Glycosaminoglycans: key players in cancer cell biology and treatment

Afratis, Nikolaos A.; Gialeli, Chrysostomi; Nikitovic, Dragana; Tsegenidis, T.; Karousou, Evgenia; Theocharis, Achilleas D.; Pavão, Mauro S.G.; Tzanakakis, George N.; Karamanos, Nikos K.

doi:10.1111/j.1742-4658.2012.08529.x

Cited by 464 publications

(449 citation statements)

References 175 publications

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“…As an enzyme that degrades hyaluronan, HYAL2 is known to be a tumor suppressor gene involved in cell adhesion, cell mobility, chemokinesis, cancer progression, angiogenesis and metastasis. [35][36][37][38][39] Our results also approved the tumor suppressor character of HYAL2 in tissue by observing higher HYAL2 methylation levels in malignant BC tumors than in benign breast tissues (Supporting Information Fig. 3).…”

Section: Discussionsupporting

confidence: 67%

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

Yang

Pfütze

Zucknick

et al. 2014

Intl Journal of Cancer

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Breast cancer (BC) is the leading cause of cancer-related mortality in women worldwide. Changes in DNA methylation in peripheral blood could be associated with malignancy at early stage. However, the BC-associated DNA methylation signatures in peripheral blood were largely unknown. Here, we performed a genome-wide methylation screening and identified a BC-associated differentially methylated CpG site cg27091787 in the hyaluronoglucosaminidase 2 gene (HYAL2) (discovery round with 72 BC case and 24 controls: p 5 2.61 3 10 29 adjusted for cell-type proportions). The substantially decreased methylation of cg27091787 in BC cases was confirmed in two validation rounds (first validation round with 338 BC case and 507 controls: p < 0.0001; second validation round with 189 BC case and 189 controls: p < 0.0001). In addition to cg27091787, the decreased methylation of a 650-bp CpG island shore of HYAL2 was also associated with increased risk of BC. Moreover, the expression and methylation of HYAL2 were inversely correlated with a p-value of 0.006. To note, the BC-associated decreased HYAL2 methylation was replicated in the T-cell fraction (p 5 0.034). The cg27091787 methylation level enabled a powerful discrimination of earlystage BC cases (stages 0 and I) from healthy controls [area under curve (AUC) 5 0.89], and was robust for the detection of BC in younger women as well (age < 50, AUC 5 0.87). Our study reveals a strong association between decreased HYAL2 methylation in peripheral blood and BC, and provides a promising blood-based marker for the detection of early BC.Breast cancer (BC) is the most common cancer and the leading cause of cancer-related mortality among women, 1 with 1.7 million new cases and 522,000 deaths in 2012. 2 In the United States, one in eight women will develop BC in her lifetime. 3 Although therapeutic advances have improved the survival rate, most BC patients still suffer from greatly

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Section: Discussionsupporting

confidence: 67%

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

Yang

Pfütze

Zucknick

et al. 2014

Intl Journal of Cancer

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“…It has been earlier reported that CSPG2 gene is upregulated in biopsy-proven NASH patients versus obese controls 44 . CS and HS were also implicated in cancer progression 45 , one of the most severe outcomes of NASH. Therefore, we predicted that these changes in gene expression, in particular as it involves complete metabolic pathways, may correlate with a change in blood concentration of the pathwayassociated metabolites.…”

Section: Article Nature Communications | Doi: 101038/ncomms4083mentioning

confidence: 99%

Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease

et al. 2014

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Several liver disorders result from perturbations in the metabolism of hepatocytes, and their underlying mechanisms can be outlined through the use of genome-scale metabolic models (GEMs). Here we reconstruct a consensus GEM for hepatocytes, which we call iHepatocytes2322, that extends previous models by including an extensive description of lipid metabolism. We build iHepatocytes2322 using Human Metabolic Reaction 2.0 database and proteomics data in Human Protein Atlas, which experimentally validates the incorporated reactions. The reconstruction process enables improved annotation of the proteomics data using the network centric view of iHepatocytes2322. We then use iHepatocytes2322 to analyse transcriptomics data obtained from patients with non-alcoholic fatty liver disease. We show that blood concentrations of chondroitin and heparan sulphates are suitable for diagnosing non-alcoholic steatohepatitis and for the staging of non-alcoholic fatty liver disease. Furthermore, we observe serine deficiency in patients with NASH and identify PSPH, SHMT1 and BCAT1 as potential therapeutic targets for the treatment of non-alcoholic steatohepatitis.

