The Distinct Roles of Sialyltransferases in Cancer Biology and Onco-Immunology

Aberrant glycosylation is a key feature of malignant transformation. Hypersialylation, the enhanced expression of sialic acid-terminated glycoconjugates on the cell surface, has been linked to immune evasion and metastatic spread, eventually by interaction with sialoglycan-binding lectins, including Siglecs and selectins. The biosynthesis of tumor-associated sialoglycans involves sialyltransferases, which are differentially expressed in cancer cells. In this review article, we provide an overview of the twenty human sialyltransferases and their roles in cancer biology and immunity. A better understanding of the individual contribution of select sialyltransferases to the tumor sialome may lead to more personalized strategies for the treatment of cancer.

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The Coevolution of Placentation and Cancer

Annual Review of Animal Biosciences ◽

10.1146/annurev-animal-020420-031544 ◽

2021 ◽

Vol 10 (1) ◽

Author(s):

Günter P. Wagner ◽

Kshitiz ◽

Anasuya Dighe ◽

Andre Levchenko

Keyword(s):

Twentieth Century ◽

Cancer Cells ◽

Immune Evasion ◽

Online Publication ◽

Cancer Biology ◽

Annual Review ◽

Publication Date ◽

Trophoblast Cells ◽

Cancer Hallmarks ◽

Placental Invasion

Analogies between placentation, in particular the behavior of trophoblast cells, and cancer have been noted since the beginning of the twentieth century. To what degree these can be explained as a consequence of the evolution of placentation has been unclear. In this review, we conclude that many similarities between trophoblast and cancer cells are shared with other, phylogenetically older processes than placentation. The best candidates for cancer hallmarks that can be explained by the evolution of eutherian placenta are mechanisms of immune evasion. Another dimension of the maternal accommodation of the placenta with an impact on cancer malignancy is the evolution of endometrial invasibility. Species with lower degrees of placental invasion tend to have lower vulnerability to cancer malignancy. We finally identify several areas in which one could expect to see coevolutionary changes in placental and cancer biology but that, to our knowledge, have not been explored. Expected final online publication date for the Annual Review of Animal Biosciences, Volume 10 is February 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

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Sialic Acid Metabolic Engineering of Breast Cancer Cells Interferes with Adhesion and Migration

Molecules ◽

10.3390/molecules25112632 ◽

2020 ◽

Vol 25 (11) ◽

pp. 2632

Author(s):

Manimozhi Nagasundaram ◽

Rüdiger Horstkorte ◽

Vinayaga Srinivasan Gnanapragassam

Keyword(s):

Breast Cancer ◽

Cell Adhesion ◽

Sialic Acid ◽

Cancer Cells ◽

Cell Biology ◽

Cancer Biology ◽

Breast Cancer Cells ◽

Cancer Resistance ◽

And Migration ◽

Mcf 7

Breast cancer is the most frequent cancer diagnosed in women and the second most common cancer-causing death worldwide. The major problem around the management of breast cancer is its high heterogeneity and the development of therapeutic resistance. Therefore, understanding the fundamental breast cancer biology is crucial for better diagnosis and therapy. Protein sialylation is a key posttranslational modification of glycoproteins, which is also involved in tumor progression and metastasis. Increased expression of sialic acids (Sia) can interfere in receptor–ligand interactions and might protect tumor cells from the immune system. Furthermore, Sia content on the cell membrane plays a role in cancer resistance towards chemo- and radiation therapy. In this study, we glycoengineered MCF-7 breast cancer cells using a series of non-natural Sia precursors, which are prolonged in their acyl side chain. We observed a significant reduction in the natural Sia (N-Acetylneuraminic acid) expression after cultivation of MCF-7 cells with these Sia precursors. In addition, the expression of polySia, a unique glycosylation of the neural cell adhesion molecule NCAM, which interferes with cell adhesion, was decreased. We conclude that sialic acid engineering i) opens up novel opportunities to study the biological role of Sia in breast cancer and ii) provides a toolbox to examine the sialic acid-dependent complex cellular alterations in breast cancer cell biology.

