Glycosylation in the Era of Cancer-Targeted Therapy: Where Are We Heading?

Mereiter, Stefan; Balmaña, Meritxell; Campos, Diana; Gomes, Joana; Reis, Celso A.

doi:10.1016/j.ccell.2019.06.006

Cited by 374 publications

(339 citation statements)

References 79 publications

(121 reference statements)

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“…Recent evidence indicates that alterations in the glycosylation process are linked to tumor development 8 . Generally, shorter/truncated glycans at the surface of cancer cells are related with a poor prognosis in some cancer types, as previously described for sialyl Tn (STn) 34 . These phenomena are frequently associated with an incomplete glycans synthesis during cell glycosylation, in comparison with the cellular pathway under healthy conditions.…”

Section: Discussionmentioning

confidence: 76%

iLoF: An intelligent Lab on Fiber Approach for Human Cancer Single-Cell Type Identification

Paiva,

Jorge,

Ribeiro

et al. 2020

Sci Rep

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With the advent of personalized medicine, there is a movement to develop "smaller" and "smarter" microdevices that are able to distinguish similar cancer subtypes. Tumor cells display major differences when compared to their natural counterparts, due to alterations in fundamental cellular processes such as glycosylation. Glycans are involved in tumor cell biology and they have been considered to be suitable cancer biomarkers. Thus, more selective cancer screening assays can be developed through the detection of specific altered glycans on the surface of circulating cancer cells. Currently, this is only possible through time-consuming assays. In this work, we propose the "intelligent" Lab on Fiber (iLof) device, that has a high-resolution, and which is a fast and portable method for tumor single-cell type identification and isolation. We apply an Artificial Intelligence approach to the back-scattered signal arising from a trapped cell by a micro-lensed optical fiber. As a proof of concept, we show that iLof is able to discriminate two human cancer cell models sharing the same genetic background but displaying a different surface glycosylation profile with an accuracy above 90% and a speed rate of 2.3 seconds. We envision the incorporation of the iLoF in an easy-to-operate microchip for cancer identification, which would allow further biological characterization of the captured circulating live cells.Recent research trends on healthcare point out to the movement to develop "smart" micro-tools to allow better personalized diagnostic and therapeutic approaches 1-3 . Considering that current medicine and biotechnology attempts are converging to novel methodologies at the micro (e.g., cancer cells detection) and nano scales (e.g., cancer-related extracellular vesicles detection), an effort towards the development of these "intelligent" microdevices with multifunctionalities is required 3 . In this regard, optical fiber tools -for example, Optical Fiber Tweezers (OFT) 1,4,5 -have emerged as suitable candidates thanks to their flexibility, small size and chemical inertness, which contributes to the advent of a novel concept of "Lab on Fiber" (LoF) devices 2 . The fruitful application of these optical-based microdevices in cancer screening has been envisioned as straightforward 1,2 . However, the high degree of heterogeneity among cancer subtypes must be taken into consideration 6,7 . This heterogeneity is mainly due to both cellular and microenvironmental factors, such as alterations in cellular glycosylation 8 . In particular, the selective detection of specific cancer-associated glycoforms expressed at the surface of circulating cancer cells could increase the specificity of cancer biomarker assays and therapeutic approaches 8-10 . In fact, tumor heterogeneity is considered to be a major barrier to an effective cancer diagnosis and treatment 6,7 . Recent evidence has shown that glycans can determine the acquisition of certain cellular features controlling tumor growth and progression 8,11,12 . For example, shorter trun...

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Section: Discussionmentioning

confidence: 76%

iLoF: An intelligent Lab on Fiber Approach for Human Cancer Single-Cell Type Identification

Paiva,

Jorge,

Ribeiro

et al. 2020

Sci Rep

Self Cite

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“…Distinct modifications in tumors include truncated N-and O-glycans, increased N-glycan branching and changes in sialylation. Ultimately, these changes affect fundamental processes of cancer biology like cell adhesion, signaling, tumor progression and metastasis 23 , making glycans attractive targets for therapeutic intervention. Recent technological advances and the prospective use of glycan-based biomarkers for patient stratification have led it to be estimated that the global glycobiology market size to grow 14.7% in the next years, with an estimated market value of USD 822.5 million in 2018.…”

Section: Discussionmentioning

confidence: 99%

“…However, little is known about the glycosylation profile of SFs, and whether this varies in health and disease, despite the glycome is being critical for dictating interactions with galectins and other carbohydrate binding proteins, and the fact that altered glycosylation is a hallmark of chronic inflammatory conditions. To illustrate this, cytokines induce aberrant glycome changes in cancer that perpetuate local inflammation via control of cell adhesion, migration and signal transduction [21][22][23] ; mechanisms that are also associated to the pathogenicity of SFs in RA and are responsible of migration to cartilage-containing areas prior to tissue damage. Furthermore, the carbohydrate binding protein galectin-3 is up-regulated in RA 24 and galectin-3 -/mice show reduced pathology in experimental arthritis 20 .…”

