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Pyong Woo Park - One of the best experts on this subject based on the ideXlab platform.
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The endothelial glycocalyx in Syndecan-1 deficient mice
Microvascular Research, 2013Co-Authors: Michele D Savery, Pyong Woo Park, John Jiang, Edward R DamianoAbstract:Abstract The existence of a hydrodynamically relevant endothelial glycocalyx has been established in capillaries, venules, and arterioles in vivo . The glycocalyx is thought to consist primarily of membrane-bound proteoglycans with glycosaminoglycan side-chains, membrane-bound glypicans, and adsorbed plasma proteins. The proteoglycans found on the luminal surface of endothelial cells are Syndecans-1, -2, and -4, and glypican-1. The extent to which any of these proteins might serve to anchor the glycocalyx to the endothelium has not yet been determined. To test whether Syndecan-1, in particular, is an essential anchoring protein, we performed experiments to determine the hydrodynamically relevant glycocalyx thickness in Syndecan-1 deficient (Sdc1 −/− ) mice. Micro-particle image velocimetry data were collected using a previously described method. Microviscometric analysis of these data consistently revealed the existence of a hydrodynamically relevant endothelial glycocalyx in Sdc1 −/− mice in vivo . The mean glycocalyx thickness found in Sdc1 −/− mice was 0.45 ± 0.10 μm ( N = 15), as compared with 0.54 ± 0.12 μm ( N = 11) in wild-type (WT) mice ( p = 0.03). The slightly thinner glycocalyx observed in Sdc1 −/− mice relative to WT mice may be due to the absence of Syndecan-1. These findings show that healthy Sdc1 −/− mice are able to synthesize and maintain a hydrodynamically relevant glycocalyx, which indicates that Syndecan-1 is not an essential anchoring protein for the glycocalyx in Sdc1 −/− mice. This may also be the case for WT mice; however, Sdc1 −/− mice might adapt to the lack of Syndecan-1 by increasing the expression of other proteoglycans. In any case, Syndecan-1 does not appear to be a prerequisite for the existence of an endothelial glycocalyx.
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Molecular functions of Syndecan-1 in disease.
Matrix Biology, 2012Co-Authors: Yvonne Hui-fang Teng, Rafael S. Aquino, Pyong Woo ParkAbstract:Syndecan-1 is a cell surface heparan sulfate proteoglycan that binds to many mediators of disease pathogenesis. Through these molecular interactions, Syndecan-1 can modulate leukocyte recruitment, cancer cell proliferation and invasion, angiogenesis, microbial attachment and entry, host defense mechanisms, and matrix remodeling. The significance of Syndecan-1 interactions in disease is underscored by the striking pathological phenotypes seen in the Syndecan-1 null mice when they are challenged with disease-instigating agents or conditions. This review discusses the key molecular functions of Syndecan-1 in modulating the onset, progression, and resolution of inflammatory diseases, cancer, and infection.
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modulation of Syndecan 1 shedding after hemorrhagic shock and resuscitation
PLOS ONE, 2011Co-Authors: Ricky J L Haywoodwatson, Pyong Woo Park, John B. Holcomb, Ernest A Gonzalez, Zhanglong Peng, Shibani Pati, Weiwei Wang, Ana Maria Zaske, Tyler Menge, Rosemary A KozarAbstract:The early use of fresh frozen plasma as a resuscitative agent after hemorrhagic shock has been associated with improved survival, but the mechanism of protection is unknown. Hemorrhagic shock causes endothelial cell dysfunction and we hypothesized that fresh frozen plasma would restore endothelial integrity and reduce Syndecan-1 shedding after hemorrhagic shock. A prospective, observational study in severely injured patients in hemorrhagic shock demonstrated significantly elevated levels of Syndecan-1 (554±93 ng/ml) after injury, which decreased with resuscitation (187±36 ng/ml) but was elevated compared to normal donors (27±1 ng/ml). Three pro-inflammatory cytokines, interferon-γ, fractalkine, and interleukin-1β, negatively correlated while one anti-inflammatory cytokine, IL-10, positively correlated with shed Syndecan-1. These cytokines all play an important role in maintaining endothelial integrity. An in vitro model of endothelial injury then specifically examined endothelial permeability after treatment with fresh frozen plasma orlactated Ringers. Shock or endothelial injury disrupted junctional integrity and increased permeability, which was improved with fresh frozen plasma, but not lactated Ringers. Changes in endothelial cell permeability correlated with Syndecan-1 shedding. These data suggest that plasma based resuscitation preserved endothelial Syndecan-1 and maintained endothelial integrity, and may help to explain the protective effects of fresh frozen plasma after hemorrhagic shock.
