Targeting Aberrant Sialylation to Treat Cancer

Abstract

Cell surface carbohydrates (known as glycans) are often aberrantly expressed or found at atypical levels in cancer. Glycans can impact all steps in tumour progression, from malignant transformation to metastasis, and have roles in all the cancer hallmarks. An increased understanding of glycans in the metastatic cascade offers exciting new therapeutic opportunities. Glycan-based targeting strategies are currently being tested in clinical trials and are a rich and untapped frontier for development. As we learn more about cancer glycobiology, new targets will continue to emerge for drug design. One key change in tumour glycosylation is the upregulation of cancer-associated sialylated glycans. Abnormal sialylation is integral to tumour growth, metastasis and immune evasion; therefore, targeting sialic acid moieties in cancer could be of high therapeutic value. Here, we summarise the changes to sialic acid biology in cancer and discuss recent advances and technologies bringing sialic-acid targeting treatments to the forefront of cancer therapeutics.

Biological Functions and Analytical Strategies of Sialic Acids in Tumor

“…Sialic acids enhance tumor progression at multiple levels by facilitating escape from immunological surveillance, angiogenesis, the formation of metastasis, and resistance to apoptosis and therapy. For this reason, the therapeutic approaches to modulate sialic acids and their receptors can be of high potency in tumor therapy [152][153][154]. As the coated sialic acids on tumor cells masked the antigenic sites of glycoproteins, removing sialic acids by sialidases is expected to become potential treatment.…”

Human T cell glycosylation and implications on immune therapy for cancer

“…64,[91][92][93][94] Considering the abundance of Siglec ligands on the surface of tumor cells and the inhibitory nature of many Siglecs, multiple studies have recently been initiated, investigating the effect of altering the levels of sialylation on tumor cells. 95 They are targeted using blocking antibodies, aiming to improve cancer immunotherapy. 96 Anti-Siglec-15 monoclonal antibody (targeting tumor-infiltrated macrophages-TIMs) inhibited the growth of established tumors in murine models.…”

“…98 Interfering with Selectin and Galectin functioning can also influence the interaction of T cells with tumor cells. 95,99 For example, interference with L-Selectin-mediated trafficking by treating patients with idelalisib, a phosphoinositide-3-kinase δ inhibitor, in high endothelial venules could limit dissemination of CLL to lymph nodes. 74 Galectin inhibitors have been evaluated in combination with chemotherapy drugs (5-fluorouracil) against solid tumors in several clinical trials, however, only one trial has been completed so far, suggesting that not all Galectin inhibitors are effective.…”

Heat shock protein 60 is a disease-associated sialoglycoprotein in human non-small cell lung cancer

“…Aberrant sialylation of cellular glycoconjugates were shown to modulate different cellular processes associated with tumorigenesis (Isaji et al, 2019). Altered sialylation has been detected in various epithelial cancers (Ma et al, 2016;Munkley and Scott, 2019). Neo-expression or overexpression of sialylated epitopes, for example, sialyl-Tn, sialyl-T, sialyl-Le x and sialyl-Le a was also noted on the surface of lung cancer cells (Hauselmann and Borsig, 2014).…”

“…Aberrant sialylation of cell surface glycoproteins has also been found to be related to the poor prognosis of various malignancies (Munkley and Scott, 2019). Thus, exploration of disease-associated sialoglycoproteins and study on their role in the disease progression is a relevant approach to gain a deeper insight into the disease pathogenesis.…”