scholarly journals Hypersialylation in Cancer: Modulation of Inflammation and Therapeutic Opportunities

Cancers ◽  
2018 ◽  
Vol 10 (6) ◽  
pp. 207 ◽  
Author(s):  
Emily Rodrigues ◽  
Matthew Macauley
Keyword(s):  
Sialic Acid ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Immune Cell ◽  
Cell Types ◽  
Functional Roles ◽  
Cell Responses ◽  
Disease Prognosis ◽  
Sialic Acid Binding ◽  
Cancer Types

Cell surface glycosylation is dynamic and often changes in response to cellular differentiation under physiological or pathophysiological conditions. Altered glycosylation on cancers cells is gaining attention due its wide-spread occurrence across a variety of cancer types and recent studies that have documented functional roles for aberrant glycosylation in driving cancer progression at various stages. One change in glycosylation that can correlate with cancer stage and disease prognosis is hypersialylation. Increased levels of sialic acid are pervasive in cancer and a growing body of evidence demonstrates how hypersialylation is advantageous to cancer cells, particularly from the perspective of modulating immune cell responses. Sialic acid-binding receptors, such as Siglecs and Selectins, are well-positioned to be exploited by cancer hypersialylation. Evidence is also mounting that Siglecs modulate key immune cell types in the tumor microenvironment, particularly those responsible for maintaining the appropriate inflammatory environment. From these studies have come new and innovative ways to block the effects of hypersialylation by directly reducing sialic acid on cancer cells or blocking interactions between sialic acid and Siglecs or Selectins. Here we review recent works examining how cancer cells become hypersialylated, how hypersialylation benefits cancer cells and tumors, and proposed therapies to abrogate hypersialylation of cancer.

Siglecs as Immune Cell Checkpoints in Disease

2020 ◽  
Vol 38 (1) ◽  
pp. 365-395 ◽  
Author(s):  
Shiteng Duan ◽  
James C. Paulson
Keyword(s):  
Immune System ◽  
Sialic Acid ◽  
Cell Signaling ◽  
Blood Cells ◽  
Immune Cell ◽  
White Blood Cells ◽  
Therapeutic Interventions ◽  
Cell Type ◽  
Cell Responses ◽  
Sialic Acid Binding

Sialic acid–binding immunoglobulin-type lectins (Siglecs) are expressed on the majority of white blood cells of the immune system and play critical roles in immune cell signaling. Through recognition of sialic acid–containing glycans as ligands, they help the immune system distinguish between self and nonself. Because of their restricted cell type expression and roles as checkpoints in immune cell responses in human diseases such as cancer, asthma, allergy, neurodegeneration, and autoimmune diseases they have gained attention as targets for therapeutic interventions. In this review we describe the Siglec family, its roles in regulation of immune cell signaling, current efforts to define its roles in disease processes, and approaches to target Siglecs for treatment of human disease.

scholarly journals Probing the binding specificities of human Siglecs by cell-based glycan arrays

2021 ◽  
Vol 118 (17) ◽  
pp. e2026102118
Author(s):  
Christian Büll ◽  
Rebecca Nason ◽  
Lingbo Sun ◽  
Julie Van Coillie ◽  
Daniel Madriz Sørensen ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Cell Surface ◽  
Immune Cell ◽  
Late Onset ◽  
Cell Types ◽  
Hek293 Cells ◽  
Cell Functions ◽  
Binding Epitope ◽  
Sialic Acid Binding ◽  
Complex Glycan

Siglecs are a family of sialic acid–binding receptors expressed by cells of the immune system and a few other cell types capable of modulating immune cell functions upon recognition of sialoglycan ligands. While human Siglecs primarily bind to sialic acid residues on diverse types of glycoproteins and glycolipids that constitute the sialome, their fine binding specificities for elaborated complex glycan structures and the contribution of the glycoconjugate and protein context for recognition of sialoglycans at the cell surface are not fully elucidated. Here, we generated a library of isogenic human HEK293 cells with combinatorial loss/gain of individual sialyltransferase genes and the introduction of sulfotransferases for display of the human sialome and to dissect Siglec interactions in the natural context of glycoconjugates at the cell surface. We found that Siglec-4/7/15 all have distinct binding preferences for sialylated GalNAc-type O-glycans but exhibit selectivity for patterns of O-glycans as presented on distinct protein sequences. We discovered that the sulfotransferase CHST1 drives sialoglycan binding of Siglec-3/8/7/15 and that sulfation can impact the preferences for binding to O-glycan patterns. In particular, the branched Neu5Acα2–3(6-O-sulfo)Galβ1–4GlcNAc (6′-Su-SLacNAc) epitope was discovered as the binding epitope for Siglec-3 (CD33) implicated in late-onset Alzheimer’s disease. The cell-based display of the human sialome provides a versatile discovery platform that enables dissection of the genetic and biosynthetic basis for the Siglec glycan interactome and other sialic acid–binding proteins.