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Syndecan 1 promotes staphylococcus aureus corneal infection by counteracting neutrophil mediated host defense
Journal of Biological Chemistry, 2011Co-Authors: Atsuko Hayashida, Shiro Amano, Pyong Woo ParkAbstract:Many microbial pathogens subvert cell surface heparan sulfate proteoglycans (HSPGs) to infect host cells in vitro. The significance of HSPG-pathogen interactions in vivo, however, remains to be determined. In this study, we examined the role of Syndecan-1, a major cell surface HSPG of epithelial cells, in Staphylococcus aureus corneal infection. We found that Syndecan-1 null (Sdc1−/−) mice significantly resist S. aureus corneal infection compared with wild type (WT) mice that express abundant Syndecan-1 in their corneal epithelium. However, Syndecan-1 did not bind to S. aureus, and Syndecan-1 was not required for the colonization of cultured corneal epithelial cells by S. aureus, suggesting that Syndecan-1 does not mediate S. aureus attachment to corneal tissues in vivo. Instead, S. aureus induced the shedding of Syndecan-1 ectodomains from the surface of corneal epithelial cells. Topical administration of purified Syndecan-1 ectodomains or heparan sulfate (HS) significantly increased, whereas inhibition of Syndecan-1 shedding significantly decreased the bacterial burden in corneal tissues. Furthermore, depletion of neutrophils in the resistant Sdc1−/− mice increased the corneal bacterial burden to that of the susceptible WT mice, suggesting that Syndecan-1 moderates neutrophils to promote infection. We found that Syndecan-1 does not affect the infiltration of neutrophils into the infected cornea but that purified Syndecan-1 ectodomain and HS significantly inhibit neutrophil-mediated killing of S. aureus. These data suggest a previously unknown bacterial subversion mechanism where S. aureus exploits the capacity of Syndecan-1 ectodomains to inhibit neutrophil-mediated bacterial killing mechanisms in an HS-dependent manner to promote its pathogenesis in the cornea.
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Syndecan 1 ectodomain shedding is regulated by the small gtpase rab5
Journal of Biological Chemistry, 2008Co-Authors: Kazutaka Hayashida, Philip D Stahl, Pyong Woo ParkAbstract:The ectodomain shedding of Syndecan-1, a major cell surface heparan sulfate proteoglycan, modulates molecular and cellular processes central to the pathogenesis of inflammatory diseases. Syndecan-1 shedding is a highly regulated process in which outside-in signaling accelerates the proteolytic cleavage of Syndecan-1 ectodomains at the cell surface. Several extracellular agonists that induce Syndecan-1 shedding and metalloproteinases that cleave Syndecan-1 ectodomains have been identified, but the intracellular mechanisms that regulate Syndecan-1 shedding are largely unknown. Here we examined the role of the Syndecan-1 cytoplasmic domain in the regulation of agonist-induced Syndecan-1 shedding. Our results showed that the Syndecan-1 cytoplasmic domain is essential because mutation of invariant cytoplasmic Tyr residues abrogates ectodomain shedding, but not because it is Tyr phosphorylated upon shedding stimulation. Instead, our data showed that the Syndecan-1 cytoplasmic domain binds to Rab5, a small GTPase that regulates intracellular trafficking and signaling events, and this interaction controls the onset of Syndecan-1 shedding. Syndecan-1 cytoplasmic domain bound specifically to Rab5 and preferentially to inactive GDP-Rab5 over active GTP-Rab5, and shedding stimulation induced the dissociation of Rab5 from the Syndecan-1 cytoplasmic domain. Moreover, the expression of dominant-negative Rab5, unable to exchange GDP for GTP, interfered with the agonist-induced dissociation of Rab5 from the Syndecan-1 cytoplasmic domain and significantly inhibited Syndecan-1 shedding induced by several distinct agonists. Based on these data, we propose that Rab5 is a critical regulator of Syndecan-1 shedding that serves as an on-off molecular switch through its alternation between the GDP-bound and GTP-bound forms.
