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PubMed1994

Aggregation-induced association of syndecan-1 with microfilaments mediated by the cytoplasmic domain.

Expression of the transmembrane proteoglycan syndecan-1 in Schwann cells leads to enhanced spreading and cytoskeletal reorganization, but without an apparent stable association of syndecan-1 with cytoskeletal structures such as focal adhesions. Since cell surface oligomerization may be a mechanism for regulating the activities of transmembrane receptors, we wanted to investigate whether antibody-induced aggregation of the proteoglycan would promote its association with the cytoskeleton. When syndecan-1-expressing cells were incubated with anti-syndecan-1 and anti-IgG antibodies, clustering of proteoglycan on the cell surface was observed by immunofluorescence microscopy. The resulting pattern of syndecan-1 distribution was very similar to that of the underlying microfilament network, as visualized by fluorescent-phalloidin staining. In cells that were fixed briefly with paraformaldehyde before addition of the anti-IgG antibodies no such colocalization of syndecan-1 and microfilaments was observed. Additional findings supported the conclusion that this pattern of syndecan-1 distribution reflected an association with microfilaments: aggregated syndecan-1 was resistant to extraction by nonionic detergent; incubation of the cells with cytochalasin b, but not colchicine, altered the pattern of aggregated syndecan-1 distribution; antibody-induced clustering of syndecan-1 led to a reorganization of actin filaments. Syndecan-1 remained on the cell surface following antibody-induced clustering, as revealed by immunogold staining and transmission electron microscopy. A mutant form of syndecan-1 lacking most of the cytoplasmic domain failed to exhibit actin filament association or induce actin reorganization following antibody-mediated aggregation. These results suggest that transient associations of syndecan family proteoglycans with microfilaments may be important aspects of their biological functions.

Actin Cytoskeleton↗

PubMed2002

Immunoreactivity to cell surface syndecans in cytoplasm and nucleus: tubulin-dependent rearrangements.

Syndecans are transmembrane proteoglycans implicated in the regulation of cell growth and differentiation, by interacting with growth factors. Although syndecans play a major role in regulating cell morphology, little is known about their subcellular distribution and in vivo association with the cytoskeleton. To address this question, we investigated the subcellular distribution and dynamic rearrangement of syndecans-1, -2, and -4, using confocal laser microscopy. Furthermore, we monitored the spatial relation of syndecans to tubulin in both mitotic and interphase cells. Initially, the reactivity to syndecans was confined to the cytoplasm, staining of the cell membranes appearing later. Syndecan-1 also seems to translocate to the nucleus in a time-dependent manner. The mitotic spindle shows unexpectedly more syndecans than that found in interphase cells. After vinblastine treatment, both syndecan-1 and tubulin were recovered as paracrystalline occlusion bodies, and the nuclear reactivity to syndecan-1 disappeared, suggesting tubulin-mediated nuclear transport of this proteoglycan. Plasma membrane staining reappeared in the postmitotic cells. Nuclear translocation predominantly affected syndecan-1, whereas syndecan-2 and -4 remained in cytoplasm and cell membrane. This is the first report on regulated nuclear translocation and the presence of syndecan-1 in the mitotic spindle, where it may stabilize the mitotic machinery. The syndecan-1/tubulin complex may also act as a vehicle for the transport of protein growth factors to the cell nucleus.

Active Transport, Cell Nucleus↗

PubMed2006

Effect of treatment of larynx and hypopharynx carcinomas on serum syndecan-1 concentrations.