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“…There are literally thousands of different HA sizes in remodeling microenvironments, including tumors. HA polymers bind to cells via at least six known receptors (16,19,20,(26)(27)(28)(29)(30)(31)(32). Two of these, cluster designation 44 (CD44) and receptor for HA-mediated motility/HA-mediated motility receptor (RHAMM/HMMR), form multivalent complexes with different ranges of HA sizes (19,29,33), and both receptors are implicated in BCa progression (19-21, 23, 29, 30, 33-36).…”

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confidence: 99%

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

Veiseh

Kwon

Borowsky

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Tumor heterogeneity confounds cancer diagnosis and the outcome of therapy, necessitating analysis of tumor cell subsets within the tumor mass. Elevated expression of hyaluronan (HA) and HA receptors, receptor for HA-mediated motility (RHAMM)/HA-mediated motility receptor and cluster designation 44 (CD44), in breast tumors correlates with poor outcome. We hypothesized that a probe for detecting HA-HA receptor interactions may reveal breast cancer (BCa) cell heterogeneity relevant to tumor progression. A fluorescent HA (F-HA) probe containing a mixture of polymer sizes typical of tumor microenvironments (10-480 kDa), multiplexed profiling, and flow cytometry were used to monitor HA binding to BCa cell lines of different molecular subtypes. Formulae were developed to quantify binding heterogeneity and to measure invasion in vivo. Two subsets exhibiting differential binding (HA −/low vs. HA high ) were isolated and characterized for morphology, growth, and invasion in culture and as xenografts in vivo. F-HA-binding amounts and degree of heterogeneity varied with BCa subtype, were highest in the malignant basal-like cell lines, and decreased upon reversion to a nonmalignant phenotype. Binding amounts correlated with CD44 and RHAMM displayed but binding heterogeneity appeared to arise from a differential ability of HA receptor-positive subpopulations to interact with F-HA. HA high subpopulations exhibited significantly higher local invasion and lung micrometastases but, unexpectedly, lower proliferation than either unsorted parental cells or the HA −/low subpopulation. Querying F-HA binding to aggressive tumor cells reveals a previously undetected form of heterogeneity that predicts invasive/metastatic behavior and that may aid both early identification of cancer patients susceptible to metastasis, and detection/therapy of invasive BCa subpopulations.tumor cell heterogeneity | hyaluronan binding | heterogeneity index B reast tumors display substantial heterogeneity driven by genetic and epigenetic mechanisms (1-3). These processes select and support tumor cell subpopulations with distinct phenotypes in proliferation, metastatic/invasive proclivity, and treatment susceptibility that contribute to clinical outcomes. Currently, there is a paucity of biomarkers to identify these subpopulations (3-12). Although detection of genetic heterogeneity may itself be a breast cancer (BCa) prognostic marker (3, 13-15), the phenotypes manifested from this diversity are context-dependent. Therefore, phenotypic markers provide additional powerful tools for biological information required to design diagnostics and therapeutics. Glycomic approaches have enormous potential for revealing tumor cell phenotypic heterogeneity because glycans are themselves highly heterogeneous and their complexity reflects the nutritional, microenvironmental, and genetic dynamics of the tumors (16-18).We used hyaluronan (HA) as a model carbohydrate ligand for probing heterogeneity in glycosaminoglycan-BCa cell receptor interactions. We reasoned this approach...

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Glycosaminoglycans: key players in cancer cell biology and treatment

Cited by 464 publications

References 175 publications

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

DNA methylation array analyses identified breast cancer‐associated HYAL2 methylation in peripheral blood

Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease

Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset

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