Ralph D. Sanderson - One of the best experts on this subject based on the ideXlab platform.
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Heparanase Regulates Levels of Syndecan-1 in the Nucleus
PLoS ONE, 2009Co-Authors: Ligong Chen, Ralph D. SandersonAbstract:Syndecan-1 is a transmembrane heparan sulfate-bearing proteoglycan known to regulate multiple biological functions at the cell surface and within the extracellular matrix. Its functional activity can be modulated by heparanase, an enzyme that cleaves heparan sulfate chains and whose expression has been associated with an aggressive phenotype in many cancers. In addition to remodeling Syndecan-1 by cleaving its heparan sulfate chains, heparanase influences Syndecan-1 location by upregulating expression of enzymes that accelerate its shedding from the cell surface. In the present study we discovered that heparanase also alters the level of nuclear Syndecan-1. Upon upregulation of heparanase expression or following addition of recombinant heparanase to myeloma cells, the nuclear localization of Syndecan-1 drops dramatically as revealed by confocal microscopy, western blotting and quantification by ELISA. This effect requires enzymatically active heparanase because cells expressing high levels of mutated, enzymatically inactive heparanase, failed to diminish Syndecan-1 levels in the nucleus. Although heparan sulfate function within the nucleus is not well understood, there is emerging evidence that it may act to repress transcriptional activity. The resulting changes in gene expression facilitated by the loss of nuclear Syndecan-1 could explain how heparanase enhances expression of MMP-9, VEGF, tissue factor and perhaps other effectors that condition the tumor microenvironment to promote an aggressive cancer phenotype.
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Identification of an invasion regulatory domain within the core protein of Syndecan-1.
Journal of Biological Chemistry, 2004Co-Authors: J. Kevin Langford, Yang Yang, Thomas Kieber-emmons, Ralph D. SandersonAbstract:Among the four members of the Syndecan family there exists a high level of divergence in the ectodomain core protein sequence. This has led to speculation that these core proteins bear important functional domains. However, there is little information regarding these functions, and thus far, the biological activity of Syndecans has been attributed largely to their heparan sulfate chains. We have previously demonstrated that cell surface Syndecan-1 inhibits invasion of tumor cells into three-dimensional gels composed of type I collagen. Inhibition of invasion is dependent on the Syndecan heparan sulfate chains, but a role for the Syndecan-1 ectodomain core protein was also indicated. To more closely examine this possibility and to map the regions of the ectodomain essential for Syndecan-1-mediated inhibition of invasion, a panel of Syndecan-1 mutational constructs was generated, and each construct was transfected individually into myeloma tumor cells. The anti-invasive effect of Syndecan-1 is dramatically reduced by deletion of an ectodomain region close to the plasma membrane. Further mutational analysis identified a stretch of 5 hydrophobic amino acids, AVAAV (amino acids 222-226), critical for Syndecan-1-mediated inhibition of cell invasion. This invasion regulatory domain is 26 amino acids from the start of the transmembrane domain. Importantly, this domain is functionally specific because its mutation does not affect Syndecan-1-mediated cell binding to collagen, Syndecan-1-mediated cell spreading, or targeting of Syndecan-1 to specific cell surface domains. This invasion regulatory domain may play an important role in inhibiting tumor cell invasion, thus explaining the observed loss of Syndecan-1 in some highly invasive cancers.
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Soluble Syndecan-1 promotes growth of myeloma tumors in vivo.
Blood, 2002Co-Authors: Yang Yang, Shmuel Yaccoby, Wei Liu, J. Kevin Langford, Carla Y. Pumphrey, Allison Theus, Joshua Epstein, Ralph D. SandersonAbstract:Syndecan-1 (CD138) is a transmembrane heparan sulfate–bearing proteoglycan expressed by most myeloma plasma cells that regulates adhesion, migration, and growth factor activity. In patients with myeloma, shed Syndecan-1 accumulates in the bone marrow, and high levels of Syndecan-1 in the serum are an indicator of poor prognosis. To test the effect of soluble Syndecan-1 on tumor cell growth and dissemination, ARH-77 B-lymphoid cells were engineered to produce a soluble form of Syndecan-1. Controls included vector only (neo)–transfected cells and cells transfected with full-length Syndecan-1 complementary DNA that codes for the cell surface form of Syndecan-1. Assays reveal that all 3 transfectants have similar growth rates in vitro, but cells expressing soluble Syndecan-1 are hyperinvasive in collagen gels relative to controls. When injected into the marrow of human bones that were implanted in severe combined immunodeficient mice, tumors formed by cells expressing soluble Syndecan-1 grow faster than tumors formed by neo-transfected cells or by cells expressing cell surface Syndecan-1. In addition, cells bearing cell surface Syndecan-1 exhibit a diminished capacity to establish tumors within the mice as compared with both neo- and soluble Syndecan-1–transfected cells. Tumor cell dissemination to a contralateral human bone is detected significantly more often in the tumors producing soluble Syndecan-1 than in controls. Thus, high levels of soluble Syndecan-1 present in patients with myeloma may contribute directly to the growth and dissemination of the malignant cells and thus to poor prognosis.
