Rapid discrimination of human oesophageal squamous cell carcinoma by mass spectrometry based on differences in amino acid metabolism

Abstract Background Oesophageal squamous cell carcinoma (ESCC) is a major global health burden associated with poor survival. Patients suffering from this condition typically present at an advanced stage due to non-specific early symptoms. An increasing emphasis on early detection has led to the investigation of novel biomarkers of ESCC. This systematic review aims to define existing biomarkers of ESCC and to identify perturbations in associated metabolic pathways. Methods A systematic online literature search (1946–January 2018) was performed to identify studies reporting metabolic biomarkers of ESCC. Pooled point estimate of the hierarchal summary ROC curve of analysed metabolites was performed using bivariate meta-analyses. Conduct of this review was in accordance with the recommendations of the Cochrane Library and MOOSE guidelines. Results An online search identified 628 potential relevant studies, of which eight (including a total 508 patients) met inclusion criteria. All publications represented phase-I biomarker discovery studies. Methods used to assess metabolites in patients with ESCC included liquid chromatography-mass spectrometry (n = 6), gas chromatography-mass spectrometry (n = 1) and 1H-nuclear magnetic resonance (n = 1). Sample types utilised were plasma (n = 5), tissue (n = 2) and urine (n = 1). A total of 1670 metabolites were identified as being associated with ESCC. Key metabolic pathways involved included tricarboxylic acid cycle and in pathways of oxidative stress. Metabolites identified increased in ESCC are breakdown products of fatty acid synthesis and glycerophospholipid metabolism e.g.: palmitic acid, oleic acid, LysoPC(24:0), LysoPC(18:2), L-carnitine, branched chain amino acids e.g.: valine, leucine, isoleucine and phenylalanine. Metabolites decreased in ESCC are breakdown products of amino acid metabolism e.g: glutamine, carbohydrates e.g.: glucose and organic acids e.g.: α-ketoglutaric acid oxime. Pooled analysis of findings from five studies showed an area under the receiver-operating characteristic analysis curve of 0.96, sensitivity 88.0% (95% CI 80.8%-92.7%) and specificity 93.5% (95% CI 96.9%- 86.8%). Conclusion This is the first review to define metabolic biomarkers associated with ESCC. Significant variability in identified metabolites is evidence of the broad range of analytical techniques employed and the diversity of metabolic pathways associated with this disease. Notwithstanding, findings provide important insight in to those metabolites associated with ESCC and provide a basis for future studies. Disclosure All authors have declared no conflicts of interest.

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Metabolomic Characterization Reveals ILF2 and ILF3 Affected Metabolic Adaptions in Esophageal Squamous Cell Carcinoma

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.721990 ◽

2021 ◽

Vol 8 ◽

Author(s):

Bin Zang ◽

Wen Wang ◽

Yiqian Wang ◽

Pengfei Li ◽

Tian Xia ◽

...

Keyword(s):

Mass Spectrometry ◽

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Acid Metabolism ◽

Metabolic Reprogramming ◽

Chain Acyl ◽

Glycolysis Pathway ◽

Cancer Tissues

Esophageal cancer (EC) is a common malignant disease in eastern countries. However, a study of the metabolomic characteristics associated with other biological factors in esophageal squamous cell carcinoma (ESCC) is limited. Interleukin enhancer binding factor 2 (ILF2) and ILF3, double-stranded RNA-binding proteins, have been reported to contribute to the occurrence and development of various types of malignancy. Nevertheless, the underlying functions of ILF2 and ILF3 in ESCC metabolic reprogramming have never been reported. This study aimed to contribute to the metabolic characterization of ESCC and to investigate the metabolomic alterations associated with ILF2 and ILF3 in ESCC tissues. Here, we identified 112 differential metabolites, which were mainly enriched in phosphatidylcholine biosynthesis, fatty acid metabolism, and amino acid metabolism pathways, based on liquid chromatography–mass spectrometry and capillary electrophoresis–mass spectrometry approaches using ESCC tissues and paired para-cancer tissues from twenty-eight ESCC patients. In addition, ILF2 and ILF3 expression were significantly elevated in EC tissues compared to the histologically normal samples, and closely associated with PI3K/AKT and MAPK signaling pathways in ESCC. Moreover, in ESCC tissues with a high ILF2 expression, several short-chain acyl-carnitines (C3:0, C4:0, and C5:0) related to the BCAA metabolic pathway and long-chain acyl-carnitines (C14:0, C16:0, C16:0-OH, and C18:0) involved in the oxidation of fatty acids were obviously upregulated. Additionally, a series of intermediate metabolites involved in the glycolysis pathway, including G6P/F6P, F1,6BP, DHAP, G3P, and 2,3BPG, were remarkably downregulated in highly ILF3-expressed ESCC tissues compared with the corresponding para-cancer tissues. Overall, these findings may provide evidence for the roles of ILF2 and ILF3 during the process of ESCC metabolic alterations, and new insights into the development of early diagnosis and treatment for ESCC. Further investigation is needed to clarify the underlying mechanism of ILF2 and ILF3 on acyl-carnitines and the glycolysis pathway, respectively.

