Syndecans as Modulators and Potential Pharmacological Targets in Cancer Progression

Abstract

Extracellular matrix (ECM) components form a dynamic network of key importance for cell function and properties. Key macromolecules in this interplay are syndecans (SDCs), a family of transmembrane heparan sulfate proteoglycans (HSPGs). Specifically, heparan sulfate (HS) chains with their different sulfation pattern have the ability to interact with growth factors and their receptors in tumor microenvironment, promoting the activation of different signaling cascades that regulate tumor cell behavior. The affinity of HS chains with ligands is altered during malignant conditions because of the modification of chain sequence/sulfation pattern. Furthermore, matrix degradation enzymes derived from the tumor itself or the tumor microenvironment, like heparanase and matrix metalloproteinases, ADAM as well as ADAMTS are involved in the cleavage of SDCs ectodomain at the HS and protein core level, respectively. Such released soluble SDCs “shed SDCs” in the ECM interact in an autocrine or paracrine manner with the tumor or/and stromal cells. Shed SDCs, upon binding to several matrix effectors, such as growth factors, chemokines, and cytokines, have the ability to act as competitive inhibitors for membrane proteoglycans, and modulate the inflammatory microenvironment of cancer cells. It is notable that SDCs and their soluble counterparts may affect either the behavior of cancer cells and/or their microenvironment during cancer progression. The importance of these molecules has been highlighted since HSPGs have been proposed as prognostic markers of solid tumors and hematopoietic malignancies. Going a step further down the line, the multi-actions of SDCs in many levels make them appealing as potential pharmacological targets, either by targeting directly the tumor or indirectly the adjacent stroma.

Syndecan-1 alters heparan sulfate composition and signaling pathways in malignant mesothelioma

“…The localization of SDC1 is crucial: In malignant mesothelioma SDC1 is expressed mainly at the membrane of the tumor cells with epitheloid phenotype and in the epithelial component of biphasic mesotheliomas which are associated with a less aggressive biological behavior and longer survival. Noteworthy, shed SDC1 may act in opposite way as membrane HSPGs by interfering with the growth factor gradients in the environment of tumor cell [13]. Whether lowered level of SULF1 is specifically due to shed or membrane-bound SDC1 in mesothelioma patients remains to be elucidated, nevertheless these findings support our in vitro observations that SDC1 inhibits SULF1 in malignant mesothelioma cells.…”

“…In addition, several post-synthetic changes can occur at the cell surface and affect HS structure and function: i) fragmentation of HS by heparanase into oligosaccharides of different lengths, regulating the release of HS-bound ligands [12]; ii) selective removal of the 6-O-sulfate groups from HS chains by the two isoforms of extracellular endosulfatases, SULF1 and SULF2; and iii) shedding of the core protein ectodomain with the HS chains from the cell surface by sheddases. The shed syndecans may act as competitive inhibitors for membrane HSPGs or alter growth factor gradients in the neighborhood of the cell [13].…”

Complexity of Danger: The Diverse Nature of Damage-associated Molecular Patterns

“…The resulting low molecular weight (LMW)-HA fragments accumulate and stimulate TLR2/4 and inflammatory gene expression, thereby promoting angiogenesis and cancer metastasis (7,23,24). Furthermore, active heparan sulfate (HS) fragments generated by heparanase-1 from extracellular barriers (25) and HS proteoglycan sources, such as the basement membrane perlecan (26), the cell surface syndecans (27), and glypicans (28), serve as TLR4-interacting DAMPs (29,30) (Fig. 1).…”

Significance of heparanase in metastatic lymph nodes of cervical squamous cell cancer

“…HS combines with proteoglycan to form heparan sulfate proteoglycans as three-dimensional structures of the matrix to maintain the connection of normal cells. In certain cases, they not only provide a storage depot for heparin-binding molecules in the cell micro environment, but also decisively regulate their accessibility, function and mode of action by connecting with receptors as signal molecules (24,25). Overexpression of HPA in cervical cancer tissues degrades the side chain of heparan sulfate glycosaminoglycan (HS-GAG) connected on perlecan located on the surface of the ECM (26,27), which results in the release of multiple cytokines and growth factors that bond to HS-GAG, thus facilitating the transfer of cervical cancer cells to the lymph vessels.…”