Insights into the Role of Sialylation in Cancer Metastasis, Immunity, and Therapeutic Opportunity

Abstract

Sialylation is an enzymatic process that covalently attaches sialic acids to glycoproteins and glycolipids and terminates them by creating sialic acid-containing glycans (sialoglycans). Sialoglycans, usually located in the outmost layers of cells, play crucial biological roles, notably in tumor transformation, growth, metastasis, and immune evasion. Thus, a deeper comprehension of sialylation in cancer will help to facilitate the development of innovative cancer therapies. Cancer sialylation-related articles have consistently increased over the last four years. The primary subjects of these studies are sialylation, cancer, immunotherapy, and metastasis. Tumor cells activate endothelial cells and metastasize to distant organs in part by the interactions of abnormally sialylated integrins with selectins. Furthermore, cancer sialylation masks tumor antigenic epitopes and induces an immunosuppressive environment, allowing cancer cells to escape immune monitoring. Cytotoxic T lymphocytes develop different recognition epitopes for glycosylated and nonglycosylated peptides. Therefore, targeting tumor-derived sialoglycans is a promising approach to cancer treatments for limiting the dissemination of tumor cells, revealing immunogenic tumor antigens, and boosting anti-cancer immunity. Exploring the exact tumor sialoglycans may facilitate the identification of new glycan targets, paving the way for the development of customized cancer treatments.

Keywords: anti-tumor therapy; cancer; immunotherapy; metastasis; sialic acid; sialylation.

Figure 1

Global trends in publications on cancer sialylation: (a) the annual publications over the past decade; (b) top 10 countries with the most articles. SCP: single country publications; MCP: multiple country publications; (c) top 10 countries with the most total citations of related articles; and (d) world map showing collaborations between different countries in this field. The figures were plotted automatically using the bibliometrix package in R version 4.2.0 based on the retrieved articles.

Figure 2

Keywords and topics analysis of articles about cancer sialylation: (a) WordCloud showed the top 50 most frequent words. The frequency of keywords determined the font type; and (b) thematic map plotted by the authors’ keywords. Both (a,b) were plotted automatically using the bibliometrix package in R version 4.2.0 based on the authors’ keywords in the retrieved articles.

Figure 3

The structural basis and process of sialylation.

Figure 4

The impact of sialylation on tumor metastasis. α2,6-Sialylation of EGFR sustains its membrane retention and regulates the EMT of cancer cells, enhancing integrin tension, focal adhesion, and cell motility [43,44,45]. α2,3-Sialylation and α2,6-sialylation of integrins enhance their adherence to ECM [46,57,58]. α2,3-Sialylation of CD44 improves adhesion to HA, hence boosting cancer cell motility and metastasis [49]. α2,6-Sialylation of FGFR increases the ERK1/2-FAK signaling to promote the migration of cancer cells [50]. Furthermore, α2-6-sialylation of Fas and TNFR1 inhibits apoptotic signaling and helps the survival of bloodstream and lymphatic transport, consequently ensuring the formation of the secondary tumor site [53]. However, some labs have found that STs or sialylations play some opposite roles in cancer invasion and spread. For example, ST6Gal1 promotes the exosome-mediated export of the metastasis suppressor KAI1, which inhibits integrin signaling [59]. ST3Gal4 and ST8SIA1 are also reported to suppress the metastasis of cancer cells by inhibiting PI3K/Akt pathway and the phosphorylation of JAK2/STAT3, respectively [60,61]. SA: sialic acid, HA: hyaluronic acid, EGFR: epidermal growth factor receptor, EGF: epidermal growth factor, EMT: epithelial-to-mesenchymal transition, FGFR: fibroblast growth factor receptor, FGF: fibroblast growth factor, P: phosphorylation, TNFR1: tumor necrosis factor receptor 1, ERK: extracellular regulated protein kinases, FAK: focal adhesion kinase, ECM: extracellular matrix, KAI1: Kang-Ai 1, NEU: neuraminidase, PI3K/Akt: phosphoinositide-3 kinase/serine/threonine protein kinase B, JAK2/STAT3: Janus kinase 2/signal transducer and activator of transcription 3.

Figure 5

The impact of sialylation on immune cell functions. Siglec: sialic acid-binding immunoglobulin-like lectin; MICA: MHC class I–related chain A; NKGD2: natural-killer group 2, member D; IgG: immunoglobulin G; ADCC: antibody-dependent cell-mediated cytotoxicity; SHP: Src homology region 2 domain-containing phosphatase; MHC: major histocompatibility complex; TCR: T cell receptor; PD-1: programmed death-1; PD-L1: programmed death-ligand 1; ZAP70: zeta chain of T cell receptor associated protein kinase 70; NFAT: nuclear factor of activated T-cells.