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Syndecan-1 (CD138) Immunoreactivity in Bone Marrow Biopsies of Multiple Myeloma: Shed Syndecan-1 Accumulates in Fibrotic Regions
Modern Pathology, 2001Co-Authors: Ilene B. Bayer-garner, Ralph D. Sanderson, Madhav V. Dhodapkar, Rebecca Owens, Carla S. WilsonAbstract:Syndecan-1 (CD138) mediates myeloma cell adhesion, and loss of Syndecan-1 from the cell surface may contribute to myeloma proliferation and dissemination. Flow cytometry analysis of myeloma cells in bone marrow specimens shows heterogeneity in cell surface Syndecan-1 expression. It is not known whether weaker expression correlates with more aggressive disease. However, recent reports suggest that variations in Syndecan-1 staining intensity on myeloma cells may be an artifact of specimen handling. In this study, we evaluate Syndecan-1 expression in bone marrow biopsy sections from 28 multiple myeloma patients, to elucidate the heterogeneity of Syndecan-1 expression in situ. Immunoreactivity for Syndecan-1, using the antibody B-B4 (CD138), was found in more than 95% of multiple myeloma cells in 27 of 28 biopsies. However, one biopsy had more than 50% CD138-negative cells and cells with weak CD138 expression were identified in the majority of cases. Loss of Syndecan-1 did not appear to relate to myeloma cell differentiation. In addition, Syndecan-1 was detected on intravascular and intrasinusoidal myeloma cells suggesting that loss of Syndecan-1 may not be required for extramedullary dissemination. Bone marrow biopsies from nine additional patients, with variable CD138 staining intensity on myeloma cells as determined by flow cytometry, were studied by immunohistochemistry. The heterogenous CD138 expression was confirmed in situ, with weakly positive cells concentrated in areas of reticulin fibrosis. These cells had a disrupted pattern of membrane staining in contrast to the strong linear membrane staining seen in the other multiple myeloma cells. In addition, the fibrotic stroma stained intensely for Syndecan-1. Accumulation of Syndecan-1 within the extracellular matrix of the marrow likely is derived by shedding of the molecule from the surface of myeloma cells. Because Syndecan-1 can act to regulate the activity of heparan-binding growth factors, these reservoirs of Syndecan-1 may play a critical role in promoting myeloma pathogenesis, or in regeneration of the tumor after chemotherapy.
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Syndecan-1 expression is decreased with increasing aggressiveness of basal cell carcinoma.
The American Journal of Dermatopathology, 2000Co-Authors: Ilene B. Bayer-garner, Ralph D. Sanderson, Brad R. Dilday, Bruce R. SmollerAbstract:Syndecans, a family of cell-surface proteoglycans of which Syndecan-1 is the prototypical member, play an important role in limiting tumor growth and invasive capacity through their actions as receptors for growth factors and extracellular matrix. Cutaneous biopsy specimens of basal cell carcinoma, including superficial, nodular, infiltrative, and morpheic subtypes, were assessed regarding the pattern of Syndecan-1 expression. We found that with increasing aggressiveness of basal cell carcinomas, Syndecan-1 expression is lost from the surface of the neoplastic cells. However, within the dermis, which is normally devoid of Syndecan-1 expression, immunopositivity for Syndecan-1 is present in areas adjacent to aggressive tumors. This pattern of staining indicates that Syndecan-1 expression is produced by stromal cells rather than being shed by the carcinoma cells into the stroma.
