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Chondroitin Sulfate Disaccharides, a Serum Marker for Primary Serous Epithelial Ovarian Cancer.

ABSTRACT: Glycosaminoglycans are long polysaccharidic chains, which are mostly present in connective tissues. Modified GAG expression in tissues surrounding malignant cells has been shown to contribute to tumor progression, aggressive status and metastasis in many types of cancer. Ovarian cancer is one of the most lethal gynecological malignancies due to its late diagnosis because of the absence of clear symptoms and unavailability of early disease markers. We investigated for the first time GAG changes at the molecular level as a novel biomarker for primary epithelial ovarian cancer. To this end, serum of a cohort of 68 samples was digested with chondroitinase ABC, which releases chondroitin sulfate into disaccharides. After labeling and purification, they were measured by HPLC, yielding a profile of eight disaccharides. We proposed a novel GAG-based score named "CS- bio" from the measured abundance of disaccharides present that were of statistical relevance. CS-bio's performance was compared with CA125, the clinically used serum tumor marker in routine diagnostics. CS-bio had a better sensitivity and specificity than CA125. It was more apt in differentiating early-stage patients from healthy controls, which is of high interest for oncologists.

SUBMITTER: Biskup K

PROVIDER: S-EPMC8304809 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Chondroitin Sulfate Disaccharides, a Serum Marker for Primary Serous Epithelial Ovarian Cancer.

Biskup Karina K Stellmach Caroline C Braicu Elena Ioana EI Sehouli Jalid J Blanchard Véronique V

Diagnostics (Basel, Switzerland) 20210623 7

Glycosaminoglycans are long polysaccharidic chains, which are mostly present in connective tissues. Modified GAG expression in tissues surrounding malignant cells has been shown to contribute to tumor progression, aggressive status and metastasis in many types of cancer. Ovarian cancer is one of the most lethal gynecological malignancies due to its late diagnosis because of the absence of clear symptoms and unavailability of early disease markers. We investigated for the first time GAG changes a ...[more]

PMID: 34201657

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Project description:Chondroitin sulfate (CS) is one of several glycosaminoglycans that are major components of proteoglycans. A linear polymer consisting of repeats of the disaccharide -4GlcAβ1-3GalNAcβ1-, CS undergoes differential sulfation resulting in five unique sulfation patterns. Because of the dimer repeat, the CS glycosidic "backbone" has two distinct sets of conformational degrees of freedom defined by pairs of dihedral angles: (ϕ1, ψ1) about the β1-3 glycosidic linkage and (ϕ2, ψ2) about the β1-4 glycosidic linkage. Differential sulfation and the possibility of cation binding, combined with the conformational flexibility and biological diversity of CS, complicate experimental efforts to understand CS three-dimensional structures at atomic resolution. Therefore, all-atom explicit-solvent molecular dynamics simulations with Adaptive Biasing Force sampling of the CS backbone were applied to obtain high-resolution, high-precision free energies of CS disaccharides as a function of all possible backbone geometries. All 10 disaccharides (β1-3 vs β1-4 linkage × five different sulfation patterns) were studied; additionally, ion effects were investigated by considering each disaccharide in the presence of either neutralizing sodium or calcium cations. GlcAβ1-3GalNAc disaccharides have a single, broad, thermodynamically important free-energy minimum, whereas GalNAcβ1-4GlcA disaccharides have two such minima. Calcium cations but not sodium cations bind to the disaccharides, and binding is primarily to the GlcA -COO(-) moiety as opposed to sulfate groups. This binding alters the glycan backbone thermodynamics in instances where a calcium cation bound to -COO(-) can act to bridge and stabilize an interaction with an adjacent sulfate group, whereas, in the absence of this cation, the proximity of a sulfate group to -COO(-) results in two like charges being both desolvated and placed adjacent to each other and is found to be destabilizing. In addition to providing information on sulfation and cation effects, the present results can be applied to building models of CS polymers and as a point of comparison in studies of CS polymer backbone dynamics and thermodynamics.

