Esophageal, gastric and colorectal cancers: Looking beyond classical serological biomarkers towards glycoproteomics-assisted precision oncology

Fernandes, Elisabete; Sores, Janine; Cotton, Sofia; Peixoto, Andreia; Ferreira, Dylan; Freitas, Rui; Reis, Celso A.; Santos, Lúcio Lara; Ferreira, José Alexandre

doi:10.7150/thno.42480

Cited by 48 publications

(50 citation statements)

References 174 publications

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“…Aberrant global glycosylation has been implicated in cancer development and associated with cell adhesion, invasion and metastasis. The elevated levels of sLe A and sLe x , which are essential for the function of selectin ligands in the adhesion of cancer cells onto the endothelium during metastasis, are frequently utilized as serum biomarkers for pancreatic cancer 38 . A quantitative and qualitative measure of glycosylation is currently dependent on sequential tandem mass spectrometry analysis coupled to liquid chromatography and ion mobility spectrometry 39 .…”

Section: Discussionmentioning

confidence: 99%

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

Dalangood

Zhu

et al. 2020

Theranostics

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Background: Urinary bladder cancer (UBC) is one of the most common causes of morbidity and mortality worldwide characterized by a high risk of invasion and metastasis; however, the molecular classification biomarkers and underlying molecular mechanisms for UBC patient stratification on clinical outcome need to be investigated. Methods: A systematic transcriptomic analysis of 185 glycogenes in the public UBC datasets with survival information and clinicopathological parameters were performed using unsupervised hierarchical clustering. The gene signature for glycogene-type classification was identified using Limma package in R language, and correlated to 8 known molecular features by Gene Set Variation Analysis (GSVA). The clinical relevance and function of a glycogene was characterized by immunohistochemistry in UBC patient samples, and quantitative RT-PCR, Western blotting, promoter activity, MAL II blotting, immunofluorescence staining, wound healing, and transwell assays in UBC cells. Results: A 14-glycogene signature for glycogene-type classification was identified. Among them, ST3GAL6, a glycotransferase to transfer sialic acid to 3'-hydroxyl group of a galactose residue, showed a significant negative association with the subtype with luminal feature in UBC patients (n=2,130 in total). Increased ST3GAL6 was positively correlated to tumor stage, grade, and survival in UBCs from public datasets or our cohort (n=52). Transcription factor GATA3, a luminal-specific marker for UBC, was further identified as a direct upstream regulator of ST3GAL6 to negatively regulate its transactivation. ST3GAL6 depletion decreased MAL II level, cell invasion and migration in 5637 and J82 UBC cells. ST3GAL6 could reverse the effects of GATA3 on global sialylation and cell invasion in SW780 cells. Conclusions: Herein, we successfully identified a novel 14-gene signature for glycogene-type classification of UBC patients. ST3GAL6 gene, from this signature, was demonstrated as a potential biomarker for poor outcomes and cell invasion in UBCs.

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Section: Discussionmentioning

confidence: 99%

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

Dalangood

Zhu

et al. 2020

Theranostics

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“…Despite promising, conventional proteomics approaches on EC are yet to deliver targetable molecular signatures due to insufficient cancer specificity. Addressing alterations in the glycosylation of membrane proteins holds a great potential towards this objective [8]. In fact, over the past years, we and other research groups have demonstrated that changes in the structure and distribution of glycans in proteins at the surface of cancer cells may provide the necessary bispecificity towards unique cancer molecular signatures [8,9].…”

Section: Introductionmentioning

confidence: 99%

“…Addressing alterations in the glycosylation of membrane proteins holds a great potential towards this objective [8]. In fact, over the past years, we and other research groups have demonstrated that changes in the structure and distribution of glycans in proteins at the surface of cancer cells may provide the necessary bispecificity towards unique cancer molecular signatures [8,9]. Namely, we have identified MUC16, CD44 and nucleolin glycoforms holding potential for more accurate patient stratification and treatment follow-ups in different types of tumors [9][10][11].…”

Section: Introductionmentioning

confidence: 99%

Target Score—A Proteomics Data Selection Tool Applied to Esophageal Cancer Identifies GLUT1-Sialyl Tn Glycoforms as Biomarkers of Cancer Aggressiveness