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Leukocyte immunoglobulin-like receptor subfamily B: therapeutic targets in cancer

Antibody Therapeutics ◽

10.1093/abt/tbab002 ◽

2021 ◽

Vol 4 (1) ◽

pp. 16-33

Author(s):

Mi Deng ◽

Heyu Chen ◽

Xiaoye Liu ◽

Ryan Huang ◽

Yubo He ◽

...

Keyword(s):

Cancer Cells ◽

Immune Evasion ◽

Immune Cells ◽

Immune Checkpoint ◽

Cancer Biology ◽

Cancer Development ◽

Malignant Cells ◽

Dual Roles ◽

Anti Cancer ◽

Therapeutic Development

Abstract Inhibitory leukocyte immunoglobulin-like receptors (LILRBs 1–5) transduce signals via intracellular immunoreceptor tyrosine-based inhibitory motifs that recruit phosphatases to negatively regulate immune activation. The activation of LILRB signaling in immune cells may contribute to immune evasion. In addition, the expression and signaling of LILRBs in cancer cells especially in certain hematologic malignant cells directly support cancer development. Certain LILRBs thus have dual roles in cancer biology—as immune checkpoint molecules and tumor-supporting factors. Here, we review the expression, ligands, signaling, and functions of LILRBs, as well as therapeutic development targeting them. LILRBs may represent attractive targets for cancer treatment, and antagonizing LILRB signaling may prove to be effective anti-cancer strategies.

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Sialidase and Sialyltransferase Inhibitors: Targeting Pathogenicity and Disease

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.705133 ◽

2021 ◽

Vol 8 ◽

Author(s):

William H. D. Bowles ◽

Tracey M. Gloster

Keyword(s):

Sialic Acid ◽

Cell Surface ◽

Cancer Cells ◽

Cancer Progression ◽

Cell Function ◽

Development Of Resistance ◽

Anti Cancer ◽

Virus Progeny ◽

Recent Developments ◽

Specific Inhibitors

Sialidases (SAs) and sialyltransferases (STs), the enzymes responsible for removing and adding sialic acid to other glycans, play essential roles in viruses, bacteria, parasites, and humans. Sialic acid is often the terminal sugar on glycans protruding from the cell surface in humans and is an important component for recognition and cell function. Pathogens have evolved to exploit this and use sialic acid to either “cloak” themselves, ensuring they remain undetected, or as a mechanism to enable release of virus progeny. The development of inhibitors against SAs and STs therefore provides the opportunity to target a range of diseases. Inhibitors targeting viral, bacterial, or parasitic enzymes can directly target their pathogenicity in humans. Excellent examples of this can be found with the anti-influenza drugs Zanamivir (Relenza™, GlaxoSmithKline) and Oseltamivir (Tamiflu™, Roche and Gilead), which have been used in the clinic for over two decades. However, the development of resistance against these drugs means there is an ongoing need for novel potent and specific inhibitors. Humans possess 20 STs and four SAs that play essential roles in cellular function, but have also been implicated in cancer progression, as glycans on many cancer cells are found to be hyper-sialylated. Whilst much remains unknown about how STs function in relation to disease, it is clear that specific inhibitors of them can serve both as tools to gain a better understanding of their activity and form the basis for development of anti-cancer drugs. Here we review the recent developments in the design of SA and ST inhibitors against pathogens and humans.

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Cell surface sialic acid inhibits Cx43 gap junction functions in constructed Hela cancer cells involving in sialylated N-cadherin

Molecular and Cellular Biochemistry ◽

10.1007/s11010-010-0548-9 ◽

2010 ◽

Vol 344 (1-2) ◽

pp. 241-251 ◽

Cited By ~ 10

Author(s):

Jing Li ◽

Lei Cheng ◽

Li-juan Wang ◽

Hong-chun Liu ◽

Li Li ◽

...

