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Review
. 2021 Feb 25;11(3):349.
doi: 10.3390/biom11030349.

Syndecans and Pancreatic Ductal Adenocarcinoma

Nausika Betriu  1 , Juan Bertran-Mas  1 , Anna Andreeva  1 , Carlos E Semino  1
Affiliations
Review

Syndecans and Pancreatic Ductal Adenocarcinoma

Nausika Betriu et al. Biomolecules. .

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is a fatal disease with poor prognosis because patients rarely express symptoms in initial stages, which prevents early detection and diagnosis. Syndecans, a subfamily of proteoglycans, are involved in many physiological processes including cell proliferation, adhesion, and migration. Syndecans are physiologically found in many cell types and their interactions with other macromolecules enhance many pathways. In particular, extracellular matrix components, growth factors, and integrins collect the majority of syndecans associations acting as biochemical, physical, and mechanical transducers. Syndecans are transmembrane glycoproteins, but occasionally their extracellular domain can be released from the cell surface by the action of matrix metalloproteinases, converting them into soluble molecules that are capable of binding distant molecules such as extracellular matrix (ECM) components, growth factor receptors, and integrins from other cells. In this review, we explore the role of syndecans in tumorigenesis as well as their potential as therapeutic targets. Finally, this work reviews the contribution of syndecan-1 and syndecan-2 in PDAC progression and illustrates its potential to be targeted in future treatments for this devastating disease.

Keywords: angiogenesis; pancreatic ductal adenocarcinoma; proteoglycans; syndecans; tumor progression.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Syndecan structure. (a) Schematic representation of syndecan domains and their functions; (b) Close-up of the syndecan cytoplasmatic domain showing the constants (C1/C2) and the variable (V) regions and their potential interactions. The interaction between the variable region with α-actinin links syndecans to the cytoskeleton.
Figure 2
Figure 2
Syndecan functions and interactions. (a) Syndecan-4 cooperates with Epithelial Growth Factor Receptor (EGFR) and β1-integrin to tune cell mechanics in response to tension (b) Syndecan-1 and syndecan-4 interact with HER-2 and EGFR respectively, and with α6β4 and α3β1 to promote cell motility and survival (c) Syndecan-1 interaction with insulin-like growth factor-1 receptor (IGF1-R) activates talin, which in turn activates αvβ3 and αvβ5 integrins, leading to cell proliferation, migration, and survival. These interactions can be blocked with the synstatin peptide.
Figure 3
Figure 3
Syndecan shedding. Matrix metalloproteinases (MMPs] cleave syndecans near the transmembrane domain. Syndecan shedding prevents the transduction of intracellular signals that otherwise would be activated by the syndecan ectodomain. The soluble shed syndecan can bind to growth factors, extracellular matrix (ECM) substrates, and also receptors from other cells, which generate new signals or modify others. Soluble syndecans have implications in inflammation, cancer progression, angiogenesis, and wound healing.
Figure 4
Figure 4
Syndecan-2 and KRas cooperate to induce an invasive phenotype in pancreatic cancer cells. (a) In normal cells, RACK1 binding to syndecan-2 prevents Src activation and free p120-GAP inhibits Ras signaling triggered by TKRs (b) In pancreatic ductal adenocarcinoma (PDAC) cells, p120-GAP binding to syndecan-2 activates Src and free RACK1 enhances TKR-mediated Ras activation, promoting cell proliferation, spreading, and invasion.
Figure 5
Figure 5
Roles of syndecan-2 in promoting and inhibiting angiogenesis. (a) Syndecan-2-VEGFA165-VEGFR2 tricomplex promotes angiogenesis. Heparan sulfate chains present in syndecan-2 associate to VEGFA165 through a heparin binding domain (HBD) increasing its local concentration and enhancing the binding to its receptor VEGFR2 (b) Syndecan-2 shedding inhibits angiogenesis. Shed syndecan-2 binds to CD148 which promotes the reduction of β1-integrin activity in endothelial cells. The inactivation of β1-integrin reduces cell migration and consequently inhibits angiogenesis.
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