484 Bioturing browser: interactively explore public single cell sequencing data

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A520-A520
Author(s):  
Son Pham ◽  
Tri Le ◽  
Tan Phan ◽  
Minh Pham ◽  
Huy Nguyen ◽  
...  
Keyword(s):  
Single Cell ◽  
Immune Cell ◽  
Expression Profiles ◽  
Meta Analysis ◽  
Cell Types ◽  
Sequencing Data ◽  
Single Cell Sequencing ◽  
Data Formats ◽  
Cancer Types ◽  
Cell Data

BackgroundSingle-cell sequencing technology has opened an unprecedented ability to interrogate cancer. It reveals significant insights into the intratumoral heterogeneity, metastasis, therapeutic resistance, which facilitates target discovery and validation in cancer treatment. With rapid advancements in throughput and strategies, a particular immuno-oncology study can produce multi-omics profiles for several thousands of individual cells. This overflow of single-cell data poses formidable challenges, including standardizing data formats across studies, performing reanalysis for individual datasets and meta-analysis.MethodsN/AResultsWe present BioTuring Browser, an interactive platform for accessing and reanalyzing published single-cell omics data. The platform is currently hosting a curated database of more than 10 million cells from 247 projects, covering more than 120 immune cell types and subtypes, and 15 different cancer types. All data are processed and annotated with standardized labels of cell types, diseases, therapeutic responses, etc. to be instantly accessed and explored in a uniform visualization and analytics interface. Based on this massive curated database, BioTuring Browser supports searching similar expression profiles, querying a target across datasets and automatic cell type annotation. The platform supports single-cell RNA-seq, CITE-seq and TCR-seq data. BioTuring Browser is now available for download at www.bioturing.com.ConclusionsN/A

Molecular characterization of pancreatic cancers as seen in the SLUG gene revealing cancer progression.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 433-433 ◽  
Author(s):  
Natsuko Kawanishi ◽  
Yasmine Baca ◽  
Joanne Xiu ◽  
Hiroyuki Arai ◽  
Jingyan Wang ◽  
...  
Keyword(s):  
Cancer Progression ◽  
Immune Cell ◽  
Pancreatic Tumors ◽  
Therapeutic Effects ◽  
Expression Levels ◽  
Functional Roles ◽  
Genome Medicine ◽  
Whole Transcriptome Sequencing ◽  
Slug Expression ◽  
Tumor Mutational Burden