PURPOSE: Syndecan-1 is a multifunctional transmembrane heparan sulfate proteoglycan present on a variety of cell types that mediates basic fibroblast growth factor (bFGF) and other growth factor binding. High serum syndecan-1 (S-syndecan-1) ectodomain levels have been found to be associated with poor outcome in lung cancer and myeloma, but little is known about the effect of cancer treatment on S-syndecan-1 levels. We studied S-syndecan-1 levels longitudinally in a series of patients diagnosed with locoregional squamous cell larynx or hypopharynx carcinoma (n=44) and who we treated with surgery and/or radiation therapy. METHODS: S-syndecan-1 and S-bFGF levels were measured with ELISA prior to, during, and following primary treatment of patients. Syndecan-1 expression was assessed from formalin-fixed and paraffin-embedded tumour samples using immunohistochemistry. RESULTS: S-syndecan-1 levels tended to correlate positively with S-bFGF levels, and the pretreatment levels decreased from a median value of 75 to 58 ng/ml 3 months following treatment (P<0.0001). Patients treated with radiation therapy had a transient increase in S-syndecan-1 during the course of radiation therapy. Patients whose S-syndecan-1 decreased >or=10% from the pretreatment level had more favourable survival than those whose levels remained stable or increased (P=0.0069). Recurred cancer was associated with elevated S-syndecan-1 as compared to the levels measured 3 months following completion of primary therapy. CONCLUSIONS: These findings suggest that a part of S-syndecan-1 originates from the cancerous tissue, and that S-syndecan-1 levels generally decrease following successful cancer treatment.

Aged↗

PubMed2003

Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration.

The transmembrane heparan sulfate proteoglycan syndecan-1 was identified from a human placenta cDNA library by the expression cloning method as a gene product that interacts with membrane type matrix metalloproteinase-1 (MT1-MMP). Co-expression of MT1-MMP with syndecan-1 in HEK293T cells promoted syndecan-1 shedding, and concentration of cell-associated syndecan-1 was reduced. Treatment of cells with MMP inhibitor BB-94 or tissue inhibitor of MMP (TIMP)-2 but not TIMP-1 interfered with the syndecan-1 shedding promoted by MT1-MMP expression. In contrast, syndecan-1 shedding induced by 12-O-tetradecanoylphorbol-13-acetate treatment was inhibited by BB-94 but not by either TIMP-1 or TIMP-2. Shedding of syndecan-1 was also induced by MT3-MMP but not by other MT-MMPs. Recombinant syndecan-1 core protein was shown to be cleaved by recombinant MT1-MMP or MT3-MMP preferentially at the Gly245-Leu246 peptide bond. HT1080 fibrosarcoma cells stably transfected with the syndecan-1 cDNA (HT1080/SDC), which express endogenous MT1-MMP, spontaneously shed syndecan-1. Migration of HT1080/SDC cells on collagen-coated dishes was significantly slower than that of control HT1080 cells. Treatment of HT1080/SDC cells with BB-94 or TIMP-2 induced accumulation of syndecan-1 on the cell surface, concomitant with further retardation of cell migration. Substitution of Gly245 of syndecan-1 with Leu significantly reduced shedding from HT1080/SDC cells and cell migration. These results suggest that the shedding of syndecan-1 promoted by MT1-MMP through the preferential cleavage of Gly245-Leu246 peptide bond stimulates cell migration.

Binding Sites↗

PubMed2004

Identification of an invasion regulatory domain within the core protein of syndecan-1.

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.

Amino Acid Sequence↗

PubMed2003

Induced expression of syndecan-1 in the stroma of head and neck squamous cell carcinoma.

Syndecan-1 (CD138), a cell-surface heparan sulfate proteoglycan, is involved in cell-cell, cell-matrix interaction and growth factor binding. Loss of expression of syndecan-1 in tumor cells leads to decreased intercellular cohesion, increased potential for tumor invasiveness, and metastatic spread. Furthermore, induction of syndecan-1 expression in the tumor stroma has been postulated to promote tumor angiogenesis via its binding to growth factors such as basic fibroblast growth factor. Although syndecan-1 expression within tumor cells has been investigated in head and neck squamous cell carcinoma, stromal expression has not been studied in detail. We analyzed 38 cases of head and neck squamous cell carcinoma by immunohistochemical staining for syndecan-1 expression within the stroma. The expression of syndecan-1 within tumor cells of various histologic grades of differentiation, squamous cell carcinoma in situ cells, and benign squamous epithelium was also determined. Variable levels of diminished syndecan-1 expression were noted within the dysplastic cells of 9 of 16 (60%) squamous cell carcinoma in situ lesions and in all 38 (100%) invasive squamous cell carcinoma. In general, higher levels of syndecan-1 expression were observed in the well-differentiated tumors, in contrast to significant reduction of expression seen in poorly differentiated tumors. Syndecan-1 expression was observed within the stroma (in fibroblasts) surrounding infiltrating carcinoma cells in 28 of 38 (74%) cases. The intensity of syndecan-1 staining within the stroma showed generally an inverse correlation with the degree of tumor cell differentiation. Syndecan-1 expression was not detected in the stroma beneath normal squamous epithelium or adjacent to areas of squamous cell carcinoma in situ. We conclude that induced expression of syndecan-1 in the stroma surrounding tumor cells of invasive head and neck squamous cell carcinoma is a frequent event. The increased stromal syndecan-1 expression, coupled with its loss from the surface of carcinoma cells, may contribute to tumor cell invasion and the development of metastases.

