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

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.

Keywords: cancer; heparan sulfate; mesenchymal tumor; signaling; syndecan-1.

Figure 1

The syndecan family. Schematic illustration of structurally related syndecan genes, showing the two subfamilies of syndecans: syndecan-1 and -3, and syndecans -2 and -4, respectively. The extracellular domain is highly variable with the exception of the GAG attachment sites and the proteolytic cleavage site near the plasma membrane. In contrast the endo- and transmembrane domains are well preserved.

Figure 2

Biochemical structure of the repeating disaccharide units of heparan sulfate and chondroitin-sulfate.

Figure 3

Syndecan-1 turnover and its effect on HS modifications in malignant mesothelioma. Syndecan-1 (Syn-1) is synthesized in Golgi and it is transported to cell-membrane where it acts as a co-receptor for various growth factors (GFs) and growth factor receptors (GFRs). The ectodomain is released from the cell-surface by the action of various enzymatic reactions collectively called sheddases, and the heparan sulfate can be further fragmented by the action of heparanases. The shedding results in a soluble molecule, which is still active and thereby can bind and sequester GFs. Syndecan-1 is also internalized and translocates to the nucleus in a tubulin dependent manner, but the function of this translocation is still incompletely understood. Upon syndecan-1 overexpression, several biosynthetic enzymes are modified including, EXT, exostosin; NDST, N-deacetylase/N-sulfotransferase; OST, O-sulfotransferase; HS-EPI, C5 epimerase; and they collectively lead to altered HS synthesis and sulfation pattern (Colors represent: red = upregulated and green = downregulated). The endosulfatase SULF-1, specifically removes the 6-O-sulfate groups from the HS chains, and thereby may inhibit growth factor signaling. Downregulation of SULF-1 by syndecan-1, detected at transcriptional level, may lead to modulation of downstream growth factor signaling.