Merton Bernfield - One of the best experts on this subject based on the ideXlab platform.
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Inhibition by the soluble Syndecan-1 ectodomains delays wound repair in mice overexpressing Syndecan-1.
Journal of Biological Chemistry, 2004Co-Authors: Varpu Elenius, Martin Götte, Ofer Reizes, Klaus Elenius, Merton BernfieldAbstract:Wound repair is a tightly regulated process stimulated by proteases, growth factors, and chemokines, which are modulated by heparan sulfate. To characterize further the role of the heparan sulfate proteoglycan Syndecan-1 in wound repair, we generated mice overexpressing Syndecan-1 (Snd/Snd) and studied dermal wound repair. Wound closure, reepithelialization, granulation tissue formation, and remodeling were delayed in Snd/Snd mice. Soluble Syndecan-1 was increased, and shedding was prolonged in wounds from Snd/Snd mice. Excess Syndecan-1 increased the elastolytic activity of wound fluids. Additionally, cells in the granulation tissue and keratinocytes at wound edges showed markedly reduced proliferation rates in Snd/Snd mice. Skin grafting experiments between Snd/Snd and control mice indicated that the slower growth rate was mainly due to a soluble factor in the Snd/Snd mouse skin. Syndecan-1 immunodepletion and further degradation experiments identified Syndecan-1 ectodomain as a dominant negative inhibitor of cell proliferation. These studies indicate that shed Syndecan-1 ectodomain may enhance proteolytic activity and inhibit cell proliferation during wound repair.
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Exploitation of Syndecan-1 shedding by Pseudomonas aeruginosa enhances virulence
Nature, 2001Co-Authors: Pyong Woo Park, Gerald B. Pier, Michael T. Hinkes, Merton BernfieldAbstract:Cell-surface heparan sulphate proteoglycans (HSPGs) are ubiquitous and abundant receptors/co-receptors of extracellular ligands1,2, including many microbes3,4,5,6,7,8,9,10. Their role in microbial infections is poorly defined, however, because no cell-surface HSPG has been clearly connected to the pathogenesis of a particular microbe. We have previously shown that Pseudomonas aeruginosa, through its virulence factor LasA, enhances the in vitro shedding of Syndecan-1—the predominant cell-surface HSPG of epithelia11. Here we show that shedding of Syndecan-1 is also activated by P. aeruginosa in vivo, and that the resulting Syndecan-1 ectodomains enhance bacterial virulence in newborn mice. Newborn mice deficient in Syndecan-1 resist P. aeruginosa lung infection but become susceptible when given purified Syndecan-1 ectodomains or heparin, but not when given ectodomain core protein, indicating that the ectodomain's heparan sulphate chains are the effectors. In wild-type newborn mice, inhibition of Syndecan-1 shedding or inactivation of the shed ectodomain's heparan sulphate chains prevents lung infection. Our findings uncover a pathogenetic mechanism in which a host response to tissue injury—Syndecan-1 shedding—is exploited to enhance microbial virulence apparently by modulating host defences.
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Reduced expression of Syndecan-1 in human hepatocellular carcinoma with high metastatic potential.
International Journal of Cancer, 1997Co-Authors: Akinori Matsumoto, Merton Bernfield, Minoru Ono, Yoshinori Fujimoto, Richard L. Gallo, Yutaka KohgoAbstract:Syndecans comprise a gene family of transmembrane proteoglycans that regulate cellular behavior through interactions with various effectors, including heparin-binding growth factors and insoluble matrix components. Syndecan-1, the most extensively studied, localizes in epithelial cells and has been shown to present in normal hepatocytes. However, little is known about the change of Syndecan-1 expression in human hepatocellular carcinoma (HCC). We investigated Syndecan-1-protein expression by immunohistochemistry in 57 HCC tissue samples. Syndecan-1 gene expression was also determined. Syndecan-1 protein was expressed in cytoplasm and cell membrane of the hepatocytes and in the bile duct epithelial cells of liver with underlying hepatitis and cirrhosis. Conversely, among 57 HCC tissues, 39 HCC (68.4%) showed negative staining; 50% of well-differentiated HCC showed positive staining, whereas 82.4% of poorly differentiated HCC were negative. Loss of Syndecan-1-protein expression was more prevalent in HCC with intra-hepatic metastasis (85.2%) than those without metastasis (48.0%). Similarly, Syndecan-1 expression was significantly reduced in HCC with extra-hepatic metastasis (91.7%) as compared with the HCC without extra-hepatic metastasis (62.2%). The gene expression of Syndecan-1 was significantly lower in HCC tissue than that in non-tumoral liver tissue. In 2 human HCC cell lines with poorly differentiated phenotype, HLE and HLF, Syndecan-1 expression was markedly decreased both at the mRNA and the protein levels. These results suggest that the loss of Syndecan-1 expression is a characteristic feature of HCC with high metastatic potential. Int. J. Cancer 74:482–491, 1997. © 1997 Wiley-Liss, Inc.