Aged↗

PubMed2001

Reduced expression of syndecan-1 affects metastatic potential and clinical outcome in patients with colorectal cancer.

Syndecan-1 is a transmembrane heparansulfate proteoglycan which regulates cell-to-cell or cell-to-extracellular matrix interactions and may influence malignant cell behavior. We investigated the alterations of syndecan-1 expressions in colorectal cancers and analyzed the relationship between histological and clinical characteristics. Syndecan-1 protein expression in colorectal cancer tissues was investigated with immunohistochemical staining of resected specimens. In situ hybridization was performed using syndecan-1 riboprobe to confirm the transcriptional signals. Syndecan-1 mRNA expression in cancer cell lines cultured with or without methylation inhibitor was also analyzed by quantitative PCR. Out of 105 specimens tested, less than 25% of tumor cells were stained with anti-syndecan-1 monoclonal antibody in 36 (34.3%). In situ hybridization showed a similar staining profile to that of immunohistochemistry. Syndecan-1 mRNA expression was increased by the methylation inhibitor 5-aza-2'-deoxycytidine, suggesting that the hypermethylation is involved in the suppression of syndecan-1 expression. Clinically, the incidence of metastasis to lymphnode or liver in patients with syndecan-1-negative tumors was significantly high. Among T1 colorectal cancers displaying a primary invasive phase, lymphnode metastasis, undifferentiated characters and 'budding' of cancer cells were more common in syndecan-1-negative tumors. The survival rate in patients with syndecan-1-negative tumors was decreased significantly in a stage-independent manner. These results suggest that the reduction of syndecan-1 expression in colorectal cancer cells, which is supposed to be regulated at the transcription level, is closely related to invasive character. The evaluation of syndecan-1 expression in colorectal cancer may allow prediction of patients' survival after surgery.

Adenocarcinoma↗

PubMed2000

[The expression, secretion and regulation of membrane-soluble syndecan-1 in human multiple myeloma cells].

OBJECTIVE: To analyze the expression, secretion and regulation of membrane-soluble syndecan-1 in human multiple myeloma cells, and to explore the relationship between syndecan-1 and the development of human multiple myeloma. METHODS: Syndecan-1 expression on the surface of malignant plasma cells was analyzed by immuno-staining, the levels of soluble syndecan-1 in the supernatant of cultured tumor cells by ELISA. RESULTS: 1. Human multiple myeloma cells expressed high levels of syndecan-1. The density of syndecan-1 varied from 170,000 to 800,000 molecules per cell. The expression of syndecan-1 lost rapidly as the cells underwent apoptosis. 2. Most myeloma cells produced soluble syndecan-1, the rate of production did not correlate with the density of membrane syndecan-1. Moreover, the production of soluble syndecan-1 did not require serum. 3. The protein synthesis inhibitor cycloheximide inhibited the production of syndecan-1. The serine protease inhibitor antipain did not affect the secretion of syndecan-1. CONCLUSION: As a receptor of many growth factors, cytokines and heparin-like growth factors, syndecan-1 might play an important role in tumor cell growth and homing in multiple myeloma development.

Humans↗

PubMedDate not supplied

Predictive value of syndecan-1 expression for the response to neoadjuvant chemotherapy of primary breast cancer.

