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16 pages, 1113 KiB

Open AccessArticle

In Situ N-Glycosylation Signatures of Epithelial Ovarian Cancer Tissue as Defined by MALDI Mass Spectrometry Imaging

by Marta Grzeski, Eliane T. Taube, Elena I. Braicu, Jalid Sehouli, Véronique Blanchard and Oliver Klein

Cancers 2022, 14(4), 1021; https://doi.org/10.3390/cancers14041021 - 17 Feb 2022

Cited by 12 | Viewed by 2416

Abstract

The particularly high mortality of epithelial ovarian cancer (EOC) is in part linked to limited understanding of its molecular signatures. Although there are data available on in situ N-glycosylation in EOC tissue, previous studies focused primarily on neutral N-glycan species and, [...] Read more.

The particularly high mortality of epithelial ovarian cancer (EOC) is in part linked to limited understanding of its molecular signatures. Although there are data available on in situ N-glycosylation in EOC tissue, previous studies focused primarily on neutral N-glycan species and, hence, still little is known regarding EOC tissue-specific sialylation. In this proof-of-concept study, we implemented MALDI mass spectrometry imaging (MALDI-MSI) in combination with sialic acid derivatization to simultaneously investigate neutral and sialylated N-glycans in formalin-fixed paraffin-embedded tissue microarray specimens of less common EOC histotypes and non-malignant borderline ovarian tumor (BOT). The applied protocol allowed detecting over 50 m/z species, many of which showed differential tissue distribution. Most importantly, it could be demonstrated that α2,6- and α2,3-sialylated N-glycans are enriched in tissue regions corresponding to tumor and adjacent tumor-stroma, respectively. Interestingly, analogous N-glycosylation patterns were observed in tissue cores of BOT, suggesting that regio-specific N-glycan distribution might occur already in non-malignant ovarian pathologies. All in all, our data provide proof that the combination of MALDI-MSI and sialic acid derivatization is suitable for delineating regio-specific N-glycan distribution in EOC and BOT tissues and might serve as a promising strategy for future glycosylation-based biomarker discovery studies. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

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17 pages, 3102 KiB

Open AccessArticle

Polypeptide-GalNAc-Transferase-13 Shows Prognostic Impact in Breast Cancer

by Eugenia Fernandez, Luis Ubillos, Nabila Elgul, María Florencia Festari, Daniel Mazal, Otto Pritsch, Isabel Alonso, Eduardo Osinaga and Nora Berois

Cancers 2021, 13(22), 5616; https://doi.org/10.3390/cancers13225616 - 10 Nov 2021

Cited by 1 | Viewed by 2052

Abstract

Breast cancer is a public health concern and is currently the fifth cause of mortality worldwide. Identification of different biological subtypes is essential for clinical management; therefore, the role of pathologists is essential and useful tools for immunohistochemistry diagnosis are needed. Polypeptide-GalNAc-transferases are [...] Read more.

Breast cancer is a public health concern and is currently the fifth cause of mortality worldwide. Identification of different biological subtypes is essential for clinical management; therefore, the role of pathologists is essential and useful tools for immunohistochemistry diagnosis are needed. Polypeptide-GalNAc-transferases are emerging novel biomarkers related to cancer behavior and GalNAc-T13, correlated with aggressiveness in some tumors, is an interesting candidate. Few monoclonal antibodies reacting with native proteins, and not affected by fixation and paraffin embedding, have been reported. The aim of this work was to develop a useful monoclonal antibody anti-GalNAc-T13 and to assess its potential significance in breast cancer diagnosis. We evaluated 6 human breast cancer cell lines, 338 primary breast tumors and 48 metastatic lymph nodes and looked for clinical significance correlating GalNAc-T13 expression with patients’ clinical features and survival. We found high GalNAc-T13 expression in 43.8% of the cases and observed a significant higher expression in metastatic lymph nodes, correlating with worse overall survival. We hypothesized several possible molecular mechanisms and their implications. We conclude that GalNAc-T13 may be a novel biomarker in breast cancer, useful for routine pathological diagnosis. Elucidation of molecular mechanisms related to aggressiveness should contribute to understand the role of GalNAc-T13 in breast cancer biology. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

