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      Neuroendocrine Tumors Show Altered Expression of Chondroitin Sulfate, Glypican 1, Glypican 5, and Syndecan 2 Depending on Their Differentiation Grade

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          Abstract

          Neuroendocrine tumors (NETs) are found throughout the body and are important as they give rise to distinct clinical syndromes. Glycosaminoglycans, in proteoglycan (PG) form or as free chains, play vital roles in every step of tumor progression. Analyzing tumor samples with different degrees of histological differentiation we determined the existence of important alterations in chondroitin sulfate (CS) chains. Analysis of the transcription of the genes responsible for the production of CS showed a decline in the expression of some genes in poorly differentiated compared to well-differentiated tumors. Using anti-CS antibodies, normal stroma was always negative whereas tumoral stroma always showed a positive staining, more intense in the highest grade carcinomas, while tumor cells were negative. Moreover, certain specific cell surface PGs experienced a drastic decrease in expression depending on tumor differentiation. Syndecan 2 levels were very low or undetectable in healthy tissues, increasing significantly in well-differentiated tumors, and decreasing in poorly differentiated NETs, and its expression levels showed a positive correlation with patient survival. Glypican 5 appeared overexpressed in high-grade tumors with epithelial differentiation, and not in those that displayed a neuroendocrine phenotype. In contrast, normal neuroendocrine cells were positive for glypican 1, displaying intense staining in cytoplasm and membrane. Low-grade NETs had increased expression of this PG, but this reduced as tumor grade increased, its expression correlating positively with patient survival. Whilst elevated glypican 1 expression has been documented in different tumors, the downregulation in high-grade tumors observed in this work suggests that this proteoglycan could be involved in cancer development in a more complex and context-dependent manner than previously thought.

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          Quantitative real-time RT-PCR data analysis: current concepts and the novel "gene expression's CT difference" formula.

          For quantification of gene-specific mRNA, quantitative real-time RT-PCR has become one of the most frequently used methods over the last few years. This article focuses on the issue of real-time PCR data analysis and its mathematical background, offering a general concept for efficient, fast and precise data analysis superior to the commonly used comparative CT (DeltaDeltaCT) and the standard curve method, as it considers individual amplification efficiencies for every PCR. This concept is based on a novel formula for the calculation of relative gene expression ratios, termed GED (Gene Expression's CT Difference) formula. Prerequisites for this formula, such as real-time PCR kinetics, the concept of PCR efficiency and its determination, are discussed. Additionally, this article offers some technical considerations and information on statistical analysis of real-time PCR data.
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            Order out of chaos: assembly of ligand binding sites in heparan sulfate.

            Virtually every cell type in metazoan organisms produces heparan sulfate. These complex polysaccharides provide docking sites for numerous protein ligands and receptors involved in diverse biological processes, including growth control, signal transduction, cell adhesion, hemostasis, and lipid metabolism. The binding sites consist of relatively small tracts of variably sulfated glucosamine and uronic acid residues in specific arrangements. Their formation occurs in a tissue-specific fashion, generated by the action of a large family of enzymes involved in nucleotide sugar metabolism, polymer formation (glycosyltransferases), and chain processing (sulfotransferases and an epimerase). New insights into the specificity and organization of the biosynthetic apparatus have emerged from genetic studies of cultured cells, nematodes, fruit flies, zebrafish, rodents, and humans. This review covers recent developments in the field and provides a resource for investigators interested in the incredible diversity and specificity of this process.
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              Glycosaminoglycans: key players in cancer cell biology and treatment.

              Glycosaminoglycans are natural heteropolysaccharides that are present in every mammalian tissue. They are composed of repeating disaccharide units that consist of either sulfated or non-sulfated monosaccharides. Their molecular size and the sulfation type vary depending on the tissue, and their state either as part of proteoglycan or as free chains. In this regard, glycosaminoglycans play important roles in physiological and pathological conditions. During recent years, cell biology studies have revealed that glycosaminoglycans are among the key macromolecules that affect cell properties and functions, acting directly on cell receptors or via interactions with growth factors. The accumulated knowledge regarding the altered structure of glycosaminoglycans in several diseases indicates their importance as biomarkers for disease diagnosis and progression, as well as pharmacological targets. This review summarizes how the fine structural characteristics of glycosaminoglycans, and enzymes involved in their biosynthesis and degradation, are involved in cell signaling, cell function and cancer progression. Prospects for glycosaminoglycan-based therapeutic targeting in cancer are also discussed. © 2012 The Authors Journal compilation © 2012 FEBS.
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                Author and article information

                Contributors
                Journal
                Front Oncol
                Front Oncol
                Front. Oncol.
                Frontiers in Oncology
                Frontiers Media S.A.
                2234-943X
                07 February 2014
                2014
                : 4
                : 15
                Affiliations
                [1] 1Department of Morphology and Cell Biology, Universidad de Oviedo , Oviedo, Spain
                [2] 2Department of Functional Biology, Universidad de Oviedo , Oviedo, Spain
                [3] 3Department of Pathology, Hospital Universitario Central de Asturias , Oviedo, Spain
                [4] 4University Institute of Oncology of Asturias (IUOPA) , Oviedo, Spain
                Author notes

                Edited by: Elvira V. Grigorieva, Institute of Molecular Biology and Biophysics SB RAMS, Russia

                Reviewed by: Bernd E. R. Nuernberg, University of Tübingen Hospitals and Clinics, Germany; Katalin Dobra, Karolinska Institutet, Sweden

                *Correspondence: Luis M. Quirós, Department of Functional Biology, Universidad de Oviedo, Julian Clavería s/n, Oviedo 33006, Spain e-mail: quirosluis@ 123456uniovi.es

                This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology.

                Article
                10.3389/fonc.2014.00015
                3917325
                24570896
                fed1fca1-4a23-4319-a040-9c3392cfca08
                Copyright © 2014 García-Suárez, García, Fernández-Vega, Astudillo and Quirós.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 14 August 2013
                : 21 January 2014
                Page count
                Figures: 12, Tables: 1, Equations: 1, References: 59, Pages: 16, Words: 10941
                Categories
                Oncology
                Original Research

                Oncology & Radiotherapy
                glypican 5,glypican 1,proteoglycan,chondroitin sulfate,syndecan 2,glycosaminoglycan,neuroendocrine tumor

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