Abstract
Glycosylation in cancer is a highly dynamic process that has a significant impact on tumor biology. Further, the attachment of aberrant glycan forms is already considered a hallmark of the disease state. Mass spectrometry has become a prominent approach to analyzing glycoconjugates. Specifically, matrix-assisted laser desorption/ionisation -mass spectrometric imaging (MALDI-MSI) is a powerful technique that combines mass spectrometry with histology and enables the spatially resolved and label-free detection of glycans. The most common approach to the analysis of glycans is the use of mass spectrometry adjunct to PNGase F digestion and other chemical reactions. In the current study, we perform the analysis of formalin-fixed, paraffin-embedded (FFPE) tissues for natively occurring bioactive glycan fragments without prior digestion or chemical reactions using MALDI-FT-ICR-MSI. We examined 106 primary resected gastric cancer patient tissues in a tissue microarray and correlated native-occurring fragments with clinical endpoints, therapeutic targets such as epidermal growth factor receptor (EGFR) and HER2/neu expressions and the proliferation marker MIB1. The detection of a glycosaminoglycan fragment in tumor stroma regions was determined to be an independent prognostic factor for gastric cancer patients. Native glycan fragments were significantly linked to the expression of EGFR, HER2/neu and MIB1. In conclusion, we are the first to report the in situ detection of native-occurring bioactive glycan fragments in FFPE tissues that influence patient outcomes. These findings highlight the significance of glycan fragments in gastric cancer tumor biology and patient outcome.
Highlights
Glycosylation is arguably the most abundant and complex type of protein posttranslational modification
Distinct localization patterns of these glycan fragments were observed in whole tissue sections of individual patients (Figure 1) and between patients on the tissue microarrays (TMAs) (Figure 2) which illustrates the variability in abundance among the fragments
We present the first attempt at analyzing native glycan fragments in FFPE tissues by MALDI-FT-ICRMSI, the results of which offer novel insights into the composition and distribution of glycans in gastric cancer tissues
Summary
Glycosylation is arguably the most abundant and complex type of protein posttranslational modification. The attached modifications are glycans, which are assemblies of sugars (oligosaccharides and polysaccharides) that bind covalently to proteins or lipids (glycoconjugates), yielding protein/ lipid-glycan complexes that are separated into specific main families. The constitutions of glycans are complex and can be differentiated by sugar composition, branching structures, and molecular modifications (e.g. sulphation) among other properties [3]. Glycoconjugates are found almost everywhere in human tissue, including as nuclear or cytoplasmic proteins, as secreted product of epithelial cells (mucus), or as secreted molecules in the extracellular matrix [2]. In cancer tissues, altered glycosylation, such as incomplete synthesis and neo-synthesis processes, are highly associated with tumor biology [5]. Molecular changes, including polysialic acid attachments of N-glycans, reportedly lead to poor outcome in lung cancer patients [6], whereas truncated glycan structures have been found to be prognostic markers in colorectal cancer [7]
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