Protein Glycosylation and Tumor Microenvironment Alterations Driving Cancer Hallmarks

Peixoto, Andreia; Relvas-Santos, Marta; Azevedo, Rita; Santos, Lúcio Lara; Ferreira, José Alexandre

doi:10.3389/fonc.2019.00380

Cited by 221 publications

(196 citation statements)

References 296 publications

(301 reference statements)

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“…CD138 is also frequently upregulated in HIV associated B‐cell neoplasms, where CD138 increases B‐lymphoid cell extravasation in response to HIV‐1 Tat, the main HIV‐transactivating factor . The absence of stromal CD138 expression in normal breast tissues is compatible with earlier reports on stroma‐to‐carcinoma signaling pathways involving proteoglycans such as CD138 that are specifically activated only during cancer development …”

Section: Discussionsupporting

confidence: 87%

“…33 The absence of stromal CD138 expression in normal breast tissues is compatible with earlier reports on stroma-to-carcinoma signaling pathways involving proteoglycans such as CD138 that are specifically activated only during cancer development. 34,35 A total of 13 studies had earlier analyzed the prognostic role of CD138 in BCa in cohorts of 30 to 254 tumors (Table S5). None of these studies had comprehensively analyzed membranous, cytoplasmic, and stromal CD138 staining.…”

Section: Discussionmentioning

confidence: 99%

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A shift from membranous and stromal syndecan‐1 (CD138) expression to cytoplasmic CD138 expression is associated with poor prognosis in breast cancer

Kind

Jaretzke

Büscheck

et al. 2019

Molecular Carcinogenesis

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Syndecan‐1 (CD138) is a transmembrane proteoglycan expressed in normal and malignant tissues. It is of interest because of a possible prognostic effect in tumors and as a target for Indatuximab, a monoclonal antibody coupled to a cytotoxic agent. To assess the prognostic role of CD138 expression in breast cancer (BCa), a tissue microarray containing 1535 BCa specimens was analyzed by immunohistochemistry. Cytoplasmic, membranous, and stromal CD138 staining was separately analyzed. In normal breast tissue, CD138 staining was limited to epithelial cell membranes. In cancers, membranous staining tended to become weaker or even disappeared (38.3% of cancers with absence of membranous staining) but cytoplasmic and stromal staining newly appeared in 29.7% and 58.1% of cancers. Loss of membranous epithelial CD138 staining as well as presence of cytoplasmic and stromal CD138 positivity were—to a variable degree—associated with high pT, high grade, nodal metastasis, estrogen receptor‐negative, progesterone receptor‐negative, human epidermal growth factor receptor 2+, and poor overall patient survival. A combined analysis of epithelial and stromal CD138 expression revealed a link to overall patient survival (P < .0001) with best prognosis for patients with stromal positivity and absence of cytoplasmic staining, the worst prognosis for cancers with cytoplasmic staining and stromal negativity and intermediate prognosis for patients having either cytoplasmic staining or stromal negativity. In multivariate analyses, CD138 was not independent of established prognostic features. In summary, these data reveal a compartment depending prognostic effect of CD138 expression in BCa with cytoplasmic positivity being linked to aggressive cancer and stromal CD138 being linked to a more favorable prognosis.

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Section: Discussionsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

A shift from membranous and stromal syndecan‐1 (CD138) expression to cytoplasmic CD138 expression is associated with poor prognosis in breast cancer

Kind

Jaretzke

Büscheck

et al. 2019

Molecular Carcinogenesis

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“…2e), indicating more complex glycan structures on their surface glycoproteins. Taken together, these data suggest that enhanced hexosamine biosynthesis in KL-comutant cancer cells increase both intracellular O-GlcNAcylation and complex N-Glycan structures on cell surface glycoproteins 23 , which may contribute to tumor aggressiveness.…”

Section: Resultsmentioning

confidence: 74%

The hexosamine biosynthesis pathway is a targetable liability in lung cancers with concurrent KRAS and LKB1 mutations