433 Background: The SLUG gene plays an important role in EMT by repressing E-cadherin and promotes metastasis. Previous data suggest that overexpressed SLUG gene in pancreatic cancer (PC) showing a high frequency of metastasis and poor prognosis. As SLUG contribution to characteristics or metastatic features remains elusive, we clarified its functional roles in PC progression. Methods: A total of 2958 pancreatic tumors were analyzed using Whole Transcriptome sequencing, NextGen Sequencing (NGS) (NextSeq, 592 gene panel) or Whole Exome Sequencing (WES) (NovaSeq) (Caris Life Sciences, Phoenix, AZ). Microsatellite instability (MSI) status was tested by fragment analysis, immunohistochemistry (IHC) and NGS. PD-L1 expression was tested by IHC. Tumor mutational burden (TMB) was measured by counting all mutations found per tumor (a universal cutoff point of ≧10 mutations per MB). Immune cell fraction was calculated by quanTIseq (Finotello 2019, Genome Medicine). Results: A total of 1274 primary and 1684 metastatic pancreatic tumors were included for this study. They were divided equally into four classes in each group, according to their SLUG expression levels. Tumors in the highest quartile of SLUG expression (QH) showed significantly higher frequency in peritoneal-retroperitoneal-omentum metastasis (15.0%) compared to the lowest quartile (QL) (4.8%) (p = .0001). Similar trends were seen in the abdomen (6% vs 1%, p = .001) and bone (2.8% vs 0.0%, p = .005). However, liver (55.0% in QH vs 63.1% in QL) and lung (2.8% vs 14.1%) metastasis occurred most frequently in QL and the least frequently in QH (p = .0197 and p = .001, respectively). This data indicated that tumors with high SLUG gene expression levels tend to lead to disseminated metastasis, and with low expression levels, they tend to spread intravascularly. We detected significant differences among genetic mutations in ATM (5.7% in QL vs 1.8% in QH, p < 0.001) and APC (2.9% vs 0.5%, p < 0.001), and Wnt signaling expressions were higher in QL (4.6%) than QH (0.7%) (p < 0.001). Binary TMB-H and MSI-H tumors had higher frequencies in QL (2.7% and 2.1%) compared to QH (0.3% and 0.1%) (p < 0.001 in both). Contrastingly, PD-L1 expression levels were higher in QH (23.4%) compared to QL (11.0%) (p < 0.001) and had a linear relationship with the expression levels. The median values of the population of B cells, M1 and M2 macrophages were significantly higher in QH compared to QL, but those of myeloid dendritic and CD8+T cells conversely decrease as the SLUG expression increases. Conclusions: Our data indicated the SLUG expression level could determine the tumor characteristics in progression, especially the pattern of metastasis in PC, and it could possibly predict the prognosis and/or therapeutic effects. We also showed immune oncologic markers which have some relationships with SLUG expressions. Further investigation is warranted to better understand SLUG gene functions.

scholarly journals Crosstalk between cancer cells and blood endothelial and lymphatic endothelial cells in tumour and organ microenvironment

2015 ◽  
Vol 17 ◽  
Author(s):  
Esak Lee ◽  
Niranjan B. Pandey ◽  
Aleksander S. Popel
Keyword(s):  
Endothelial Cells ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Tumour Growth ◽  
Tumour Progression ◽  
Lymphatic Vessels ◽  
Cell Types ◽  
Malignant Cell ◽  
Lymphatic Endothelial Cells ◽  
Tumour Blood

Tumour and organ microenvironments are crucial for cancer progression and metastasis. Crosstalk between multiple non-malignant cell types in the microenvironments and cancer cells promotes tumour growth and metastasis. Blood and lymphatic endothelial cells (BEC and LEC) are two of the components in the microenvironments. Tumour blood vessels (BV), comprising BEC, serve as conduits for blood supply into the tumour, and are important for tumour growth as well as haematogenous tumour dissemination. Lymphatic vessels (LV), comprising LEC, which are relatively leaky compared with BV, are essential for lymphogenous tumour dissemination. In addition to describing the conventional roles of the BV and LV, we also discuss newly emerging roles of these endothelial cells: their crosstalk with cancer cells via molecules secreted by the BEC and LEC (also called angiocrine and lymphangiocrine factors). This review suggests that BEC and LEC in various microenvironments can be orchestrators of tumour progression and proposes new mechanism-based strategies to discover new therapies to supplement conventional anti-angiogenic and anti-lymphangiogenic therapies.

scholarly journals Toll-Like Receptor-Based Strategies for Cancer Immunotherapy

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Saghar Pahlavanneshan ◽  
Ali Sayadmanesh ◽  
Hamidreza Ebrahimiyan ◽  
Mohsen Basiri
Keyword(s):  
Cancer Immunotherapy ◽  
Immune Cells ◽  
Immune Cell ◽  
Cell Types ◽  
Genetically Engineered ◽  
Current Status ◽  
Tlr Signaling ◽  
Functional Roles ◽  
Immunotherapy Of Cancer ◽  
Signaling Components

Toll-like receptors (TLRs) are expressed and play multiple functional roles in a variety of immune cell types involved in tumor immunity. There are plenty of data on the pharmacological targeting of TLR signaling using agonist molecules that boost the antitumor immune response. A recent body of research has also demonstrated promising strategies for improving the cell-based immunotherapy methods by inducing TLR signaling. These strategies include systemic administration of TLR antagonist along with immune cell transfer and also genetic engineering of the immune cells using TLR signaling components to improve the function of genetically engineered immune cells such as chimeric antigen receptor-modified T cells. Here, we explore the current status of the cancer immunotherapy approaches based on manipulation of TLR signaling to provide a perspective of the underlying rationales and potential clinical applications. Altogether, reviewed publications suggest that TLRs make a potential target for the immunotherapy of cancer.

