Syndecan-1 Overexpressing Mesothelioma Cells Inhibit Proliferation, Wound Healing, and Tube Formation of Endothelial Cells

Abstract

Malignant mesothelioma (MM) is an aggressive tumor of the serosal cavities. Angiogenesis is important for mesothelioma progression, but so far, anti-angiogenic agents have not improved patient survival. Our hypothesis is that better understanding of the regulation of angiogenesis in this tumor would largely improve the success of such a therapy. Syndecan-1 (SDC-1) is a transmembrane heparan sulfate proteoglycan that acts as a co-receptor in various cellular processes including angiogenesis. In MM, the expression of SDC-1 is generally low but when present, SDC-1 associates to epithelioid differentiation, inhibition of tumor cell migration and favorable prognosis, meanwhile SDC-1 decrease deteriorates the prognosis. In the present study, we studied the effect of SDC-1 overexpression and silencing on MM cells ability to secrete angiogenic factors and monitored the downstream effect of SDC-1 modulation on endothelial cells proliferation, wound healing, and tube formation. This was done by adding conditioned medium from SDC-1 transfected and SDC-1 silenced mesothelioma cells to endothelial cells. Moreover, we investigated the interplay and molecular functional changes in angiogenesis in a co-culture system and characterized the soluble angiogenesis-related factors secreted to the conditioned media. We demonstrated that SDC-1 over-expression inhibited the proliferation, wound healing, and tube formation of endothelial cells. This effect was mediated by a multitude of angiogenic factors comprising angiopoietin-1 (Fold change ± SD: 0.65 ± 0.07), FGF-4 (1.45 ± 0.04), HGF (1.33 ± 0.07), NRG1-β1 (1.35 ± 0.08), TSP-1 (0.8 ± 0.02), TIMP-1 (0.89 ± 0.01) and TGF-β1 (1.35 ± 0.01). SDC-1 silencing increased IL8 (1.33 ± 0.06), promoted wound closure, but did not influence the tube formation of endothelial cells. Pleural effusions from mesothelioma patients showed that Vascular Endothelial Growth Factor (VEGF) levels correlate to soluble SDC-1 levels and have prognostic value. In conclusion, SDC-1 over-expression affects the angiogenic factor secretion of mesothelioma cells and thereby inhibits endothelial cells proliferation, tube formation, and wound healing. VEGF could be used in prognostic evaluation of mesothelioma patients together with SDC-1.

Syndecan-1 Amplifies Ovalbumin-Induced Airway Remodeling by Strengthening TGFβ1/Smad3 Action

“…SDC-1, a major component of glycocalyx, is an important signaling transmembrane protein molecule. SDC-1 has an extracellular glycosaminoglycan chain comprising HS, HA, and CS ( 13 , 15 ). First, SDC-1 protrudes from extracellular structural features and functions as a physical barrier, capturing signal molecules and directing them to receptors on the membrane ( 14 ).…”

“…SDC-1 is a transmembrane heparin sulfate proteoglycan that carries various side chains, such as heparin sulfate (HS), chondroitin sulfate (CS), and hyaluronic acid (HA) ( 13 ). The SDC-1 core protein comprises extracellular, transmembrane, and intracellular regions ( 14 ).…”

Staphylococcus aureus β-toxin exerts anti-angiogenic effects by inhibiting re-endothelialization and neovessel formation

“…During wound healing, β-toxin largely induced production of HGF, with subtle increases in PDGF-AA and endostatin, and a subtle decrease in MMP-8. Excess HGF in the serum is clinically used as an indicator of advanced atherosclerotic lesions, vascular lesions, and hypertension (63)(64)(65). Vascular lesions are accompanied by endothelial cell injury.…”

“…Vascular lesions are accompanied by endothelial cell injury. As such, it has been suggested that endothelial cells produce HGF to promote repair of damaged endothelial cells at these lesions (63)(64)(65). Hence, iHAECs might induce HGF as a protective mechanism in response to endothelial injury caused by β-toxin.…”

Endothelial Heterogeneity in Development and Wound Healing

“…The chemokine receptor Cxcr4a is indispensable for this venous-to-arterial transformation to occur in the zebrafish, and the importance of CXCR4 appears conserved in mammals where CXCR4 expression is observed in the tip cells of developing mouse retinal arterial vessels [ 72 , 73 ]. In a recapitulation of development, both VEGF and BMP signalling have been shown to be highly upregulated in immune cells, fibroblasts and keratinocytes within mouse wounds, and these pathways appear to have a distinct role in modulating wound angiogenesis by differentially regulating endothelial cell tip vs. stalk cell identity in culture [ 74 , 75 , 76 , 77 , 78 , 79 , 80 ]. Additionally, live imaging of skin wound healing studies identified the migration of tissue resident endovascular progenitors (EVP) into the centre of wound granulation tissue and subsequent differentiation.…”