Distribution and clinical significance of heparan sulfate proteoglycans in ovarian cancer

Cancer Research UK and University of Manchester Department of Medical Oncology, Paterson Institute for Cancer Research, Manchester, England.
Clinical Cancer Research (Impact Factor: 8.72). 09/2004; 10(15):5178-86. DOI: 10.1158/1078-0432.CCR-03-0103
Source: PubMed


Heparan sulfate proteoglycans have been implicated in cancer cell growth, invasion, metastasis, and angiogenesis. This study was designed to compare their expression in normal ovary and ovarian tumors and then to examine their prognostic significance in ovarian cancer.
The expression of syndecan-1, -2, -3, and -4, glypican-1, and perlecan was assessed by immunohistochemistry in 147 biopsies that included normal ovary and benign, borderline, and malignant ovarian tumors. Clinical data, including tumor stage, performance status, treatment, and survival, were collected. Univariate and multivariate analyses were performed to evaluate prognostic significance.
The expression patterns of syndecan-1 and perlecan were altered in ovarian tumors compared with normal ovary. Syndecan-1 was not detected in normal ovary but was present in the epithelial and stromal cells of benign and borderline tumors and in ovarian adenocarcinomas. Perlecan expression was decreased in basement membranes that were disrupted by cancer cells but maintained in the basement membranes of blood vessels. Syndecan-2, -3, and -4, and glypican-1 were expressed in normal ovary and benign and malignant ovarian tumors. Stromal expression of syndecan-1 and glypican-1 were poor prognostic factors for survival in univariate analysis.
We report for the first time distinct patterns of expression of cell surface and extracellular matrix heparan sulfate proteoglycans in normal ovary compared with ovarian tumors. These data reinforce the role of the tumor stroma in ovarian adenocarcinoma and suggest that stromal induction of syndecan-1 contributes to the pathogenesis of this malignancy.