Project description:BackgroundExfoliative glaucoma (XFG) is typically classified as a high-pressure type of secondary open-angle glaucoma that develops as a consequence of exfoliation syndrome (XFS). Exfoliation syndrome is an age-related, generalized disorder of the extracellular matrix characterized by production and progressive accumulation of a fibrillar exfoliation material (XFM) in intra- and extraocular tissues. Exfoliation material represents complex glycoprotein/proteoglycan structure composed of a protein core surrounded by glycosaminoglycans such as heparan sulfate (HS) and chondroitin sulfate (CS). The purpose of the present study was to investigate HS and CS concentrations in serum samples of patients with newly diagnosed XFG and compare the obtained values with those pertaining to newly diagnosed primary open-angle glaucoma (POAG), normal controls (NC) and subjects with XFS.MethodsThis case-control study involved 165 subjects, including patients with newly diagnosed XFG, patients with newly diagnosed POAG, subjects with XFS and age- and sex-matched NC. The study was conducted at the Glaucoma Department of Clinic for Eye Diseases, Clinical Centre of Serbia, as the referral center for glaucoma in Serbia.ResultsThe mean age in the XFG, POAG, XFS and NC groups was 73.3 ± 9.0, 66.3 ± 7.8, 75.5 ± 7.0 and 73.5 ± 9.5 years, respectively, XFG vs. POAG, p < 0.001. Mean serum HS concentrations in the XFG, POAG, NC and XFS groups were 3,189.0 ± 1,473.8 ng/mL, 2,091.5 ± 940.9 ng/mL, 2,543.1 ± 1,397.3 ng/mL and 2,658.2 ± 1,426.8 ng/mL respectively, XFG vs. POAG, p = 0.001 and XFG vs. NC, p = 0.032. Mean serum CS concentrations in the XFG, POAG, NC and XFS group were 43.9 ± 20.7 ng/mL, 38.5 ± 22.0 ng/mL, 35.8 ± 16.4 ng/mL and 43.3 ± 21.8 ng/mL, respectively, XFG vs. NC, p = 0.041.ConclusionsOur findings revealed greater HS and CS concentrations in XFG patients and XFS subjects compared to those without XFM. Implications of HS and CS in the pathophysiology of XFS and glaucoma should be studied further. Serum is easily accessible and should thus be explored as rich sources of potential biomarkers. Further research should aim to identify XFG biomarkers that could be utilized in routine blood analysis tests, aiding in timely disease diagnosis.

Project description:GAGs exhibit a high level of conformational and configurational diversity, which remains untapped in terms of the recognition and modulation of proteins. Although GAGs are suggested to bind to more than 800 biologically important proteins, very few therapeutics have been designed or discovered so far. A key challenge is the inability to identify, understand and predict distinct topologies accessed by GAGs, which may help design novel protein-binding GAG sequences. Recent studies on chondroitin sulfate (CS), a key member of the GAG family, pinpointing its role in multiple biological functions led us to study the conformational dynamism of CS building blocks using molecular dynamics (MD). In the present study, we used the all-atom GLYCAM06 force field for the first time to explore the conformational space of all possible CS building blocks. Each of the 16 disaccharides was solvated in a TIP3P water box with an appropriate number of counter ions followed by equilibration and a production run. We analyzed the MD trajectories for torsional space, inter- and intra-molecular H-bonding, bridging water, conformational spread and energy landscapes. An in-house phi and psi probability density analysis showed that 1→3-linked sequences were more flexible than 1→4-linked sequences. More specifically, phi and psi regions for 1→4-linked sequences were held within a narrower range because of intra-molecular H-bonding between the GalNAc O5 atom and GlcA O3 atom, irrespective of sulfation pattern. In contrast, no such intra-molecular interaction arose for 1→3-linked sequences. Further, the stability of 1→4-linked sequences also arose from inter-molecular interactions involving bridged water molecules. The energy landscape for both classes of CS disaccharides demonstrated increased ruggedness as the level of sulfation increased. The results show that CS building blocks present distinct conformational dynamism that offers the high possibility of unique electrostatic surfaces for protein recognition. The fundamental results presented here will support the development of algorithms that help to design longer CS chains for protein recognition.

Dataset Information

Chondroitin Sulfate Disaccharides, a Serum Marker for Primary Serous Epithelial Ovarian Cancer.

Publications

Chondroitin Sulfate Disaccharides, a Serum Marker for Primary Serous Epithelial Ovarian Cancer.

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