Cai

et al. 2020

Preprint

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In non–small cell lung cancer (NSCLC), concurrent mutations in the oncogene KRAS and the tumor suppressor STK11 encoding the kinase LKB1 result in aggressive tumors prone to metastasis but with liabilities arising from reprogrammed metabolism. We previously demonstrated perturbed nitrogen metabolism and addiction to an unconventional pathway of pyrimidine synthesis in KRAS/LKB1 co-mutant (KL) cancer cells. To gain broader insight into metabolic reprogramming in NSCLC, we analyzed tumor metabolomes in a series of genetically engineered mouse models with oncogenic KRAS combined with mutations in LKB1 or p53. Metabolomics and gene expression profiling pointed towards an activation of the hexosamine biosynthesis pathway (HBP), another nitrogen-related metabolic pathway, in both mouse and human KL mutant tumors. KL cells contain high levels of HBP metabolites, higher flux through the HBP pathway and elevated dependence on the HBP enzyme Glutamine-Fructose-6-Phosphate Transaminase 2 (GFPT2). GFPT2 inhibition selectively reduced KL cell growth in culture and xenografts. Our results define a new metabolic vulnerability in KL tumors and provide a rationale for targeting GFPT2 in this aggressive NSCLC subtype.

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“…Protein glycosylation has long been known as one of the most common, highly variable and versatile post-translational modifications that fine-tunes protein functions by modulating sorting, folding, enzyme activity and subcellular localization [1,2]. The astounding diversity of protein-attached glycans is the result of the concerted action of glycosyltransferases and glycosidases, which function is template-independent.…”

Section: Introductionmentioning

confidence: 99%

High Throughput Multiplex SNP-analysis in Chronic Obstructive Pulmonary Disease and Lung Cancer

Elek

Kovács

Keszler

et al. 2020

CMM

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Background: A number of human inflammatory diseases and tumors have been shown to cause alterations in the glycosylation pattern of plasma proteins in a specific manner. These highly variable and versatile post-translational modifications finetune protein functions by influencing sorting, folding, enzyme activity and subcellular localization. However, relatively little is known about regulatory factors of this procedure and about the accurate causative connection between glycosylation and disease. Objective: The aim of the present study was to investigate whether certain single nucleotide polymorphisms (SNPs) in genes encoding glycosyltransferases and glycosidases could be associated with elevated risk for chronic obstructive pulmonary disease (COPD) and lung adenocarcinoma. Methods: A total of 32 SNPs localized in genes related to N-glycosylation were selected for the association analysis. Polymorphisms with putative biological functions (missense or regulatory variants) were recruited. SNPs were genotyped by a TaqMan OpenArray platform. A single base extension-based method in combination with capillary gel electrophoresis was used for verification. Results: The TaqMan OpenArray approach provided accurate and reliable genotype data (global call rate: 94.9%, accuracy: 99.6%). No significant discrepancy was detected between the obtained and expected genotype frequency values (Hardy–Weinberg equilibrium) in the healthy control sample group in case of any SNP confirming reliable sampling and genotyping. Allele frequencies of the rs3944508 polymorphism localized in the 3’ UTR of the MGAT5 gene significantly differed between the sample groups compared. Conclusion: Our results suggest that the rs34944508 SNP might modulate the risk for lung cancer by influencing the expression of MGAT5. This enzyme catalyzes the addition of N-acetylglucosamine (GlcNAc) in beta 1-6 linkage to the alpha-linked mannose of biantennary N-linked oligosaccharides, thus, increasing branching that is the characteristic of invasive malignancies.

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Protein Glycosylation and Tumor Microenvironment Alterations Driving Cancer Hallmarks

Cited by 221 publications

References 296 publications

A shift from membranous and stromal syndecan‐1 (CD138) expression to cytoplasmic CD138 expression is associated with poor prognosis in breast cancer

A shift from membranous and stromal syndecan‐1 (CD138) expression to cytoplasmic CD138 expression is associated with poor prognosis in breast cancer

The hexosamine biosynthesis pathway is a targetable liability in lung cancers with concurrent KRAS and LKB1 mutations

High Throughput Multiplex SNP-analysis in Chronic Obstructive Pulmonary Disease and Lung Cancer

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