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Review

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27 pages, 1784 KiB

Open AccessReview

Advances in the Immunomodulatory Properties of Glycoantigens in Cancer

by Valeria da Costa and Teresa Freire

Cancers 2022, 14(8), 1854; https://doi.org/10.3390/cancers14081854 - 07 Apr 2022

Cited by 10 | Viewed by 3008

Abstract

Aberrant glycosylation in tumour progression is currently a topic of main interest. Tumour-associated carbohydrate antigens (TACAs) are expressed in a wide variety of epithelial cancers, being both a diagnostic tool and a potential treatment target, as they have impact on patient outcome and [...] Read more.

Aberrant glycosylation in tumour progression is currently a topic of main interest. Tumour-associated carbohydrate antigens (TACAs) are expressed in a wide variety of epithelial cancers, being both a diagnostic tool and a potential treatment target, as they have impact on patient outcome and disease progression. Glycans affect both tumour-cell biology properties as well as the antitumor immune response. It has been ascertained that TACAs affect cell migration, invasion and metastatic properties both when expressed by cancer cells or by their extracellular vesicles. On the other hand, tumour-associated glycans recognized by C-type lectin receptors in immune cells possess immunomodulatory properties which enable tumour growth and immune response evasion. Yet, much remains unknown, concerning mechanisms involved in deregulation of glycan synthesis and how this affects cell biology on a major level. This review summarises the main findings to date concerning how aberrant glycans influence tumour growth and immunity, their application in cancer treatment and spotlights of unanswered challenges remaining to be solved. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

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12 pages, 554 KiB

Open AccessReview

Role of GD3 Synthase ST8Sia I in Cancers

by Angelina Kasprowicz, Groux-Degroote Sophie, Chann Lagadec and Philippe Delannoy

Cancers 2022, 14(5), 1299; https://doi.org/10.3390/cancers14051299 - 03 Mar 2022

Cited by 11 | Viewed by 2857

Abstract

GD3 synthase controls the biosynthesis of complex gangliosides, bearing two or more sialic acid residues. Disialylated gangliosides GD3 and GD2 are tumor-associated carbohydrate antigens (TACA) in neuro–ectoderm-derived cancers, and are directly involved in cell malignant properties, i.e., migration, invasion, stemness, and epithelial–mesenchymal transition. [...] Read more.

GD3 synthase controls the biosynthesis of complex gangliosides, bearing two or more sialic acid residues. Disialylated gangliosides GD3 and GD2 are tumor-associated carbohydrate antigens (TACA) in neuro–ectoderm-derived cancers, and are directly involved in cell malignant properties, i.e., migration, invasion, stemness, and epithelial–mesenchymal transition. Since GD3 and GD2 levels are directly linked to GD3 synthase expression and activity, targeting GD3 synthase appears to be a promising strategy through which to interfere with ganglioside-associated malignant properties. We review here the current knowledge on GD3 synthase expression and regulation in cancers, and the consequences of complex ganglioside expression on cancer cell signaling and properties, highlighting the relationships between GD3 synthase expression and epithelial–mesenchymal transition and stemness. Different strategies were used to modulate GD3 synthase expression in cancer cells in vitro and in animal models, such as inhibitors or siRNA/lncRNA, which efficiently reduced cancer cell malignant properties and the proportion of GD2 positive cancer stem cells, which are associated with high metastatic properties, resistance to therapy, and cancer relapse. These data show the relevance of targeting GD3 synthase in association with conventional therapies, to decrease the number of cancer stem cells in tumors. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

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19 pages, 1406 KiB

Open AccessEditor’s ChoiceReview

Glycans as Targets for Drug Delivery in Cancer

by Francisca Diniz, Pedro Coelho, Henrique O. Duarte, Bruno Sarmento, Celso A. Reis and Joana Gomes

Cancers 2022, 14(4), 911; https://doi.org/10.3390/cancers14040911 - 12 Feb 2022

Cited by 20 | Viewed by 4576

Abstract

Innovative strategies have been proposed to increase drug delivery to the tumor site and avoid cytotoxicity, improving the therapeutic efficacy of well-established anti-cancer drugs. Alterations in normal glycosylation processes are frequently observed in cancer cells and the resulting cell surface aberrant glycans can [...] Read more.