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Faculty Opinions recommendation of Nivolumab versus chemotherapy in patients with advanced oesophageal squamous cell carcinoma refractory or intolerant to previous chemotherapy (ATTRACTION-3): a multicentre, randomised, open-label, phase 3 trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.736682352.793578124 ◽

2020 ◽

Author(s):

Jaffer Ajani

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Oesophageal Squamous Cell Carcinoma ◽

Open Label ◽

Phase 3 ◽

Open Label Phase

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Aspirin enhances the therapeutic efficacy of cisplatin in oesophageal squamous cell carcinoma by inhibition of putative cancer stem cells

British Journal of Cancer ◽

10.1038/s41416-021-01499-3 ◽

2021 ◽

Author(s):

Zhigeng Zou ◽

Wei Zheng ◽

Hongjun Fan ◽

Guodong Deng ◽

Shih-Hsin Lu ◽

...

Keyword(s):

Stem Cells ◽

Squamous Cell Carcinoma ◽

Cancer Stem Cells ◽

Cell Carcinoma ◽

Cell Lines ◽

Squamous Cell ◽

High Throughput Sequencing ◽

Combined Treatment ◽

Oesophageal Squamous Cell Carcinoma

Abstract Background Cancer stem cells (CSCs) are related to the patient’s prognosis, recurrence and therapy resistance in oesophageal squamous cell carcinoma (ESCC). Although increasing evidence suggests that aspirin (acetylsalicylic acid, ASA) could lower the incidence and improve the prognosis of ESCC, the mechanism(s) remains to be fully understood. Methods We investigated the role of ASA in chemotherapy/chemoprevention in human ESCC cell lines and an N-nitrosomethylbenzylamine-induced rat ESCC carcinogenesis model. The effects of combined treatment with ASA/cisplatin on ESCC cell lines were examined in vitro and in vivo. Sphere-forming cells enriched with putative CSCs (pCSCs) were used to investigate the effect of ASA in CSCs. Assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq) was performed to determine the alterations in chromatin accessibility caused by ASA in ESCC cells. Results ASA inhibits the CSC properties and enhances cisplatin treatment in human ESCC cells. ATAC-seq indicates that ASA treatment results in remarkable epigenetic alterations on chromatin in ESCC cells, especially their pCSCs, through the modification of histone acetylation levels. The epigenetic changes activate Bim expression and promote cell death in CSCs of ESCC. Furthermore, ASA prevents the carcinogenesis of NMBzA-induced ESCC in the rat model. Conclusions ASA could be a potential chemotherapeutic adjuvant and chemopreventive drug for ESCC treatment.

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Pan-ERBB kinase inhibition augments CDK4/6 inhibitor efficacy in oesophageal squamous cell carcinoma

Gut ◽

10.1136/gutjnl-2020-323276 ◽

2021 ◽

pp. gutjnl-2020-323276

Author(s):

Jin Zhou ◽

Zhong Wu ◽

Zhouwei Zhang ◽

Louisa Goss ◽

James McFarland ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Large Scale ◽

Cell Cancer ◽

Oesophageal Squamous Cell Carcinoma ◽

Squamous Cancer ◽

Striking Success

ObjectiveOesophageal squamous cell carcinoma (OSCC), like other squamous carcinomas, harbour highly recurrent cell cycle pathway alterations, especially hyperactivation of the CCND1/CDK4/6 axis, raising the potential for use of existing CDK4/6 inhibitors in these cancers. Although CDK4/6 inhibition has shown striking success when combined with endocrine therapy in oestrogen receptor positive breast cancer, CDK4/6 inhibitor palbociclib monotherapy has not revealed evidence of efficacy to date in OSCC clinical studies. Herein, we sought to elucidate the identification of key dependencies in OSCC as a foundation for the selection of targets whose blockade could be combined with CDK4/6 inhibition.DesignWe combined large-scale genomic dependency and pharmaceutical screening datasets with preclinical cell line models, to identified potential combination therapies in squamous cell cancer.ResultsWe identified sensitivity to inhibitors to the ERBB family of receptor kinases, results clearly extending beyond the previously described minority of tumours with EGFR amplification/dependence, specifically finding a subset of OSCCs with dual dependence on ERBB3 and ERBB2. Subsequently. we demonstrated marked efficacy of combined pan-ERBB and CDK4/6 inhibition in vitro and in vivo. Furthermore, we demonstrated that squamous lineage transcription factor KLF5 facilitated activation of ERBBs in OSCC.ConclusionThese results provide clear rationale for development of combined ERBB and CDK4/6 inhibition in these cancers and raises the potential for KLF5 expression as a candidate biomarker to guide the use of these agents. These data suggested that by combining existing Food and Drug Administration (FDA)-approved agents, we have the capacity to improve therapy for OSCC and other squamous cancer.

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