BACKGROUND: The overexpression of syndecan-1 in breast carcinomas correlates with poorer prognosis and an aggressive phenotype. The effect of syndecan-1 expression on tumor response to neoadjuvant chemotherapy was determined in locally advanced breast cancer. PATIENTS AND METHODS: Semi-quantitative syndecan-1 immunohistochemistry was performed in pre-chemotherapy breast cancer biopsies of 37 patients undergoing high-dose neoadjuvant treatment with cyclophosphamide and epirubicin. RESULTS: 43.2% of breast carcinomas stained positive for syndecan-1. Syndecan-1 expression was more frequent in ductal invasive carcinomas than in other histological types (p=0.062). The pathological response to chemotherapy was decreased in syndecan-1-positive patients: 37.5% of syndecan-1-positive vs. 19% of syndecan-1-negative patients attained pathologically "no change". No syndecan-1-positive patient showed complete remission. Also, a correlation between syndecan-1 immunostaining intensity and response to chemotherapy was observed. Of the responding tumors, none showed strong syndecan-1 expression (Score 3+), whereas 20% of the non-responding tumors were strongly syndecan-1-positive. CONCLUSION: Syndecan-1-expressing breast carcinomas show a trend towards a decreased response to chemotherapy.

Adult↗

PubMed1995

Syndecan family of cell surface proteoglycans: developmentally regulated receptors for extracellular effector molecules.

Syndecans are a family of integral membrane proteoglycans with conserved membrane-spanning and intracellular domains but with structurally distinct extracellular domains (ectodomains). They are known to function as heparan sulphate co-receptors in fibroblast growth factor signalling as well as to link cells directly to the extracellular matrix. These and other biological activities of syndecans involve specific interactions of the heparan sulphate side chains of syndecans with cytokines and extracellular matrix proteins. Four different vertebrate syndecans, designated as syndecans 1-4 (or syndecan, fibroglycan, N-syndecan and amphiglycan, respectively), are known. During embryonic development, syndecans have specific and highly regulated expression patterns that are distinct from the expression in adult tissue, suggesting an active role in morphogenetic processes. The developmental expression of syndecans is particularly intense in mesenchymal condensates and at epithelium mesenchyme interfaces, where a number of heparan sulphate-binding cytokines and matrix components are also expressed in a regulated manner, often spatially and temporally co-ordinated with the syndecan expression. Recent evidence indicates that the regulation of heparan sulphate fine structure (mainly the number and arrangement of sulphate groups along the polymer) provides a mechanism for the cellular control of syndecan-protein interactions. Furthermore, morphogenetically active cytokines such as fibroblast growth factor-2 and transforming growth factor-beta participate in the regulation of syndecan expression and glycosaminoglycan structure. This review discusses the developmental expression and binding functions of syndecans as well as the molecular regulation of specific heparan sulphate-protein interactions.

Animals↗

PubMed1991

Syndecan, a cell surface proteoglycan, exhibits a molecular polymorphism during lung development.

Syndecan, a cell surface proteoglycan, binds multiple extracellular ligands, and is developmentally regulated in epithelial and mesenchymal tissues. The branching morphogenesis of embryonic lung is dependent on epithelial-mesenchymal interactions and, based on studies with inhibitors, on proteoglycan synthesis. To assess the role of syndecan in lung development, we examined the structure and distribution of syndecan in Day 12 to 18 embryonic mouse lungs using monoclonal antibody 281-2 for histology, immunopurification, and Western blots. At Day 12, syndecan localizes mainly on epithelial cell surfaces, but also stains mesenchymal cells near the epithelium. By Day 14, syndecan is expressed predominantly on epithelia and by Day 18, syndecan remains on airway epithelia but is absent from the alveolar pneumocytes. This change in expression correlates with a change in syndecan structure; the relative mass of syndecan gradually falls from Day 12 to Day 18 without a change in relative mass of the core protein. The difference is due to a developmental reduction in the size of the glycosaminoglycan chains; heparan sulfate chains on syndecan from Day 14 lungs were nearly twofold larger than those from Day 18 lungs. Newly synthesized syndecan in the lungs had the same relative mass as total syndecan, indicating that the change in mass is due to a developmental change in the nature of the syndecan synthesized. The alteration in syndecan structure could alter the function of this proteoglycan during lung development.

Animals↗

PubMed2005

Syndecan-4 is a signaling molecule for stromal cell-derived factor-1 (SDF-1)/ CXCL12.

