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Cancer remains one of the deadliest diseases in the world because we still haven’t fully comprehended why and how it occurs. What we do know is that the proteins on the cell surface are at the forefront. Normally these proteins carry out essential cellular functions, such as division, migration, and transport of material. When they undergo unusual modifications, cells can awry, dividing uncontrollably and consuming the resources of the body rapidly.
Glycosylation, the addition of complex sugars to these proteins, is perhaps the most influential modification. It is particularly challenging to explore because of the mind-blowing structural and functional diversity of these sugars. However, innovation in glycobiology research can allow us to reach the lesser-explored territories of cancer. With advanced glycan arrays, synthetic chemistry, and high-throughput screening, we can improve the accuracy and speed of glycobiology research to drive a deeper understanding of glycosylation in cancer. This article highlights some areas within cancer research utilizing glycobiology. If you’re interested in learning more about glycobiology and cancer, be sure to check out our eBook, Examining Altered Glycobiology in Cancer.
Biomarkers indicate how protein expression, function, and structure are altered in cancer. The vast majority of FDA-approved cancer biomarkers are glycoproteins, cell surface proteins covalently attached to sugar chains called glycans. Therefore, looking at changes in glycosylation in cancer can reveal what led to the formation of aberrant glycoproteins. This creates opportunities to discover novel biomarker candidates. With a concrete knowledge of these biomarkers, researchers can design more targeted anti-cancer therapeutics to mitigate the effects of aberrant glycosylation.
One of the primary indicators of cancer is changes in the glycome. These changes can manifest in various ways. Certain glycan epitopes might be present, while others may be unusually absent in cancer cells. The relative abundance of specific glycans might vary from healthy to cancerous tissue. Glycan chains can undergo further modifications, such as the addition of fucose or sialic acid at the end of the sugar chain.
For example, the mucin peptide is found on the surface of epithelial cells in the lungs, stomach, intestines, and various other tissues. Studies have discovered an abundance of mucin with shorter glycans in breast cancer where the glycans were truncated with sialic acid, therefore demonstrating the detection of sialylated mucin structures is an indicator of tumor growth (1).
Another site of interest is the group of enzymes catalyzing the formation and dissociation of glycoconjugates. Going back to our mucin example, the overexpression of sialyltransferases (e.g., ST6GalNAc-I and II), which add sialic acid to the terminal sugar, can be attributed to the increased levels of shorter glycan chains prevalent in breast cancer (2).
Biomarker studies have already started to benefit from altered glycan structure discoveries. FDA-approved glycoprotein antigens as cancer biomarkers are on the rise, including CA 15-3 derived from mucin-1 as a serum marker for breast cancer, CA-125 (mucin16) for ovarian cancer, and CA 19-9 (sialyl-LewisA) for pancreatic cancer (3–5).
Precision is key to successful cancer treatment. Unfortunately, conventional radiation, chemotherapy, and surgery approaches are inadequate. These treatments often result in severe adverse effects and recurrence. This clearly indicates a dire need for state-of-the-art strategies employing a more targeted approach.
Targeted approaches are often hampered due to therapy resistance, and success is achieved in only a subset of patients. High-throughput drug screening can overcome these challenges by screening large compound libraries to discover a broader range of potential hits. Screening methods are accelerated further through automated HTS workflows. However, conventional HTS-derived candidates have failed to reach clinical trials due to their lack of targeted inhibition.
The target preference for HTS assays is mainly glycosyltransferases. Because one enzyme can modify multiple proteins, the most suitable HTS target is aberrant glycosyltransferase activity. Over the past few years, promising studies have emerged with regard to targeted HTS. The first use of a cell-based HTS assay was in 2017 when researchers discovered a potential inhibitor for the transferase ppGalNAc-T3 (6). Since then, various cell-based and biochemical assays have been developed to target O-GlcNAc transferase (OGT), Galactosyltransferase B4GALT1, and ST6Gal I, among many others. Recent advances in glycosyltransferase-specific HTS assays are summarized in a review article published in Cell (7).
Besides initiating tumor-associated behavior in cells, aberrant glycosylation also affects the body’s response to existing anti-cancer therapeutics.
For example, recent studies revealed the role of glycosylation in metastasis, a characteristic of aggressive cancers. Altered glycosylation was shown to mediate cell migration in hypoxic tumor microenvironments, whereby tumor cells started to relocate due to the low oxygen concentration in the original tumor site (8). This makes it harder for therapeutics to eliminate rapidly-metastasizing tumors.
Immunotherapeutic antibody treatment is also negatively impacted by glycosylation. In particular, human T cells undergo aberrant glycosylation that disrupts their interaction with tumor cells. This allows the tumor to evade immune checkpoints (9).
Vaccines are becoming increasingly compelling in cancer prevention and treatment. There are already vaccines preventing cancer, namely the Human Papillomavirus (HPV) vaccine. Since HPV can cause cervical cancer in the long term, the HPV vaccine is commonly used as a precaution against cervical cancer. However, cancer vaccine development is still in its infancy.
These vaccines work by introducing tumor-associated carbohydrate antigens (TACAs—the collective name referring to the carbohydrate structures found on the glycoproteins in cancer cells) to the body to trigger an immune response from the body. However, these antigens have proved insufficient in causing immunogenicity. In other words, the body did not necessarily recognize these carbohydrates as threats, even if they are abundant in cancer.
One of the approaches to overcome this weakness is to develop multivalent vaccines comprising multiple TACAs. Introducing multiple TACAs to the body might elicit a stronger immune response. Glycan arrays have shown promising results by elaborately mapping out immune responses against a myriad of glycan epitopes. The pancreatic cancer vaccine GVAX was recently studied with glycan microarrays. Researchers found a large set of glycan-antigens, including N-linked glycans, O-linked glycans, and blood group antigens that prompted an immune response in pancreatic cancer patients. The findings of this study could guide vaccine manufacturers to improve vaccine efficacy (10).
Another approach is to couple TACAs with protein carriers to drive immune response. This stems from the idea that even though the body might tolerate a standalone carbohydrate antigen, it will recognize the whole structure (carbohydrate and protein) as a much bigger threat. Preliminary studies demonstrate this hypothesis through improvements in T-cell mediated immune response upon conjugating TACAs to carrier proteins, such as KLH, MUC1, and BSA (11).
With cutting-edge imaging and quantification methods, scientists can design and run more complex glycobiology experiments. The results of these experiments will continue to shed light on the complicated relationship between glycosylation and cancer. Targeting the deviations in glycosylation patterns will bring cancer research one step closer to conquering the current bottlenecks in inadequate treatments.
If you’re interested in learning more about glycobiology and how you can use it to unlock deeper insights in your research, be sure to check out our Glycobiology Resources page and stay tuned to the blog as well.
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