This review provides insights on the impact of glycosylation in cancer biology and its influence in the current approaches of targeted cancer therapies in the clinical setting. The roles of glycosylation in cancer signaling, tumor progression, and metastasis are reviewed as well as glycans and glycan-binding proteins in tumor immunomodulation. Moreover, the latest reports on glycans influencing targeted therapeutic approaches in cancer are summarized. Finally, we discuss the future challenges of the field, outlining potential applications of glycan-based biomarkers for patient stratification and strategies for improving personalized cancer treatment.

Cancer is a deadly disease that encompasses numerous cellular modifications. Among them, alterations in glycosylation are a proven reliable hallmark of cancer, with most biomarkers used in the clinic detecting cancer-associated glycans. Despite their clear potential as therapy targets, glycans have been overlooked in drug discovery strategies. The complexity associated with the glycosylation process, and lack of specific methodologies to study it, have long hampered progress. However, recent advances in new methodologies, such as glycoengineering of cells and high-throughput screening (HTS), have opened new avenues of discovery. We envision that glycan-based targeting has the potential to start a new era of cancer therapy. In this article, we discuss the promise of cancer-associated glycosylation for the discovery of effective cancer drugs. What Are We Still Missing in Cancer Treatment?Cancer is one of the leading causes of global mortality. According to the World Health Organization, cancer was responsible for an estimated 9.6 million deaths in 2018. The traditional methods of cancer management are chemotherapy, radiation therapy, and surgery. The success of such strategies relies on several factors, such as the type of tumor and stage of the disease. Unfortunately, the majority of tumors are detected in an advanced stage, leading to treatment failure. This therapeutic failure often results in tumor recurrence and metastasis, which accounts for approximately 90% of cancer deaths [1]. HighlightsCancer is a leading cause of death, mainly due to the lack of efficacy of existing cancer treatments, such as chemotherapy and radiotherapy.Aberrant protein glycosylation is a hallmark of cancer and specific glycans actively drive tumor development and progression.

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Sialyl-Lewis X (SLex) is a sialylated glycan antigen expressed on the cell surface during malignant cell transformation and is associated with cancer progression and poor prognosis. The increased expression of sialylated glycans is associated with alterations in the expression of sialyltransferases (STs). In this study we determined the capacity of ST3GAL3 and ST3GAL4 sialyltransferases to synthesize the SLex antigen in MKN45 gastric carcinoma cells and evaluated the effect of SLex overexpression in cancer cell behavior both in vitro and in vivo using the chicken chorioallantoic membrane (CAM) model. The activation of tyrosine kinase receptors and their downstream molecular targets was also addressed. Our results showed that the expression of ST3GAL4 in MKN45 gastric cancer cells leads to the synthesis of SLex antigens and to an increased invasive phenotype both in vitro and in the in vivo CAM model. Analysis of phosphorylation of tyrosine kinase receptors showed a specific increase in c-Met activation. The characterization of downstream molecular targets of c-Met activation, involved in the invasive phenotype, revealed increased phosphorylation of FAK and Src proteins and activation of Cdc42, Rac1 and RhoA GTPases. Inhibition of c-Met and Src activation abolished the observed increased cell invasive phenotype. In conclusion, the expression of ST3GAL4 leads to SLex antigen expression in gastric cancer cells which in turn induces an increased invasive phenotype through the activation of c-Met, in association with Src, FAK and Cdc42, Rac1 and RhoA GTPases activation.