Caj Haglund - One of the best experts on this subject based on the ideXlab platform.
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Syndecan-1 expression--a novel prognostic marker in pancreatic cancer.
Oncology, 2005Co-Authors: Anne Juuti, Johan Lundin, Stig Nordling, Johanna Louhimo, Caj HaglundAbstract:Objective: Syndecan-1 is a transmembrane receptor that participates in cell-cell and cell-matrix interactions, cell proliferation and cell migration. Expression of Syndecan-1 is dow
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Prognostic value of Syndecan-1 expression in breast cancer.
Oncology, 2004Co-Authors: Marja Leivonen, Johan Lundin, Stig Nordling, Kristina Von Boguslawski, Caj HaglundAbstract:Objective: Syndecan-1 is a cell surface heparan sulphate proteoglycan which participates in cell proliferation, cell migration and cell-matrix interactions. Epithelial Syndecan-1 ex
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Epithelial and stromal Syndecan-1 expression as predictor of outcome in patients with gastric cancer.
International Journal of Cancer, 2001Co-Authors: Jan-patrik Wiksten, Johan Lundin, Stig Nordling, Arto Kokkola, Kristina Von Boguslawski, Mikael Lundin, Caj HaglundAbstract:The prognostic value of the immunohistochemical expression of epithelial and stromal Syndecan-1 was evaluated in 296 patients with gastric carcinoma. Formalin-fixed, paraffin-embedded specimens of gastric adenocarcinomas were stained with mouse monoclonal antibody B-B4 against human Syndecan-1. Loss of immunoreactivity (≤60% of cancer cells stained) was observed in 197 (67%) patients. Stromal immunoreactivity was observed in 28 (9%) patients. Loss of epithelial Syndecan-1 immunoreactivity correlated with a higher stage of disease (stages II–IV), tumour location in the upper third of the stomach, nodal metastases (N1 or N2), positive stromal Syndecan-1 staining, deep tumour penetration (to subserosa or deeper = T2–T4), larger tumour size (≥5 cm) and intestinal type of cancer. No correlation between epithelial Syndecan-1 immunoreactivity and age, gender, distant metastases, grade of differentiation or Borrmann classification was observed. Positive stromal Syndecan-1 immunoreactivity correlated with decreased epithelial Syndecan-1 expression, intestinal type of cancer and Borrmann type I. Patients with low epithelial Syndecan-1 expression in cancer cells had worse overall survival than patients with strong epithelial Syndecan-1 staining (p = 0.0012). Stromal Syndecan-1-positive patients had a worse outcome than patients with Syndecan-1-negative stroma (p = 0.0193). In Cox multivariate analysis, stromal Syndecan-1 immunoreactivity was a prognostic factor independent of TNM stage, surgery for cure and tumour size. Thus, the immunohistochemical expression of Syndecan-1 might be a predictor of outcome in patients with gastric adenocarcinoma. © 2001 Wiley-Liss, Inc.
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A prognostic value of Syndecan-1 in gastric cancer.
Anticancer research, 2000Co-Authors: Jan-patrik Wiksten, Johan Lundin, Stig Nordling, Arto Kokkola, Caj HaglundAbstract:BACKGROUND: Syndecan-1, a cell surface heparan sulphate proteoglycan, has a role in cell adhesion, maturation and proliferation. Syndecan-1 has been reported to be a promising prognostic marker in various cancer forms. MATERIALS AND METHODS: We analysed tumour specimens from 296 gastric cancer patients. Syndecan-1 expression was studied by immunohistochemistry. RESULTS: Syndecan-1 immunoreactivity was observed in 234 (79%) patients. The expression of Syndecan-1 did not correlate significantly with the presence of lymph node metastases, distant metastases, peritoneal spreading, penetration depth, tumour size, tumour location, Borrmann's classification, Lauren's classification, age or gender. Syndecan-1 immunoreactivity correlated significantly with survival in the whole patient series (p = 0.0499) and also in the subgroup of patients with stage I cancer (p = 0.0417), but not in patients with stage II, III or IV disease. In multivariate survival analysis, stage of disease and tumour size emerged as the only independent prognostic factors. CONCLUSIONS: In conclusion, immunohistochemical expression of Syndecan-1 is a potential prognostic factor in gastric cancer, especially in patients with stage I disease.