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    • "High levels of soluble syndecan-1 have been shown to play a role in the growth and dissemination of malignant cells in myeloma, and are associated with poor prognosis (Yang et al., 2002). All types of syndecans (syndecan-1, -2, -3, and -4) have been shown to be expressed by malignant glioma cells (Watanabe et al., 2006) and malignant ovarian tumors (Davies et al., 2004). Glypican-1 is highly expressed in gliomas (Su et al., 2006), pancreatic cancer (Kleeff et al., 1998) and breast cancer (Matsuda et al., 2001). "
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    ABSTRACT: The stroma surrounding tumors can either restrict or promote tumor growth and progression, and both the cellular and non-cellular components of the stroma play an active role. The cellular components in the surrounding stroma include tumor-associated fibroblasts, host tissue cells and immune cells. The non-cellular components, which form the extracellular matrix (ECM) scaffold, include proteoglycans, collagen, proteinases, growth factors and cytokines. For tumorigenesis to occur it is necessary for tumor cells to modify the surrounding stroma. Tumor cells have mechanisms for achieving this, such as co-opting fibroblasts and modifying the ECM they produce, degrading the surrounding ECM and/or synthesizing a favorable ECM to support invasion. Proteoglycans are an important component of the ECM and play an active role in tumor growth and progression. The expression and glycosylation patterns of proteoglycans are altered in the stroma surrounding tumors and these molecules may support or restrict tumor growth and progression depending on the type and stage of tumor. In the present review we discuss the difference between the tumor promoting and restricting stromal reactions surrounding tumors and the role proteoglycans play.
    Histology and histopathology 06/2014; 30(1). · 2.10 Impact Factor
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    • "Recent publications about the influence of Sdc-1 on apoptosis revealed a Janus-faced attitude, since in some cancer types a low Sdc-1 expression was correlated with high malignancy (Anttonen et al., 1999; Mikami et al., 2001; Pulkkinen et al., 1997; Matsumoto et al., 1997; Anttonen et al., 2001; Numa et al., 2002), whereas in other cancer types the contrary was observed (Chen and Ou, 2006; Ito et al., 2003; Barbareschi et al., 2003; Davies et al., 2004) In endometrial cancer Sdc-1 expression was significantly upregulated (Choi et al., 2007). "
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    ABSTRACT: Endometrial epithelial cells are known to undergo apoptosis during trophoblast invasion. We postulate that the cell surface molecule Syndecan-1 which is expressed on endometrial cells and syncytiotrophoblast is important for implantation in general and especially for induction of maternal cell apoptosis during trophoblast invasion because Syndecan-1's influence on apoptotic susceptibility of cancer cells is already described in the literature. Using the human endometrial epithelial cell line RL95-2, a new stable cell line with Syndecan-1 knock down was generated. Via antibody array analysis, a significant decrease in the expression of anti-apoptotic proteins like inhibitors of apoptosis ( IAPs), Clusterin, heme oxygenase (HO-2), heat shock protein (HSP)27 and -70 and Survivin due to the Syndecan-1 knock down was discovered. Correspondingly, active Caspase-3 as an indicator for apoptosis was increased more severely in these cells compared to unmodified RL95-2 after treatment with implantation related stimuli, which are the cytokines interleukin (IL)-1β, interferon (IFN)-γ, tumor necrosis factor (TNF)-α and transforming growth factor (TGF)-β1 and an anti-Fas antibody. Furthermore, a treatment with a combination of all factors caused a higher Caspase-3 induction compared to each single treatment. These results demonstrate that Syndecan-1 is involved in the control of apoptosis in RL95-2 cells and therefore may affect the fine tuning of apoptosis in endometrial epithelium regulating the embryo's invasion depth as a crucial step for regular implantation followed by successful pregnancy.
    Molecular Human Reproduction 01/2014; 20(6). DOI:10.1093/molehr/gau009 · 3.75 Impact Factor
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    • "Syndecan-1 modulates the biological behaviour of parenchymal cells in several types of carcinomas. Additionally, its stromal appearance has been identified as a prognostic factor [33], [34], [35], [36], [37], [38]. Recently the number of studies focusing on syndecan-1 in tumours of mesenchymal origin rapidly increases. "
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    ABSTRACT: Syndecans are transmembrane heparan sulphate proteoglycans. Their role in the development of the malignant phenotype is ambiguous and depends upon the particular type of cancer. Nevertheless, syndecans are promising targets in cancer therapy, and it is important to elucidate the mechanisms controlling their various cellular effects. According to earlier studies, both syndecan-1 and syndecan-2 promote malignancy of HT-1080 human fibrosarcoma cells, by increasing the proliferation rate and the metastatic potential and migratory ability, respectively. To better understand their tumour promoter role in this cell line, syndecan expression levels were modulated in HT-1080 cells and the growth rate, chemotaxis and invasion capacity were studied. For in vivo testing, syndecan-1 overexpressing cells were also inoculated into mice. Overexpression of full length or truncated syndecan-1 lacking the entire ectodomain but containing the four juxtamembrane amino acids promoted proliferation and chemotaxis. These effects were accompanied by a marked increase in syndecan-2 protein expression. The pro-migratory and pro-proliferative effects of truncated syndecan-1 were not observable when syndecan-2 was silenced. Antisense silencing of syndecan-2, but not that of syndecan-1, inhibited cell migration. In vivo, both full length and truncated syndecan-1 increased tumour growth and metastatic rate. Based on our in vitro results, we conclude that the tumour promoter role of syndecan-1 observed in HT-1080 cells is independent of its ectodomain; however, in vivo the presence of the ectodomain further increases tumour proliferation. The enhanced migratory ability induced by syndecan-1 overexpression is mediated by syndecan-2. Overexpression of syndecan-1 also leads to activation of IGF1R and increased expression of Ets-1. These changes were not evident when syndecan-2 was overexpressed. These findings suggest the involvement of IGF1R and Ets-1 in the induction of syndecan-2 synthesis and stimulation of proliferation by syndecan-1. This is the first report demonstrating that syndecan-1 enhances malignancy of a mesenchymal tumour cell line, via induction of syndecan-2 expression.
    PLoS ONE 06/2012; 7(6):e39474. DOI:10.1371/journal.pone.0039474 · 3.23 Impact Factor
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