# Status Quo of Glycoslation in Cancer: What Is, What Is Not and What Is to Be
## 2 Milestones of Glycoslation in Cancer
### Glycosylation for Cancer Biomarkers
Several researchers have attempted to design the N-glycosylation pathway of expression systems. Among the total endorsed biopharmaceuticals, practically 70% are glycoproteins [127, 128, 129, 130]. Numerous functions of anticancer glycoproteins are related to solubility, pharmacodistribution, pharmacokinetics, proper structural folding, binding to receptors and serum half-life of glycans [131]. The most noteworthy anticancer therapeutic recombinant proteins are mAbs, which are glycosylated in their Fc area [132]. The glycocalyx is said to drive the interaction between malignant cells and the tumor microenvironment (TME). Both glycans, glycoconjugates and the TME effectively add to cancer hallmarks, by affecting various interactions [11, 133, 134]. Generally, the crosstalk between neoplastic cells and the TME guarantees smooth progress of the associated processes. Glycoslation generally impacts the extrinsic apoptotic process including both TNF-Related Apoptosis Inducing Ligand (TRAIL) and Fas passing receptors, just as integrin and galectin-mediated signaling. Glycans, glycosyltransferases, and glycosidases assume significant functions in apoptosis [135] by thwarting ligand-receptor interactions [135, 136]. The tumor necrosis factor (TNT)-related apoptosis-inducing ligand (Apo2L/TRAIL) advances tumor cell apoptosis through TRAIL-R1 and TRAIL-R2, whose O-glycosylation status decides its sensitivity to the ligand. In particular, GALNT14 shows a strong link to TRAIL sensitivity in pancreatic cancer, non-small-cell lung carcinoma (NSCLC) and melanoma. The expression of GALNT3 and O-glycan processing enzymes FUT3 and FUT6 is unique in CCCs. This information is useful in recognizing cancer patients who are bound to react to TRAIL-based therapies [136]. Furthermore, a lower degree of fucosylation, due to mutation of GDP-mannose-4-6-dehydratase (GMDS), expands the resistance from TRAIL-initiated apoptosis in CCC [137]. N-glycosylation has a regulatory function in TRAIL-R1-mediated apoptosis, yet not in TRAIL-R2 (without N-glycans). Defective apoptotic signaling by N-glycan-deficient TRAIL receptors is related to lower TRAIL receptor aggregation and reduced death inducing signaling complex (DISC) formation, without diminished TRAIL-binding affinity [138]. In addition, the death receptor Fas (CD95/APO-1) has two N glycosylation sites at N136 and N118 modestly influencing Fas induced apoptosis. The addition of sialic acids by ST6 Gal-I in a \(\alpha\)2-6 linkage to the N-glycans of Fas provides security against Fas-induced apoptosis in CCCs. Specifically, \(\alpha\)2-6 sialylation of Fas hinders Fas-induced apoptosis, blockage of Fas-Fas-associated death domain (FADD) association with Fas cytoplasmic tails and inhibition of Fas internalization [139, 140, 141]. Also, N-deglycosylation of Fas prompts the slowing down of proaspase-8 activation at the DISC complex, with no effect on DISC formation or FADD recruitment [142]. Glycosyltransferases, otherwise called N-acetyl galactosaminyltransferase 1 (GALNT1), are reported to activate survival signals that stifle apoptosis. In particular, overexpression of N acetyl galactosaminyltransferase 1 (GALNT1) adds to aberrant glycosylation of integrin \(\alpha\)3\(\beta\)1, changing the conformation of integrin heterodimers and promoting signal transduction to incite focal adhesion kinase (FAK) activation in bladder cancer cells [143]. Another significant molecular mechanism is the crosstalk among lectins and death receptors. Traditionally, the impact of galectin-3 (Gal-3) in apoptosis relies upon its subcellular localization [144, 145, 146, 147]. O-6-sialylation of integrin \(\beta\)1 N-glycans, mediated by ST6 Gal-I, totally impeded its recognition by Gal-3; then again, O-3-sialylation did not influence Gal-3 recognition in gastric cancer [148, 144]. These perceptions unequivocally demonstrate that Gal-3 binding to glycans is dependent on sialylation. Unraveling the sialome of cancer cells is expected to give new insights on programmed cell death pathways.