Cancer glycomics offers potential biomarkers and therapeutic targets in the framework of 3P medicine

Abstract

Glycosylation is one of the most important post-translational modifications (PTMs) in a protein, and is the most abundant and diverse biopolymer in nature. Glycans are involved in multiple biological processes of cancer initiation and progression, including cell-cell interactions, cell-extracellular matrix interactions, tumor invasion and metastasis, tumor angiogenesis, and immune regulation. As an important biomarker, tumor-associated glycosylation changes have been extensively studied. This article reviews recent advances in glycosylation-based biomarker research, which is useful for cancer diagnosis and prognostic assessment. Truncated O-glycans, sialylation, fucosylation, and complex branched structures have been found to be the most common structural patterns in malignant tumors. In recent years, immunochemical methods, lectin recognition-based methods, mass spectrometry (MS)-related methods, and fluorescence imaging-based in situ methods have greatly promoted the discovery and application potentials of glycomic and glycoprotein biomarkers in various cancers. In particular, MS-based proteomics has significantly facilitated the comprehensive research of extracellular glycoproteins, increasing our understanding of their critical roles in regulating cellular activities. Predictive, preventive and personalized medicine (PPPM; 3P medicine) is an effective approach of early prediction, prevention and personalized treatment for different patients, and it is known as the new direction of medical development in the 21st century and represents the ultimate goal and highest stage of medical development. Glycosylation has been revealed to have new diagnostic, prognostic, and even therapeutic potentials. The purpose of glycosylation analysis and utilization of biology is to make a fundamental change in health care and medical practice, so as to lead medical research and practice into a new era of 3P medicine.

Keywords: 3P medicine; cancer biomarker; fluorescence imaging; glycosylation; immunochemical method; immunotherapy; lectin recognition; mass spectrometry.

Figure 1

Common glycoconjugates in mammalian cells. N-glycans have a pentasaccharide core or a trimannosyl core, and the ends are further modified by GlcNAc, Gal, and SIa. O-glycans contain 6 main basic core structures and are further extended to generate structures of various core and different terminal glycans. Glycosphingolipids are composed of ceramides and a series of variable glycans.

Figure 2

Representative tumor-associated aberrant glycosylation. O-glycan truncation, sialylation, fucosylation, and N-linked glycan branching are abnormally present in cancer and contribute to cancer growth and metastasis.

Figure 3

ELISA analysis of protein glycosylation. Four main types of ELISA assays are used: direct (A), indirect (B), sandwich (C), and competition (D).

Figure 4

Lectin microarray analysis of protein glycosylation. Three main types of lectin microarray are used: fluorescent labeling of glycoproteins (A), biotin labeling of glycoproteins (B), and antibody recognition of glycoproteins (C).

Figure 5

Mass spectrometry analysis of protein glycosylation. Top-down and bottom-up mass spectrometry approaches are used for protein glycosylation analysis. Top-down approach can directly assess the protein backbone and PTMs without any enzymatic digestion prior to MS analysis. Bottom-up approach firstly digests extracted proteins to generate peptides, and then the peptides are used for MS analysis.