scholarly journals Characterizing Intercellular Communication of Pan-Cancer Reveals SPP1+ Tumor-Associated Macrophage Expanded in Hypoxia and Promoting Cancer Malignancy Through Single-Cell RNA-Seq Data

2021 ◽  
Vol 9 ◽  
Author(s):  
Jinfen Wei ◽  
Zixi Chen ◽  
Meiling Hu ◽  
Ziqing He ◽  
Dawei Jiang ◽  
...  
Keyword(s):  
Single Cell ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Single Cells ◽  
Matrix Remodeling ◽  
Rna Seq ◽  
Mesenchymal Transition ◽  
Tumor Associated Macrophage ◽  
Cancer Types

Hypoxia is a characteristic of tumor microenvironment (TME) and is a major contributor to tumor progression. Yet, subtype identification of tumor-associated non-malignant cells at single-cell resolution and how they influence cancer progression under hypoxia TME remain largely unexplored. Here, we used RNA-seq data of 424,194 single cells from 108 patients to identify the subtypes of cancer cells, stromal cells, and immune cells; to evaluate their hypoxia score; and also to uncover potential interaction signals between these cells in vivo across six cancer types. We identified SPP1+ tumor-associated macrophage (TAM) subpopulation potentially enhanced epithelial–mesenchymal transition (EMT) by interaction with cancer cells through paracrine pattern. We prioritized SPP1 as a TAM-secreted factor to act on cancer cells and found a significant enhanced migration phenotype and invasion ability in A549 lung cancer cells induced by recombinant protein SPP1. Besides, prognostic analysis indicated that a higher expression of SPP1 was found to be related to worse clinical outcome in six cancer types. SPP1 expression was higher in hypoxia-high macrophages based on single-cell data, which was further validated by an in vitro experiment that SPP1 was upregulated in macrophages under hypoxia-cultured compared with normoxic conditions. Additionally, a differential analysis demonstrated that hypoxia potentially influences extracellular matrix remodeling, glycolysis, and interleukin-10 signal activation in various cancer types. Our work illuminates the clearer underlying mechanism in the intricate interaction between different cell subtypes within hypoxia TME and proposes the guidelines for the development of therapeutic targets specifically for patients with high proportion of SPP1+ TAMs in hypoxic lesions.

scholarly journals MBNL1 alternative splicing isoforms play opposing roles in cancer

2018 ◽  
Vol 1 (5) ◽  
pp. e201800157 ◽  
Author(s):  
Tommaso Tabaglio ◽  
Diana HP Low ◽  
Winnie Koon Lay Teo ◽  
Pierre Alexis Goy ◽  
Piotr Cywoniuk ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Gene Function ◽  
Dominant Negative ◽  
Individual Gene ◽  
Cancer Types ◽  
Splicing Isoforms ◽  
Isoform Switching ◽  
And Migration

The extent of and the oncogenic role played by alternative splicing (AS) in cancer are well documented. Nonetheless, only few studies have attempted to dissect individual gene function at an isoform level. Here, we focus on the AS of splicing factors during prostate cancer progression, as these factors are known to undergo extensive AS and have the potential to affect hundreds of downstream genes. We identified exon 7 (ex7) in the MBNL1 (Muscleblind-like 1) transcript as being the most differentially included exon in cancer, both in cell lines and in patients' samples. In contrast, MBNL1 overall expression was down-regulated, consistently with its described role as a tumor suppressor. This observation holds true in the majority of cancer types analyzed. We first identified components associated to the U2 splicing complex (SF3B1, SF3A1, and PHF5A) as required for efficient ex7 inclusion and we confirmed that this exon is fundamental for MBNL1 protein homodimerization. We next used splice-switching antisense oligonucleotides (AONs) or siRNAs to compare the effect of MBNL1 splicing isoform switching with knockdown. We report that whereas the absence of MBNL1 is tolerated in cancer cells, the expression of isoforms lacking ex7 (MBNL1 Δex7) induces DNA damage and inhibits cell viability and migration, acting as dominant negative proteins. Our data demonstrate the importance of studying gene function at the level of alternative spliced isoforms and support our conclusion that MBNL1 Δex7 proteins are antisurvival factors with a defined tumor suppressive role that cancer cells tend to down-regulate in favor of MBNL +ex7 isoforms.