Markku Jalkanen - One of the best experts on this subject based on the ideXlab platform.
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Altered expression of Syndecan-1 in prostate cancer.
APMIS, 2004Co-Authors: Johanna Kiviniemi, Markku Jalkanen, Markku Kallajoki, Iina Kujala, Marja-terttu Matikainen, Kalle Alanen, Markku SalmivirtaAbstract:Syndecan-1 is a cell surface heparan sulfate proteoglycan expressed by epithelial cells. It interacts with growth factors, matrix components, and other extracellular proteins, and is thought to be involved in processes such as cell growth, differentiation and adhesion. The expression of Syndecan-1 appears generally downregulated in human carcinomas and in experimental cancer models, whereas transfectional expression of Syndecan-1 in cultured cancer cells has been shown to inhibit their growth and other aspects of malignant behavior. These findings suggest that analysis of Syndecan-1 expression might be of prognostic value in cancer diagnosis, and studies on some carcinomas indeed point to an inverse correlation between Syndecan-1 expression and cancer prognosis. So far, little information has been available on the expression of Syndecan-1 in human prostate and prostate disease. We have generated and characterized novel antibodies against Syndecan-1 and applied them to immunohistochemical staining of specimens representing normal prostate as well as benign and malignant (n=23) prostate disease. The results indicate that Syndecan-1 expression is altered but not uniformly absent in prostate cancer, which is in contrast to the expression of high-molecular-weight cytokeratins. The data initially suggest an inverse correlation between Syndecan-1 expression and Gleason grade of the tumor, and warrant a larger study to assess the potential prognostic value of analysing Syndecan-1 expression in prostate carcinoma.
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Transcriptional Regulation of Syndecan-1 Expression by Growth Factors
Progress in Nucleic Acid Research and Molecular Biology, 1999Co-Authors: Panu Jaakkola, Markku JalkanenAbstract:Syndecan-1 is a prototype member of a family of transmembrane heparan sulfate proteoglycans. Syndecan-1 binds extracellular matrix components and fibroblast growth factors (FGFs) and modifies the function of FGFs. Syndecan-1 is constitutively expressed by several epithelial cells, but expression is also induced during many biological phenomena, such as tissue regeneration and the epithelial-mesenchymal interactions during organ development. Growth factors have been the prime candidates to induce Syndecan-1 expression in these situations. In fibroblasts Syndecan-1 is induced by FGF-2 and in keratinocytes by epidermal growth factor (EGF) and keratinocyte growth factor (KGF). The search for cis-acting elements regulating the growth factor-induced Syndecan-1 expression has led to identification of a novel FGF-inducible response element (FiRE). FiRE is activated in fibroblasts and keratinocytes by the same growth factors that induce Syndecan-1 expression in these cells. In adult tissues the activation of FiRE is restricted to migrating keratinocytes of healing wounds. The composition of the transcription factor binding to FiRE differs depending on the cell type and the activating growth factor. The FiRE provides a powerful tool for studies on growth factor specificity and regeneration of tissues. Moreover, it implies a novel transcriptional link that creates an FGF action-controlling autoregulatory loop between the heparan sulfate proteoglycans and the heparin-binding FGFs.