Section: Introductionmentioning

confidence: 99%

Loss of α2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in Rheumatoid Arthritis

Wang

Khan

Antonopoulos

et al. 2020

Preprint

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In healthy joints, synovial fibroblasts (SFs) provide the microenvironment required to mediate homeostasis but are recognized to adopt a pathological role in rheumatoid arthritis (RA), promoting the infiltration and activation of immune cells to perpetuate local inflammation, pain and joint destruction.Carbohydrates (glycans) attached to cell surface proteins are fundamental regulators of cellular interactions between stromal and immune cells, but very little is known about the glycome of SFs or how glycosylation regulates their biology. Here we fill these gaps in our understanding of stromal guided pathophysiology by systematically mapping glycosylation pathways in healthy and arthritic SFs. We used a combination of transcriptomic and glycomic analysis to show that transformation of fibroblasts into pro-inflammatory cells in RA is associated with profound glycan remodeling, a process that involves reduction of a2-6 terminal sialylation that is mostly mediated by TNFa-dependent inhibition of the glycosyltransferase ST6Gal1. We also show that sialylation of SFs correlates with distinct disease stages and SFs functional subsets in both human RA and models of mouse arthritis. We propose that pro-inflammatory cytokines in the joint remodel the SF-glycome, transforming a regulatory tissue intended to preserve local homeostasis, into an under-sialylated and highly pro-inflammatory microenvironment that contributes to an amplificatory inflammatory network that perpetuates chronic inflammation. These results highlight the importance of cell glycosylation in stromal immunology.

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“…Changes to sialylated glycans in cancer include an upregulation of the Sialyl Lewis antigens (sLe A and sLe X ), an increase in the truncated O-glycan sialyl-Tn (STn) and an increase in the sialylated ganglioside GM2 [52] (Figure 1). The sialyl Lewis antigens are part of the Lewis family of blood group antigens, named after the discoverer of a series of antigens found on red blood cells, and are the minimal recognition motif for ligands of selectins (a family of lectins with roles in leukocyte trafficking and cancer metastasis).…”

Section: Cancer-associated Sialyloglycansmentioning

confidence: 99%

“…Many solid tumours and adenocarcinomas express high levels of sLe A and sLe X , and thus targeting selectins and sLe A/X is attractive therapeutically [53]. Potential strategies include the use of glycomimetic drugs, such as the selectin inhibitors Uproleselan (GMI-1271) and Rivipansel (GMI-1070), which have been tested in clinical trials [52,54] (Table 2). Uproleselan (GMI-1271) is in phase 3 clinical trials, in combination with chemotherapy, to treat relapsed acute myeloid leukemia (NCT03616470), and has also shown promise in pre-clinical models of breast cancer, where it can prevent bone metastasis and improve survival [55].…”

Section: Cancer-associated Sialyloglycansmentioning

confidence: 99%

Targeting Aberrant Sialylation to Treat Cancer

Munkley

Scott

2019

Medicines

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Cell surface carbohydrates (known as glycans) are often aberrantly expressed or found at atypical levels in cancer. Glycans can impact all steps in tumour progression, from malignant transformation to metastasis, and have roles in all the cancer hallmarks. An increased understanding of glycans in the metastatic cascade offers exciting new therapeutic opportunities. Glycan-based targeting strategies are currently being tested in clinical trials and are a rich and untapped frontier for development. As we learn more about cancer glycobiology, new targets will continue to emerge for drug design. One key change in tumour glycosylation is the upregulation of cancer-associated sialylated glycans. Abnormal sialylation is integral to tumour growth, metastasis and immune evasion; therefore, targeting sialic acid moieties in cancer could be of high therapeutic value. Here, we summarise the changes to sialic acid biology in cancer and discuss recent advances and technologies bringing sialic-acid targeting treatments to the forefront of cancer therapeutics.

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Glycosylation in the Era of Cancer-Targeted Therapy: Where Are We Heading?

Cited by 374 publications

References 79 publications

iLoF: An intelligent Lab on Fiber Approach for Human Cancer Single-Cell Type Identification

iLoF: An intelligent Lab on Fiber Approach for Human Cancer Single-Cell Type Identification

Loss of α2-6 sialylation promotes the transformation of synovial fibroblasts into a pro-inflammatory phenotype in Rheumatoid Arthritis

Targeting Aberrant Sialylation to Treat Cancer

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