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Glycosylation is the most frequent and structurally complex posttranslational modification in cell-surface and secreted proteins. Glycans are major orchestrators of biological processes, namely, by controlling protein folding and key biological functions such as cell adhesion, migration, signaling and immune recognition. Altered glycosylation is considered a hallmark of malignant transformations that decisively contributes to disease outcome. This review comprehensively summarizes the main findings related with gastrointestinal cancers and the decisive impact of aberrant glycosylation on tumor biology toward more aggressive phenotypes. Particular emphasis is given to alterations in O-glycosylation, namely, the overexpression of immature O-glycans, and the sialylated Lewis antigens sialyl-LeA and sialyl-LeX, frequently implicated in lymphohematogenous metastasis. We further discuss how recent contributions from glycoproteomics and glycoengineering fields have broadened our understanding of the human O-glycoproteome and its implications for cancer research. Finally, we address the tremendous potential of glycans in the context of targeted therapeutics (selective inhibition of glycosylation pathways, immunotherapy) and discuss the need to include glycomics/glycoproteomics in holistic panomics models toward true precision medicine settings. [ABSTRACT FROM AUTHOR]

CD44 is a heavily glycosylated membrane receptor playing a key role in cell adhesion, signal transduction and cytoskeleton remodelling. It is also one of the most studied glycoproteins in cancer, frequently explored for stem cell identification, and associated with chemoresistance and metastasis. However, CD44 is a general designation for a large family of splicing variants exhibiting different degrees of glycosylation and, potentially, functionally distinct roles. Moreover, structural diversity associated with ambiguous nomenclature has delayed clinical developments. Herein, we attempt to comprehensively address these aspects and systematize CD44 nomenclature, setting milestones for biomarker discovery. In addition, we support that CD44 may be an important source of cancer neoantigens, most likely resulting from altered splicing and/or glycosylation. The discovery of potentially targetable CD44 (glyco)isoforms will require the combination of glycomics with proteogenomics approaches, exploring customized protein sequence databases generated using genomics and transcriptomics. Nevertheless, the necessary high-throughput analytical and bioinformatics tools are now available to address CD44 role in health and disease. [ABSTRACT FROM AUTHOR]