Distribution and clinical significance of heparan sulfate proteoglycans in ovarian cancer.
ABSTRACT 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.
- SourceAvailable from: Jan Steffen Kruessel[Show abstract] [Hide abstract]
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; · 4.54 Impact Factor
Article: Heparan sulfate signaling in cancer.[Show abstract] [Hide abstract]
ABSTRACT: Heparan sulfate (HS) is a biopolymer consisting of variably sulfated repeating disaccharide units. The anticoagulant heparin is a highly sulfated intracellular variant of HS. HS has demonstrated roles in embryonic development, homeostasis, and human disease via non-covalent interactions with numerous cellular proteins, including growth factors and their receptors. HS can function as a co-receptor by enhancing receptor-complex formation. In other contexts, HS disrupts signaling complexes or serves as a ligand sink. The effects of HS on growth factor signaling are tightly regulated by the actions of sulfyltransferases, sulfatases, and heparanases. HS has important emerging roles in oncogenesis, and heparin derivatives represent potential therapeutic strategies for human cancers. Here we review recent insights into HS signaling in tumor proliferation, angiogenesis, metastasis, and differentiation. A cancer-specific understanding of HS signaling could uncover potential therapeutic targets in this highly actionable signaling network.Trends in Biochemical Sciences 04/2014; · 13.08 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: The tumor microenvironment, consisting of stromal myofibroblasts, endothelial cells, and leukocytes, is growingly perceived to be a major contributor to the pathogenesis and disease progression in practically all cancer types. Stromal myofibroblasts produce angiogenic factors, proteases, growth factors, immune response-modulating proteins, anti-apoptotic proteins, and signaling molecules, and express surface receptors and respond to stimuli initiated in the tumor cells to establish a bi-directional communication network in the microenvironment to promote tumor cell invasion and metastasis. Many of these molecules are candidates for targeted therapy and the cancer stroma has been recently regarded as target for biological intervention. This review provides an overview of the biology and clinical role of the stroma in ovarian cancer.Frontiers in oncology. 01/2014; 4:104.