scholarly journals Decidual glycodelin-A polarizes human monocytes into a decidual macrophage-like phenotype through Siglec-7

2020 ◽  
Vol 133 (14) ◽  
pp. jcs244400 ◽  
Author(s):  
Madhavi Vijayan ◽  
Cheuk-Lun Lee ◽  
Vera H. H. Wong ◽  
Xia Wang ◽  
Kungfeng Bai ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Immune Cell ◽  
Fetal Loss ◽  
Cell Types ◽  
Dependent Manner ◽  
Human Monocytes ◽  
Placental Development ◽  
Cell Functions ◽  
Surface Marker Expression ◽  
Glycodelin A

ABSTRACTDecidual macrophages constitute 20–30% of the total leukocytes in the uterus of pregnant women, regulating the maternal immune tolerance and placenta development. Abnormal number or activities of decidual macrophages (dMs) are associated with fetal loss and pregnancy complications, such as preeclampsia. Monocytes differentiate into dMs in a decidua-specific microenvironment. Despite their important roles in pregnancy, the exact factors that regulate the differentiation into dMs remain unclear. Glycodelin-A (PAEP, hereafter referred to as GdA) is a glycoprotein that is abundantly present in the decidua, and plays an important role in fetomaternal defense and placental development. It modulates the differentiation and activity of several immune cell types residing in the decidua. In this study, we demonstrated that GdA induces the differentiation of human monocytes into dM-like phenotypes in terms of transcriptome, cell surface marker expression, secretome, and regulation of trophoblast and endothelial cell functions. We found that Sialic acid-binding Ig-like lectin 7 (Siglec-7) mediates the binding and biological actions of GdA in a sialic acid-dependent manner. We, therefore, suggest that GdA, induces the polarization of monocytes into dMs to regulate fetomaternal tolerance and placental development.

scholarly journals The Number and Position of Orai3 Units within Heteromeric Store-Operated Ca2+ Channels Alter the Pharmacology of ICRAC

2020 ◽  
Vol 21 (7) ◽  
pp. 2458 ◽  
Author(s):  
Sven Kappel ◽  
Tatiana Kilch ◽  
Roland Baur ◽  
Martin Lochner ◽  
Christine Peinelt
Keyword(s):  
Prostate Cancer ◽  
Cancer Cells ◽  
Immune Cell ◽  
Outward Current ◽  
Cell Types ◽  
Prostate Cancer Cells ◽  
Channel Change ◽  
Outward Currents ◽  
Patch Clamp Electrophysiology ◽  
Ca2 Channels

Store-operated heteromeric Orai1/Orai3 channels have been discussed in the context of aging, cancer, and immune cell differentiation. In contrast to homomeric Orai1 channels, they exhibit a different pharmacology upon application of reactive oxygen species (ROS) or 2-aminoethoxydiphenyl borate (2-APB) in various cell types. In endogenous cells, subunit composition and arrangement may vary and cannot be defined precisely. In this study, we used patch-clamp electrophysiology to investigate the 2-APB profile of store-operated and store-independent homomeric Orai1 and heteromeric Orai1/Orai3 concatenated channels with defined subunit compositions. As has been shown previous, one or more Orai3 subunit(s) within the channel result(s) in decreased Ca2+ release activated Ca2+ current (ICRAC). Upon application of 50 µM 2-APB, channels with two or more Orai3 subunits exhibit large outward currents and can be activated by 2-APB independent from storedepletion and/or the presence of STIM1. The number and position of Orai3 subunits within the heteromeric store-operated channel change ion conductivity of 2-APB-activated outward current. Compared to homomeric Orai1 channels, one Orai3 subunit within the channel does not alter 2-APB pharmacology. None of the concatenated channel constructs were able to exactly simulate the complex 2-APB pharmacology observed in prostate cancer cells. However, 2-APB profiles of prostate cancer cells are similar to those of concatenated channels with Orai3 subunit(s). Considering the presented and previous results, this indicates that distinct subtypes of heteromeric SOCE channels may be selectively activated or blocked. In the future, targeting distinct heteromeric SOCE channel subtypes may be the key to tailored SOCE-based therapies.

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