| 1. |
- Björkander, Sofia, et al.
(author)
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Peripheral Monocyte Expression of the Chemokine Receptors CCR2, CCR5 and CXCR3 is Altered at Parturition in Healthy Women and in Women with Systemic Lupus Erythematosus
- 2013
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In: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 77:3, s. 200-212
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Journal article (peer-reviewed)abstract
- Monocytes are precursors of macrophages and recruited to the uterus throughout pregnancy to perform important immunological functions. In this study, we hypothesized that pregnant women have reduced peripheral monocyte expression of chemokine receptors and alterations in PBMC responses to microbial stimuli as an adaption to pregnancy and that these changes are less pronounced in women with autoimmunity. We therefore investigated the chemokine receptor expression, migratory behaviour and responses to microbial stimulation of peripheral monocytes from pregnant women at parturition (n=13) and from non-pregnant women (n=9). In addition, we compared healthy pregnant women with women suffering from SLE (n=5), a condition with pronounced systemic inflammation increasing the risk for pregnancy complications. We demonstrate that peripheral monocytes are affected by pregnancy with reduced percentages of CCR2+, CCR5+ and CXCR3+ monocytes of both classical (CD16) and inflammatory (CD16+) subsets and that the trophoblast-secreted chemokine CCL2/MCP-1 recruited monocytes of both subsets in vitro. Further, PBMCs from pregnant women had a divergent response to microbial stimulation with lower CCL5/RANTES and higher CCL2/MCP-1 secretion compared with non-pregnant women. In addition, pregnant women had lower basal PBMC-secretion of CCL5/RANTES and higher basal secretion of IL-10 and CCL2/MCP-1. Interestingly, the women with SLE responded similar to pregnancy as did healthy women with lower percentages of CCR2+, CCR5+ and CXCR3+ monocytes. However, they had increased expression of CCR5 on CD16+ monocytes and heightened PBMC-secretion of CCL5/RANTES. In conclusion, our data indicate that monocyte chemokine receptor expression and the chemokine milieu during pregnancy are tightly regulated to support pregnancy.
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| 2. |
- Heidari-Hamedani, Ghazal
(author)
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Syndecan-1 insights in mesothelioma
- 2017
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Doctoral thesis (other academic/artistic)abstract
- Syndecan-1 is a cell surface heparan sulfate proteoglycan expressing on epithelial cells. Heparan sulfate (HS) chains on syndecan-1 constitute growth factor attachment sites and facilitate growth factors to bind their respective receptors. This binding property of HS chains allows syndecan-1 to be involved in various cellular processes. The fine structure of HS defines the binding properties of these chains. Sulfatase-1 is one of the enzymes that regulates sulfation pattern of HS chains. On the cell membrane syndecan-1 can get shed and the soluble proteoglycan can compete with cell surface-bound and might have counteracting roles. Malignant mesothelioma (MM) is highly aggressive tumor of mesothelial cells lining the serosal cavities. Presence of syndecan-1 on the cell surface of MM is associated with favorable prognosis, whereas the decrease of syndecan-1 deteriorates the prognosis. With this thesis work, we aimed to disclose syndecan-1 roles and the underlying mechanisms by which syndecan-1 affect the behavior of malignant mesothelioma. We focused on genes and pathways modulated by syndecan-1 overexpression and silencing in a mesothelioma cell line (paper I), and we found out that TGF-β, EGF, VEGF and ERK/MAPK pathways were affected in both settings. Syndecan-1 silencing enriched cell cycle pathways and syndecan-1 overexpression had the opposite effects. Syndecan-1 overexpression affected gene expression involved in angiogenesis, adhesion, proliferation, cell cycle, migration, interleukins, extracellular matrix proteins and HS modifying enzymes. Among the HS modifying enzymes affected by syndecan-1 overexpression, sulfatase-1 gene was highly downregulated (paper III). HS content was decreased but overall sulfation was increased by syndecan-1 overexpression. Studying downstream signaling molecules showed that syndecan-1 affects PI3K and MAPK signaling pathways in mesothelioma, which leads to cell cycle arrest at G1. Syndecan-1 level was evaluated in two cohorts of patients both in pleural effusions and sera (paper II). Syndecan-1 was elevated in malignant effusions than benign conditions and could predict malignant disease. In addition, patients with higher levels of syndecan-1 in pleural effusion had shorter survival compared to the patients with lower syndecan-1 levels. However these effects were not observed with syndecan-1 levels in serum. Syndecan-1 overexpression on mesothelioma cells inhibited endothelial cell proliferation, migration and tube formation (paper IV). Endothelial cell tube formation was reverted by MMP7 silencing, which is one of the important sheddases of syndecan-1. Co-cultured HUVEC and mesothelioma cells showed less nuclear Yes-associated protein (YAP) expression, which is associated with less migration. The angiogenesis inhibitory effects of syndecan-1 overexpressing cells were conducted by both pro- and anti-angiogenic factors comprising Angiopoietin-1, FGF-4, HGF, NRG1-β1, TSP-1, TIMP-1 and TGF-β1. VEGF levels in pleural effusions from mesothelioma patients correlate to soluble syndecan-1 levels and have prognostic value in these patients. Combining shed syndecan-1 and VEGF seemed to be better for prognostic evaluation of mesothelioma patients than these factors alone.