Stromal cell-derived factor-1 (SDF-1)/CXCL12, the ligand for CXCR4, induces signal transduction. We previously showed that CXCL12 binds to high- and low-affinity sites expressed by primary cells and cell lines, and forms complexes with CXCR4 as expected and also with a proteoglycan, syndecan-4, but does not form complexes with syndecan-1, syndecan-2, CD44 or beta-glycan. We also demonstrated the occurrence of a CXCL12-independent heteromeric complex between CXCR4 and syndecan-4. However, our data ruled out the glycosaminoglycan-dependent binding of CXCL12 to HeLa cells facilitating the binding of this chemokine to CXCR4. Here, we demonstrate that CXCL12 directly binds to syndecan-4 in a glycosaminoglycan-dependent manner. We show that upon stimulation of HeLa cells by CXCL12, CXCR4 becomes tyrosine phosphorylated as expected, while syndecan-4 (but not syndecan-1, syndecan-2 or beta-glycan) also undergoes such tyrosine phosphorylation. Moreover, tyrosine-phosphorylated syndecan-4 from CXCL12-stimulated HeLa cells physically coassociates with tyrosine phosphorylated CXCR4. Pretreatment of the cells with heparitinases I and III prevented the tyrosine phosphorylation of syndecan-4, which suggests that the heparan sulfate-dependent binding of SDF-1 to this proteoglycan is involved. Finally, by reducing syndecan-4 expression using RNA interference or by pretreating the cells with heparitinase I and III mixture, we suggest the involvement of syndecan-4 and heparan sulfate in p44/p42 mitogen-activated protein kinase and Jun N-terminal/stress-activated protein kinase activation by action of CXCL12 on HeLa cells. However, these treatments did not modify the calcium mobilization induced by CXCL12 in these cells. Therefore, syndecan-4 behaves as a CXCL12 receptor, selectively involved in some transduction pathways induced by SDF-1, and heparan sulfate plays a role in these events.

Calcium↗

PubMed2003

Syndecan-4 distribution during the differentiation of satellite cells isolated from soleus muscle treated by phorbol ester and calphostin C.

It was shown that syndecans have a potential role in muscle development. We focused this study on the role of syndecan-4 distribution and phosphorylation during the differentiation of satellite cells isolated from Soleus muscle. Syndecans are cell surface heparan sulfate proteoglycans (HSPGs) that bind numerous ligands through their HS glycosaminoglycan chains (GAG). They play a role in cell-extracellular matrix and cell-cell adhesion, signal transduction and the targeting of growth factors and other molecules to the cell surface. Syndecan-4 acts as a co-receptor or, along with integrins, is localized to the cell membrane of focal contacts. Syndecan-4 participates in the organization of the structure of focal contacts reacting with extracellular matrix molecules. The interaction of syndecan-4 with protein kinase C (PKC) isoforms is the main mechanism regulating its distribution in cells. Our current study focused on the role of the distribution of syndecan-4, and its interactions with PKC isoforms during the differentiation of activated satellite cells. We used the PKC activator TPA (12-O-tetradecanoyl phorbol 13-acetate) and the PKC inhibitor Calphostin C (Cal C). We concluded that syndecan-4 was important not only in the activation of satellite cells, but also in myoblast differentiation. During our research, we observed the presence of syndecan-4 and changes in its location over the course of that process. We also showed that TPA and Cal C treatment had an influence on the subcellular distribution of syndecan-4, but there was no influence on myoblast differentiation. We speculated that the reason for changes after TPA treatment was the interactions with activated PKC alpha, which provoked syndecan-4/PKC alpha complex translocation to integrins. We also supposed that Cal C treatment inhibited PKC delta activity and probably induced PKC lpha association to syndecan-4, and syndecan-4 translocation to integrins.

Animals↗

PubMed1996

N-syndecan: structure and function of a transmembrane heparan sulfate proteoglycan.

