvironment encompassing stromal and immune cells, extracellular matrix, and physicochemical conditions such as oxygen level or acidity, may also influence the therapy effectiveness. Hypoxia and acidification are able to reprogram the metabolism of melanoma cells, enhance their survival and invasiveness, as well as promote the immunosuppressive environment. For this reason, these physicochemical features of the melanoma niche and signaling pathways related to them emerge as potential therapeutic targets.

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Section: Hypoxiamentioning

confidence: 99%

Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance

Dratkiewicz

Simiczyjew

Mazurkiewicz

et al. 2021

Cells

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“…A vital member of the SDC family, syndecan 3 (SDC3) is essential for cell adhesion, migration, and development. SDC3 expression is boosted by hypoxia in the tumor microenvironment, which influences pro-inflammatory reactions and the overall survival of melanoma patients ( 65 ). Additionally, SDC3 was linked to more dangerous tumors and a worse prognosis in prostate cancer ( 66 ).…”

Section: Discussionmentioning

confidence: 99%

Regulatory T-cells-related signature for identifying a prognostic subtype of hepatocellular carcinoma with an exhausted tumor microenvironment

Zhang

2022

Front. Immunol.

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Regulatory T-Cells (Tregs) are important in the progression of hepatocellular cancer (HCC). The goal of this work was to look into Tregs-related genes and develop a Tregs-related prognostic model. We used the weighted gene coexpression network analysis (WGCNA) to look for Tregs-related genes in the TCGA, ICGC, and GSE14520 cohorts and then used the non-negative matrix factorization (NMF) algorithm to find Tregs-related subpopulations. The LASSO-Cox regression approach was used to determine Tregs-related genes, which were then condensed into a risk score. A total of 153 overlapping genes among the three cohorts were considered Tregs-related genes. Based on these genes, two Tregs-associated clusters that varied in both prognostic and biological characteristics were identified. When compared with Cluster 1, Cluster 2 was a TME-exhausted HCC subpopulation with substantial immune cell infiltration but a poor prognosis. Five Tregs-related genes including HMOX1, MMP9, CTSC, SDC3, and TNFRSF11B were finally used to construct a prognostic model, which could accurately predict the prognosis of HCC patients in the three datasets. Patients in the high-risk scores group with bad survival outcomes were replete with immune/inflammatory responses, but exhausted T cells and elevated PD-1 and PD-L1 expression. The results of qRT-PCR and immunohistochemical staining (IHC) analysis in clinical tissue samples confirmed the above findings. Moreover, the signature also accurately predicted anti-PD-L1 antibody responses in the IMvigor210 dataset. Finally, HMOX1, MMP9, and TNFRSF11B were expressed differently in Hep3B and Huh7 cells after being treated with a PD1/PD-L1 inhibitor. In conclusion, our study uncovered a Tregs-related prognostic model that could identify TMEexhausted subpopulations and revealed that PD1/PD-L1 inhibitors could alter the expression levels of HMOX1, MMP9, and TNFRSF11B in Hep3B and Huh7 cells, which might help us better understand Tregs infiltration and develop personalized immunotherapy treatments for HCC patients.

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“…Also in melanoma, Sdc3 expression is induced by hypoxia-inducible factors such as HIF1α. Interestingly, cells of the tumor microenvironment such as macrophages and endothelial cells express Sdc3 [ 32 ]. In pancreatic ductal carcinoma, Sdc3 expression correlates with primary tumor size in a mouse model [ 33 ].…”

Section: Discussionmentioning

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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Hypoxia Promotes Syndecan-3 Expression in the Tumor Microenvironment

Cited by 14 publications

References 49 publications

Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance

Hypoxia and Extracellular Acidification as Drivers of Melanoma Progression and Drug Resistance

Regulatory T-cells-related signature for identifying a prognostic subtype of hepatocellular carcinoma with an exhausted tumor microenvironment

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

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