Innovative strategies have been proposed to increase drug delivery to the tumor site and avoid cytotoxicity, improving the therapeutic efficacy of well-established anti-cancer drugs. Alterations in normal glycosylation processes are frequently observed in cancer cells and the resulting cell surface aberrant glycans can be used as direct molecular targets for drug delivery. In the present review, we address the development of strategies, such as monoclonal antibodies, antibody–drug conjugates and nanoparticles that specific and selectively target cancer-associated glycans in tumor cells. The use of nanoparticles for drug delivery encompasses novel applications in cancer therapy, including vaccines encapsulated in synthetic nanoparticles and specific nanoparticles that target glycoproteins or glycan-binding proteins. Here, we highlight their potential to enhance targeting approaches and to optimize the delivery of clinically approved drugs to the tumor microenvironment, paving the way for improved personalized treatment approaches with major potential importance for the pharmaceutical and clinical sectors. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

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42 pages, 5014 KiB

Open AccessEditor’s ChoiceReview

Targeting Tumor Glycans for Cancer Therapy: Successes, Limitations, and Perspectives

by Nora Berois, Alvaro Pittini and Eduardo Osinaga

Cancers 2022, 14(3), 645; https://doi.org/10.3390/cancers14030645 - 27 Jan 2022

Cited by 41 | Viewed by 8482

Abstract

Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to [...] Read more.

Aberrant glycosylation is a hallmark of cancer and can lead to changes that influence tumor behavior. Glycans can serve as a source of novel clinical biomarker developments, providing a set of specific targets for therapeutic intervention. Different mechanisms of aberrant glycosylation lead to the formation of tumor-associated carbohydrate antigens (TACAs) suitable for selective cancer-targeting therapy. The best characterized TACAs are truncated O-glycans (Tn, TF, and sialyl-Tn antigens), gangliosides (GD2, GD3, GM2, GM3, fucosyl-GM1), globo-serie glycans (Globo-H, SSEA-3, SSEA-4), Lewis antigens, and polysialic acid. In this review, we analyze strategies for cancer immunotherapy targeting TACAs, including different antibody developments, the production of vaccines, and the generation of CAR-T cells. Some approaches have been approved for clinical use, such as anti-GD2 antibodies. Moreover, in terms of the antitumor mechanisms against different TACAs, we show results of selected clinical trials, considering the horizons that have opened up as a result of recent developments in technologies used for cancer control. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

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12 pages, 685 KiB

Open AccessReview

Expression and Impact of C1GalT1 in Cancer Development and Progression

by Yangu Wan and Lu-Gang Yu

Cancers 2021, 13(24), 6305; https://doi.org/10.3390/cancers13246305 - 15 Dec 2021

Cited by 9 | Viewed by 3450

Abstract

C1GalT1 (T-synthase) is one of the key glycosyltransferases in the biosynthesis of O-linked mucin-type glycans of glycoproteins. It controls the formation of Core-1 disaccharide Galβ1,3GalNAcα- (Thomsen–Friedenreich oncofetal antigen, T or TF antigen) and Core-1-associated carbohydrate structures. Recent studies have shown that C1GalT1 is [...] Read more.

C1GalT1 (T-synthase) is one of the key glycosyltransferases in the biosynthesis of O-linked mucin-type glycans of glycoproteins. It controls the formation of Core-1 disaccharide Galβ1,3GalNAcα- (Thomsen–Friedenreich oncofetal antigen, T or TF antigen) and Core-1-associated carbohydrate structures. Recent studies have shown that C1GalT1 is overexpressed in many cancers of epithelial origin including colon, breast, gastric, head and neck, pancreatic, esophageal, prostate, and hepatocellular cancer. Overexpression of C1GalT1 is often seen to also be associated with poorer prognosis and poorer patient survival. Change of C1GalT1 expression causes glycosylation changes of many cell membrane glycoproteins including mucin proteins, growth factor receptors, adhesion molecules, and death receptors. This leads to alteration of the interactions of these cell surface molecules with their binding ligands, resulting in changes of cancer cell activity and behaviors. This review summarizes our current understanding of the expression of C1GalT1 in various cancers and discusses the impact of C1GalT change on cancer cell activities in cancer development and progression. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