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Syndecan-1: A New Prognostic Marker in Laryngeal Cancer
Acta oto-laryngologica, 1997Co-Authors: Jaakko Pulkkinen, Markku Jalkanen, Marjatta Penttinen, Pekka J. Klemi, Reidar GrénmanAbstract:The cell adhesion molecule Syndecan-1 expression is induced during keratinocyte differentiation and reduced during the formation of squamous cell carcinomas (SCCs). A significant correlation between decreased Syndecan-1 expression in head and neck SCC measured from frozen sections with immuohistochemical methods and clinical outcome are reported. The clinical relevance of the cellular proliferation marker Ki-67 is controversial in SCC of the head and neck. The purpose of this study was to determine the expression of Syndecan-1 and Ki-67 in SCC of the larynx and correlate the results with known prognostic factors and clinical outcome. Paraffin-embedded samples of 100 patients with laryngeal SCC (44 glottic, 36 supraglottic, 20 transglottic) treated at Turku University Central Hospital were re-examined and divided into four histological grades of differentiation, four grades of keratinisation, and four grades of 104-9 (Syndecan-1) immunostaining. The mitotic index was analysed as the number of mitoses per volume corrected high power fields. The relative number of Ki-67 positive cells was evaluated. The patients mean age was 64 years and the 5-year survival was 69%. In univariate analysis, intermediate or strong staining for Syndecan-1 was associated with higher overall survival than those tumours with no or little Syndecan-1 expression (p = 0.048). Nodal status (p = 0.0001), tumour size (p = 0.0004) and localisation (p = 0.0008), general condition (p = 0.0001), histological grade (p = 0.02) and patient age (p = 0.03) correlated with overall survival whereas the Ki-67 index (p = 0.093), mitotic index (p = 0.23) and grade of keratinisation (p = 0.90) failed to do so. The results suggest that Syndecan-1 could be a useful prognostic factor in SCC of the larynx.
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Suppression of Syndecan-1 Expression in Endothelial Cells by Tumor Necrosis Factor-α
Journal of Biological Chemistry, 1996Co-Authors: Varpu Kainulainen, Markku Jalkanen, Lassi Nelimarkka, Hannu Järveläinen, Matti Laato, Klaus EleniusAbstract:Abstract Syndecan-1 is a cell surface proteoglycan that binds extracellular matrix components and modulates the activity of heparin-binding growth factors. The expression of Syndecan-1 is modified during development, carcinogenesis, and tissue regeneration. During cutaneous wound healing, Syndecan-1 expression is transiently induced in newly-formed capillaries of granulation tissue as well as in proliferating keratinocytes. To study the mechanisms underlying this regulation we investigated the effects of several growth factors/cytokines on Syndecan-1 expression in two human cell lines: EA.hy 926 endothelial cells and HaCaT keratinocytes. None of these factors significantly altered Syndecan-1 mRNA expression in cultured keratinocytes, but when given to endothelial cells, tumor necrosis factor-α (TNF-α) specifically and dose-dependently suppressed Syndecan-1 expression at both mRNA and protein levels. TNF-α reduced the amount of Syndecan-1 protein in EA.hy 926 cells in both the presence and absence of serum and, at the same time, induced the expression of intercellular adhesion molecule-1 (ICAM-1). The suppressive effect of TNF-α on endothelial Syndecan-1 expression was reproducible in in vivo experiments in which TNF-α-coated beads were administered directly to healing skin wounds of mice. Data supporting these findings were further obtained by injecting TNF-α into an experimental rat granulation tissue model. In this tissue TNF-α suppressed Syndecan-1 mRNA expression by approximately 80%. These results indicate that TNF-α is capable of down-regulating Syndecan-1 expression in endothelial cells both in vitro and in vivo and suggest that similar mechanisms may be responsible for the changes in Syndecan-1 expression observed during various regenerative, developmental, and malignant processes.
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The role of Syndecan-1 in malignancies.
Annals of Medicine, 1996Co-Authors: Pirjo Inki, Markku JalkanenAbstract:Syndecans form a family of cell surface proteoglycans, which can interact with various effector molecules, such as extracellular matrix (ECM) molecules and growth factors. Syndecan-1 is the most extensively studied member of the Syndecan family. It is found mainly in epithelial cells, but its expression is developmentally regulated during embryonic development. It has been shown to mediate cell adhesion to several ECM molecules, and to act as a coreceptor for fibroblast growth factors, potent angiogenic growth factors involved also in differentiation. Syndecan-1 expression is reduced during malignant transformation of various epithelia, and this loss correlates with the histological differentiation grade of squamous cell carcinomas, lacking from poorly differentiated tumours. In squamous cell carcinomas of the head and neck, positive Syndecan-1 expression correlates with a more favourable prognosis. Recent experimental studies on the role of Syndecan-1 in malignant transformation have shown that Syndecan-...