Keyword(s):

Sialic Acid ◽

Cell Surface ◽

Gap Junction ◽

Cancer Cells

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Nutrient-deprived cancer cells preferentially use sialic acid to maintain cell surface glycosylation

Biomaterials ◽

10.1016/j.biomaterials.2015.08.020 ◽

2015 ◽

Vol 70 ◽

pp. 23-36 ◽

Cited By ~ 20

Author(s):

Haitham A. Badr ◽

Dina M.M. AlSadek ◽

Mohit P. Mathew ◽

Chen-Zhong Li ◽

Leyla B. Djansugurova ◽

...

Keyword(s):

Sialic Acid ◽

Cell Surface ◽

Cancer Cells

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Long Chain Non-Coding RNA HOTTIP Enhances IL-6 Expression to Promotes Immune Evasion of Ovarian Cancer Cells by Promoting the Expression of PD-L1 in Neutrophils

SSRN Electronic Journal ◽

10.2139/ssrn.3369763 ◽

2019 ◽

Author(s):

Anquan Shang ◽

Weiwei Wang ◽

Chenzheng Gu ◽

Chen Chen ◽

Bingjie Zeng ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Immune Evasion ◽

Ovarian Cancer Cells ◽

Non Coding Rna ◽

Long Chain

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Fas Ligand Enhances Apoptosis of Human Lung Cancer Cells Cotreated with RIG-I-like Receptor Agonist and Radiation

Current Cancer Drug Targets ◽

10.2174/1568009620666200115161717 ◽

2020 ◽

Vol 20 (5) ◽

pp. 372-381

Author(s):

Yoshiaki Sato ◽

Hironori Yoshino ◽

Eichi Tsuruga ◽

Ikuo Kashiwakura

Keyword(s):

Lung Cancer ◽

Cell Surface ◽

Cancer Cells ◽

Fas Ligand ◽

Human Lung ◽

Lung Cancer Cells ◽

Poly I:C ◽

Human Lung Cancer ◽

Human Lung Cancer Cells ◽

Induced Apoptosis

Background: Retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs) play key roles in the antiviral response, but recent works show that RLR activation elicits anticancer activity as well, including apoptosis. Previously, we demonstrated that the anticancer activity of the RLR agonist Poly(I:C)-HMW/LyoVec™ [Poly(I:C)-HMW] against human lung cancer cells was enhanced by cotreatment with ionizing radiation (IR). In addition, cotreatment with Poly(I:C)-HMW and IR induced apoptosis in a Fas-independent manner, and increased Fas expression on the cell surface. Objective: The current study investigated the resultant hypothesis that Fas ligand (FasL) may enhance apoptosis in lung cancer cells cotreated with Poly(I:C)-HMW+IR. Methods: FasL was added into culture medium at 24 h following cotreatment with Poly(I:C)- HMW+IR, after upregulation of cell surface Fas expression on human lung cancer cells A549 and H1299 have already been discussed. Results: FasL enhanced the apoptosis of A549 and H1299 cells treated with Poly(I:C)-HMW+IR. Similarly, IR alone - and not Poly(I:C)-HMW - resulted in the upregulation of cell surface Fas expression followed by a high response to FasL-induced apoptosis, thus suggesting that the high sensitivity of cells treated with Poly(I:C)-HMW+IR to FasL-induced apoptosis resulted from the cellular response to IR. Finally, knockdown of Fas by siRNA confirmed that the high response of treated cells to FasL-induced apoptosis is dependent on Fas expression. Conclusion: In summary, the present study indicates that upregulated Fas expression following cotreatment with Poly(I:C)-HMW and IR is responsive to FasL-induced apoptosis, and a combination of RLR agonist, IR, and FasL could be a potential promising cancer therapy.

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