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16 pages, 1460 KiB

Open AccessReview

The Cancer-Associated Antigens Sialyl Lewis^a/x and Sd^a: Two Opposite Faces of Terminal Glycosylation

by Fabio Dall’Olio, Michela Pucci and Nadia Malagolini

Cancers 2021, 13(21), 5273; https://doi.org/10.3390/cancers13215273 - 21 Oct 2021

Cited by 13 | Viewed by 2962

Abstract

Terminal carbohydrate structures are particularly relevant in oncology because they can serve as cancer markers and alter the phenotype of cancer cells. The Sd^a antigen and the sialyl Lewis^x and sialyl Lewis^a (sLe^x and sLe^a) antigens are [...] Read more.

Terminal carbohydrate structures are particularly relevant in oncology because they can serve as cancer markers and alter the phenotype of cancer cells. The Sd^a antigen and the sialyl Lewis^x and sialyl Lewis^a (sLe^x and sLe^a) antigens are terminal structures whose biosynthesis is mutually exclusive. In this review, we describe the main features of the Sd^a antigen in cancer and its relationship with sLe^x/a antigens. Information was obtained from an extensive literature search and from The Cancer Genome Atlas (TCGA) public database. The Sd^a biosynthetic enzyme B4GALNT2 undergoes downregulation in colorectal (CRC) and stomach cancer, while it is ectopically expressed by a minority of breast cancer (BRCA) patients. High expression of B4GALNT2 is associated with better prognosis and a less malignant gene expression profile in CRC, while the opposite occurs in BRCA. The regulation of B4GALNT2 expression in CRC is multifactorial, involving gene methylation and miRNA expression. Forced expression of B4GALNT2 inhibited sLe^a/sLe^x and reduced malignancy and stemness in cells constitutively expressing sLe^x/a antigens. However, consistent effects were observed upon B4GALNT2 forced expression and in cells not expressing sLe^x/a antigens. Thus, B4GALNT2 and the Sd^a antigen exert a tumor-restraining activity in CRC and probably other gastrointestinal cancers, independently of sLe^x/a antigens. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

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29 pages, 484 KiB

Open AccessReview

Aberrant Sialylation in Cancer: Biomarker and Potential Target for Therapeutic Intervention?

by Silvia Pietrobono and Barbara Stecca

Cancers 2021, 13(9), 2014; https://doi.org/10.3390/cancers13092014 - 22 Apr 2021

Cited by 59 | Viewed by 4544

Abstract

Sialylation is an integral part of cellular function, governing many biological processes including cellular recognition, adhesion, molecular trafficking, signal transduction and endocytosis. Sialylation is controlled by the levels and the activities of sialyltransferases on glycoproteins and lipids. Altered gene expression of these enzymes [...] Read more.

Sialylation is an integral part of cellular function, governing many biological processes including cellular recognition, adhesion, molecular trafficking, signal transduction and endocytosis. Sialylation is controlled by the levels and the activities of sialyltransferases on glycoproteins and lipids. Altered gene expression of these enzymes in cancer yields to cancer-specific alterations of glycoprotein sialylation. Mounting evidence indicate that hypersialylation is closely associated with cancer progression and metastatic spread, and can be of prognostic significance in human cancer. Aberrant sialylation is not only a result of cancer, but also a driver of malignant phenotype, directly impacting key processes such as tumor cell dissociation and invasion, cell-cell and cell-matrix interactions, angiogenesis, resistance to apoptosis, and evasion of immune destruction. In this review we provide insights on the impact of sialylation in tumor progression, and outline the possible application of sialyltransferases as cancer biomarkers. We also summarize the most promising findings on the development of sialyltransferase inhibitors as potential anti-cancer treatments. Full article

(This article belongs to the Special Issue Advances in Tumor Glycans)

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