Cotton

Ferreira

Soares

et al. 2021

IJMS

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Esophageal cancer (EC) is a life-threatening disease, demanding the discovery of new biomarkers and molecular targets for precision oncology. Aberrantly glycosylated proteins hold tremendous potential towards this objective. In the current study, a series of esophageal squamous cell carcinomas (ESCC) and EC-derived circulating tumor cells (CTCs) were screened by immunoassays for the sialyl-Tn (STn) antigen, a glycan rarely expressed in healthy tissues and widely observed in aggressive gastrointestinal cancers. An ESCC cell model was glycoengineered to express STn and characterized in relation to cell proliferation and invasion in vitro. STn was found to be widely present in ESCC (70% of tumors) and in CTCs in 20% of patients, being associated with general recurrence and reduced survival. Furthermore, STn expression in ESCC cells increased invasion in vitro, while reducing cancer cells proliferation. In parallel, an ESCC mass spectrometry-based proteomics dataset, obtained from the PRIDE database, was comprehensively interrogated for abnormally glycosylated proteins. Data integration with the Target Score, an algorithm developed in-house, pinpointed the glucose transporter type 1 (GLUT1) as a biomarker of poor prognosis. GLUT1-STn glycoproteoforms were latter identified in tumor tissues in patients facing worst prognosis. Furthermore, healthy human tissues analysis suggested that STn glycosylation provided cancer specificity to GLUT1. In conclusion, STn is a biomarker of worst prognosis in EC and GLUT1-STn glycoforms may be used to increase its specificity on the stratification and targeting of aggressive ESCC forms.

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“…CRC is very complicated at the molecular level which makes it reasonable to predict that patient’s management is required to be stratified. To establish comprehensive patient stratification models, identification of targetable biomarkers which directs to therapeutic personalization will be crucial [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Clinico-Pathological Study of K-ras Mutations in Colorectal Tumors: A Single-Center Retrospective Study of 51 Patients in Madinah, Saudi Arabia

Mulla¹,

Alshareef²,

Syed

et al. 2020

Cureus

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Background Colorectal cancer (CRC) is one of the leading types of cancer worldwide and in Saudi Arabia. At the molecular level, CRC is very complicated and requires establishing comprehensive patient stratification models through identification of patients who will benefit or will not benefit from targeted therapy. We retrospectively investigated and analyzed the frequency of Kirsten-ras (K-ras) mutation and its correlation with patients’ characteristics as weel as its association with clinicopathological features (i.e age, gender, clinical stage, anatomical site, histological subtype, degree of histological differentiation and metastatic site) in patients with CRC. Methods Medical records and paraffin-embedded tumor samples from 51 patients with histologically proven colorectal adenocarcinoma referred to Madinah center in Saudi Arabia were analyzed for the occurrence of rat sarcoma virus (RAS) mutations. Results RAS mutations occurred in 43% of the patients; 91% of these mutations were in K-ras. Seventy-five percent of these K-ras mutations were in codon 12, most commonly p.G12D. Codon 13 mutations occurred in 20% of tumors: all of these were p.G13D (100%). The percentage of K-ras mutations occurrence was higher in young patients (≤50) compared with the older patients (>50) (54.5% and 35%, respectively). Similarly, the percentage of K-ras mutations occurrence was higher in the right-sided tumors compared with the left-sided tumors (57.1% and 32.4%, respectively). Patients’ characteristics and clinicopathological features were not significantly associated with K-ras mutations. Conclusions K-ras mutations are common among Saudi patients diagnosed with CRC in Madinah, especially pG12V and pG12D in codon 12. Further investigation would be required to establish correlation of K-ras mutations in larger cohorts.

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Esophageal, gastric and colorectal cancers: Looking beyond classical serological biomarkers towards glycoproteomics-assisted precision oncology

Cited by 48 publications

References 174 publications

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

Identification of glycogene-type and validation of ST3GAL6 as a biomarker predicts clinical outcome and cancer cell invasion in urinary bladder cancer

Target Score—A Proteomics Data Selection Tool Applied to Esophageal Cancer Identifies GLUT1-Sialyl Tn Glycoforms as Biomarkers of Cancer Aggressiveness

Clinico-Pathological Study of K-ras Mutations in Colorectal Tumors: A Single-Center Retrospective Study of 51 Patients in Madinah, Saudi Arabia

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