The role of syndecan-1 in cellular signaling and its effects on heparan sulfate biosynthesis in mesenchymal tumors

Our plain-English summary of The role of syndecan-1 in cellular signaling and its effects on heparan sulfate biosynthesis in mesenchymal tumors, by T. Szatmári, K. Dobra (Frontiers in Oncology, 2013).

The study

• Authors: T. Szatmári, K. Dobra
• Journal: Frontiers in Oncology
• Published: 2013;3:310
• Type of article: Review
• Cited by: 63 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Proteoglycans (PGs) and in particular the syndecans are involved in the differentiation process across the epithelial-mesenchymal axis, principally through their ability to bind growth factors and modulate their downstream signaling. Malignant tumors have individual proteoglycan profiles, which are closely associated with their differentiation and biological behavior, mesenchymal tumors showing a different profile from that of epithelial tumors. Syndecan-1 is the main syndecan of epithelial malignancies, whereas in sarcomas its expression level is generally low, in accordance with their mesenchymal phenotype and highly malignant behavior. This proteoglycan is often overexpressed in adenocarcinoma cells, whereas mesothelioma and fibrosarcoma cells express syndecan-2 and syndecan-4 more abundantly. Increased expression of syndecan-1 in mesenchymal tumors changes the tumor cell morphology to an epithelioid direction whereas downregulation results in a change in shape from polygonal to spindle-like morphology. Although syndecan-1 plays major roles on the cell-surface, there are also intracellular functions, which are not very well studied. On the functional level, syndecan-1 affects mesenchymal tumor cell proliferation, adhesion, migration and motility, and the effect varies with the different domains of the core protein. Syndecan-1 may exert stimulatory or inhibitory effects, depending on the concentration of various mitogens, enzymes, and signaling molecules, the ratio between the shed and membrane-associated syndecan-1 and histological grade of the tumour. Growth factor signaling seems to be delicately controlled by regulatory loops involving the syndecan expression levels and their sulfation patterns. Overexpression of syndecan-1 modulates the biosynthesis and sulfation of heparan sulfate and it also affects the expression of other PGs. On transcriptomic level, syndecan-1 modulation results in profound effects on genes involved in regulation of cell growth.

In plain English

This was a review article. The authors summarized published research on syndecan-1, a molecule on the surface of cells, and how it affects cell signaling and the making of heparan sulfate in mesenchymal tumors, mainly malignant mesothelioma and fibrosarcoma. It reported no new patient data and did not discuss asbestos. The studies it reviewed found that syndecan-1 is relatively low in malignant mesothelioma, and its expression relates to epithelioid differentiation. In laboratory cells, extra syndecan-1 was reported to inhibit the growth and migration of malignant mesothelioma cells. Citing their own earlier study of a mesothelioma cell line, the authors reported that extra syndecan-1 affected many signaling pathways. It also reduced the expression of genes for several enzymes, including SULF-1, whose gene showed a fold change of −52.3 compared with vector-control cells. The authors concluded that syndecan-1 regulates the expression of multiple proteoglycans and coordinates heparan sulfate biosynthesis. They noted that the effects seem to differ by cell type and cannot be directly extended to other cells, and that the functional meaning of the SULF-1 findings needs further investigation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: review article (narrative review of laboratory and pathology literature)
• Who was studied: Published studies of syndecan-1 in tumors, focusing on mesenchymal tumors (malignant mesothelioma and fibrosarcoma) compared with epithelial cancers. Much of the work described is on tumor cell lines grown in the laboratory.
• Exposure: No asbestos or other occupational exposure was studied. The 'exposure' in the reviewed experiments was laboratory overexpression or silencing of syndecan-1 in tumor cells.
• Main results:
  • Reviewed studies reported that syndecan-1 expression in malignant mesothelioma relates to epithelioid differentiation.
  • Reviewed laboratory studies reported that overexpression of syndecan-1 inhibited growth and migration of malignant mesothelioma cells, while cell adhesion was enhanced.
  • In the authors' earlier study of a mesothelioma cell line, syndecan-1 overexpression changed the expression of genes encoding heparan sulfate enzymes, compared with vector-control cells. Expression of the genes for EXT1 and NDST1 went down. The gene for SULF-1 went down strongly (fold change −52.3), while SULF-2 was not affected. These were changes detected at the transcriptional (gene-expression) level.
  • In malignant mesothelioma cells, syndecan-1 overexpression was associated with higher glypican-3 and lower glypican-6 and perlecan.
  • In reviewed fibrosarcoma studies, syndecan-1 overexpression inhibited proliferation and migration of sarcomatoid fibrosarcoma cells, but enhanced them in an epithelioid fibrosarcoma cell line.
• The authors' conclusion: The authors concluded that syndecan-1 regulates the expression of multiple proteoglycans and coordinates heparan sulfate biosynthesis, and that growth factor signaling appears to be controlled by regulatory loops involving syndecan-1 levels, its location in the cell and sulfation patterns.
• Limitations the authors state:
  • The effects appear to be cell-type specific and cannot be directly extrapolated to other cells.
  • The functional significance of the SULF-1 findings in mesothelioma needs further investigation.
  • Most studies of syndecans and signaling were done in carcinomas or blood cancers, so syndecan-1 is less studied in mesenchymal cells.

Topics

Medical terms in this study, explained in our Lexicon: Mesenchymal Tumor, Sarcoma, Adenocarcinoma, Mesothelioma, Epithelioid.

Related studies

• Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma — G. Heidari-Hamedani, R.R. Vivès, et al. (2015)
• Mapping the Interactome of the Nuclear Heparan Sulfate Proteoglycan Syndecan-1 in Mesothelioma Cells — A. Kumar-Singh, J. Shrinet, et al. (2020)
• Extracellular superoxide dismutase protects against matrix degradation of heparan sulfate in the lung — C.R. Kliment, J.M. Tobolewski, et al. (2008)
• Effect of syndecan-1 overexpression on mesenchymal tumour cell proliferation with focus on different functional domains — F. Zong, E. Fthenou, et al. (2010)
• Epithelial-mesenchymal transition involved in pulmonary fibrosis induced by multi-walled carbon nanotubes via TGF-beta/Smad signaling pathway — T. Chen, H. Nie, et al. (2014)
• Novel genes and pathways modulated by syndecan-1: implications for the proliferation and cell-cycle regulation of malignant mesothelioma cells — T. Szatmári, F. Mundt, et al. (2012)

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