N-syndecan is a member of the syndecan family of transmembrane heparan sulfate proteoglycans that was cloned initially from neonatal rat Schwann cells and is the principal syndecan expressed during early postnatal development in the central and peripheral nervous systems. Purified N-syndecan binds in vitro with high affinity to several extracellular regulatory ligands, including basic fibroblast growth factor, the secreted adhesive protein heparin binding growth-associated molecule, and a novel collagen-like protein secreted by Schwann cells. These extracellular ligands utilize the heparan sulfate chains of N-syndecan for binding. Based on the striking amino acid sequence homology of the cytoplasmic domain of N-syndecan to syndecan-1, it is proposed that N-syndecan associates with the actin-based cytoskeleton. N-syndecan core proteins self associate by means of an unusual dimerization motif comprised of the transmembrane domain and a short flanking sequence in the ectodomain. Similar to other single transmembrane domain receptor proteins, it is suggested that ligand-regulated dimerization of N-syndecan represents a mechanism for regulating downstream signaling activities. In rat brain tissue a significant fraction of the N-syndecan molecules are present in a soluble form, presumably as a result of proteolytic membrane shedding. A model is presented for morphoregulatory activity of N-syndecan in which extracellular ligand-induced clustering of N-syndecan molecules on the cell surface promotes cytoskeletal association and reorganization. Membrane shedding separates the functional domains of the proteoglycan and terminates this activity.

Animals↗

PubMed2002

Differential expression and distribution of syndecan-1 and -2 in periodontal wound healing of the rat.

Cell-surface proteoglycans participate in several biological functions including interactions with adhesion molecules, growth factors and a variety of other effector molecules. Accordingly, these molecules play a central role in various aspects of cell-cell and cell-matrix interactions. To investigate the expression and distribution of the cell surface proteoglycans, syndecan-1 and -2, during periodontal wound healing, immunohistochemical analyses were carried out using monoclonal antibodies against syndecan-1, or -2 core proteins. Both syndecan-1 and -2 were expressed and distributed differentially at various stages of early inflammatory cell infiltration, granulation tissue formation, and tissue remodeling in periodontal wound healing. Expression of syndecan-1 was noted in inflammatory cells within and around the fibrin clots during the earliest stages of inflammatory cells infiltration. During granulation tissue formation it was noted in fibroblast-like cells and newly formed blood vessels. Syndecan-1 was not seen in newly formed bone or cementum matrix at any of the time periods studied. Syndecan-1 expression was generally less during the late stages of wound healing but was markedly expressed in cells that were close to the repairing junctional epithelium. In contrast, syndecan-2 expression and distribution was not evident at the early stages of inflammatory cell infiltration. During the formation of granulation tissue and subsequent tissue remodeling, syndecan-2 was expressed extracellularly in the newly formed fibrils which were oriented toward the root surface. Syndecan-2 was found to be significantly expressed on cells that were close to the root surface and within the matrix of repaired cementum covering root dentin as well as at the alveolar bone edge. These findings indicate that syndecan-1 and -2 may have distinctive functions during wound healing of the periodontium. The appearance of syndecan-1 may involve both cell-cell and cell-matrix interactions, while syndecan-2 showed a predilection to associate with cell-matrix interactions during hard tissue formation.

Alveolar Process↗

PubMed1996

Syndecans-1 and -4 are induced during wound repair of neonatal but not fetal skin.

Syndecans are a family of four cell surface proteoglycans that bind to various components of the extracellular environment and can regulate many cellular behaviors including growth, adhesion, and movement. To determine whether syndecans can function during wound repair, we have examined expression of the syndecans during wound repair of adult mouse and neonatal or fetal human skin. Syndecan-1 and -4 were induced in the dermis within 12 h after incisional injury of murine or neonatal human skin. Syndecan-1 was induced primarily on endothelium, and syndecan-4 was present throughout the dermis at the site of injury. Following re-epithelialization, expression of the syndecans return to their baseline level. In marked contrast to these observations, wounded human fetal skin showed no increase in expression of syndecans. This lack of increase in the expression of syndecans by cells of the dermis correlates with prior observations that fetal skin heals without a polymorphonuclear cell infiltrate, appreciable fibrosis, or clinically apparent scar. Thus, induced expression of syndecans is not an absolute requirement for wound repair but does correlate with the occurrence of fibrosis in mature skin. These findings support the role of syndecans as regulators of cell behavior and suggest that syndecan-1 and -4 induction in the dermis may contribute to events that lead to inflammation and fibrosis.