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| 3. |
- Javadi, Joman, et al.
(author)
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Syndecan-1 Overexpressing Mesothelioma Cells Inhibit Proliferation, Wound Healing, and Tube Formation of Endothelial Cells
- 2021
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In: Cancers. - : MDPI. - 2072-6694. ; 13:4
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Journal article (peer-reviewed)abstract
- Simple Summary The transmembrane proteoglycan syndecan-1 (SDC-1) is an important mediator of cell-matrix interactions. The heparan sulfate side-chains of SDC-1 can bind to a multitude of growth factors, cytokines, and chemokines, thereby regulating a plethora of physiological and pathological processes, including angiogenesis. The extracellular region of SDC-1 can be released from the cell surface by the action of sheddases including matrix metalloproteinase-7 and 9, resulting in a soluble protein that is still active and can act as a competitive activator or inhibitor of the cell surface receptor. Accelerated shedding and loss of cell surface SDC-1 is associated with epithelial to mesenchymal transition (EMT) and achievement of a more invasive phenotype in malignant mesothelioma (MM). Transfection with SDC-1 reverts the morphology in epithelioid direction and inhibits the proliferation and migration of MM cells. This study aimed to investigate the role of SDC-1 in angiogenesis. We demonstrate that overexpression and silencing of SDC-1 alters the secretion of angiogenic proteins in MM cells. Upon SDC-1 overexpression, several factors collectively inhibit the proliferation, wound closure, and tube formation of endothelial cells, whereas SDC-1 silencing only affects wound healing. 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-beta 1 (1.35 +/- 0.08), TSP-1 (0.8 +/- 0.02), TIMP-1 (0.89 +/- 0.01) and TGF-beta 1 (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.
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| 4. |
- Mundt, Filip, et al.
(author)
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Diagnostic and Prognostic Value of Soluble Syndecan-1 in Pleural Malignancies
- 2014
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In: BioMed Research International. - : Hindawi Limited. - 2314-6133 .- 2314-6141. ; , s. 419853-
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Journal article (peer-reviewed)abstract
- Background. The distinction between malignant and benign pleural effusions is a diagnostic challenge today and measuring soluble biomarkers could add to the diagnostic accuracy. Syndecan-1 is a proteoglycan involved in various cellular functions and is cleaved from the cell surface in a regulated manner. The shed fragment, which can be recovered in effusion supernatant and in serum, retains its binding capacities, but often with different functions and signalling properties than the cell-bound form. Aim. This study aimed to investigate the diagnostic and prognostic value of soluble syndecan-1 in pleural effusions and sera from patients with pleural malignancies. Study Design. Using two cohorts of patients, we assessed the diagnostic and prognostic value of soluble syndecan-1 in pleural effusions and sera, using enzyme-linked immunosorbent assays. Results. In pleural effusions, syndecan-1 distinguished malignant and benign diseases, with an odds ratio of 8.59 (95% CI 3.67 to 20.09). Furthermore, syndecan-1 in pleural effusions predicted a survival difference for patients with pleural metastatic disease and malignant mesothelioma of 11.2 and 9.2 months, respectively. However, no such effects were seen when syndecan-1 was measured in serum. Conclusion. Soluble syndecan-1 is a promising candidate biomarker for the cytopathological diagnosis and prognostication of malignant pleural effusions.
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