Animals↗

PubMed2003

High syndecan-1 expression in breast carcinoma is related to an aggressive phenotype and to poorer prognosis.

BACKGROUND: Syndecan-1 is a transmembrane heparan sulphate proteoglycan that is involved in cell-cell adhesion, organization of cell-matrix adhesion, and regulation of growth factor signaling. METHODS: Specimens from 254 consecutive breast carcinoma (BC) cases (110 N0, 144 N1/2) with long-term follow-up (median, 95 months) were immunostained for syndecan-1, estrogen receptor (ER), progesterone receptor (PgR), and p53; in 154 cases, c-erbB-2 status was known. Syndecan-1 mRNA and protein expression also were evaluated in 20 breast tissue samples (10 normal and tumor pairs). RESULTS: Syndecan-1 was expressed at high levels in 106 (42%) BCs; syndecan-1 up-regulation was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) studies. High syndecan-1 expression was associated with high histologic grade, large tumor size, high mitotic count, c-erbB-2 overexpression, and ER and PgR negative status. At univariate survival analysis syndecan overexpression was related to poor prognosis (P < 0.01 for both overall survival (OS) and disease-free survival). Bivariate survival analysis showed an additive adverse effect for syndecan-1 and c-erbB-2 overexpression. At multivariate analysis, syndecan-1 overexpression was independently associated with poor OS (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.08-2.69). High syndecan-1 expression also was of independent prognostic value for OS in the group of 102 ER-negative patients (HR, 2.42; 95% CI, 1.21-4.82). Stratifying patients on the basis of the type of adjuvant therapy given, high syndecan-1 expression was associated with a higher risk of death only in patients treated with the cyclophosphamide-methotrexate-fluorouracil regimen (HR, 1.9; P = 0.09); at multivariate analysis for OS, this association proved to be of independent statistical significance (P = 0.03; HR, 2.15). CONCLUSIONS: Syndecan-1 is expressed at high levels in a significant percentage of breast carcinomas and is related to an aggressive phenotype and poor clinical behavior.

Adenocarcinoma↗

PubMed1999

Association of syndecan-1 with tumor grade and histology in primary invasive cervical carcinoma.

OBJECTIVES: The expression of syndecan-1, a cell surface heparan sulfate proteoglycan, is reduced during malignant transformation of squamous cells. Studies on squamous cell carcinoma of the head and neck have shown that syndecan-1-positive tumors are associated with longer overall and recurrence-free survival. The purpose of this study was to analyze syndecan-1 expression in invasive cervical carcinoma and to examine the association of syndecan-1 expression with prognostic factors and overall survival. METHODS: The study population consisted of 124 patients treated for primary invasive carcinoma of the uterine cervix at the Turku University Central Hospital during the years 1970-1988. The material consisted of 102 (82.3%) squamous cell carcinomas, 16 (12.9%) adenocarcinomas and 1 (0.8%) adenosquamous carcinoma, 1 (0.8%) small cell carcinoma, 1 (0. 8%) adenoid basal carcinoma, 1 (0.8%) carcinosarcoma, and 2 (1.6%) unclassified cervical carcinomas. Syndecan-1 expression was determined on paraffin-embedded tissue blocks using a human syndecan-1-specific monoclonal antibody B-B4 and immunohistochemistry. The expression of syndecan-1 was classified according to staining intensity as well as the percentage of positively stained tumor cells. RESULTS: Staining intensity was strong in 44 (36%) samples, while 24 (19%) specimens remained syndecan-1-negative. In 49 (40%) samples, the percentage of syndecan-1-positive cells was >/=90%. Syndecan-1 expression, as determined by >/=50% positively stained tumor cells, was associated with the grade of differentiation (P = 0.03) and squamous histology (P < 0.001), but was not associated with clinical stage (P = 0.16) or disease-free survival (P = 0.86). Age (P = 0.003) and clinical stage (P < 0.001) were significant prognostic factors, but syndecan-1 expression determined neither by percentage of positively stained tumor cells nor by staining intensity was associated with the outcome. CONCLUSIONS: In cervical carcinoma syndecan-1 is associated with histological differentiation grade and squamous histology, but does not predict clinical outcome.

Adult↗