Disturbed tryptophan metabolism correlating to progression and metastasis of esophageal squamous cell carcinoma

Cheng, Jing; Jin, Hai; Hou, Xiaobei; Lv, Jie; Gao, Xianfu; Zheng, Guangyong

doi:10.1016/j.bbrc.2017.03.120

Cited by 30 publications

(21 citation statements)

References 23 publications

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“…Previously, Cheng et al found the ratio of kynurenine/tryptophan in plasm to be significantly increased in ESCC, and correlated with lymph node metastasis. However, the relationship between kynurenine levels and their survival outcome were not considered (18). To the best of our knowledge, our study is the first to identify circulating kynurenine as a prognostic factor for ESCC, in which higher levels of kynurenine were correlated with poorer OS, and higher N stage and tumor grade levels.…”

Section: Discussionmentioning

confidence: 86%

“…Previous metabolomic studies have demonstrated various metabolic alterations in patients with ESCC including changes in amino acids, glucose, lipids, organic acids, nucleotides, and fatty acids (18)(19)(20)(21). Though many promising serum/plasma metabolites have been found to be diagnostic biomarkers for ESCC (18,22,23), no metabolite with prognostic value has been identified, nor has a potential metabolic therapeutic target been recognized. Gu et al found serum D-mannose to be a novel prognostic biomarker for patients with esophageal adenocarcinoma (the main histological subtype in the USA).…”

Section: Introductionmentioning

confidence: 99%

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Combined Metabolomic Analysis of Plasma and Tissue Reveals a Prognostic Risk Score System and Metabolic Dysregulation in Esophageal Squamous Cell Carcinoma

et al. 2020

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Background: Esophageal squamous cell carcinoma (ESCC) is a gastrointestinal malignancy with a poor prognosis. Although studies have shown metabolic reprogramming to be linked to ESCC development, no prognostic metabolic biomarkers or potential therapeutic metabolic targets have been identified. Method: The present study investigated some circulating metabolites associated with overall survival in 276 curatively resected ESCC patients using liquid chromatography/mass spectrometry metabolomics and Kaplan-Meier analysis. Tissue metabolomic analysis of 23-paired ESCC tissue samples was performed to discover metabolic dysregulation in ESCC cancerous tissue. A method consisting of support vector machine recursive feature elimination and LIMMA differential expression analysis was utilized to select promising feature genes within transcriptomic data from 179-paired ESCC tissue samples. Joint pathway analysis with genes and metabolites identified relevant metabolic pathways and targets for ESCC. Results: Four metabolites, kynurenine, 1-myristoyl-glycero-3-phosphocholine (LPC(14:0)sn-1), 2-piperidinone, and hippuric acid, were identified as prognostic factors in the preoperative plasma from ESCC patients. A risk score consisting of kynurenine and LPC(14:0)sn-1 significantly improved the prognostic performance of the tumor-node-metastasis staging system and was able to stratify risk for ESCC. Combined tissue metabolomic analysis and support vector machine recursive feature elimination gene selection revealed dysregulated kynurenine pathway as an important metabolic feature of ESCC, including accumulation of tryptophan, formylkynurenine, and kynurenine, as well as up-regulated indoleamine 2,3-dioxygenase 1 in ESCC cancerous tissue. Chen et al. Metabolic Features of ESCC Conclusions: This work identified for the first time four potential prognostic circulating metabolites. In addition, kynurenine pathway metabolism was shown to be up-regulated tryptophan-kynurenine metabolism in ESCC. Results not only provide a metabolite-based risk score system for prognosis, but also improve the understanding of the molecular basis of ESCC onset and progression, and as well as novel potential therapeutic targets for ESCC.

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Section: Discussionmentioning

confidence: 86%

Section: Introductionmentioning

confidence: 99%

Combined Metabolomic Analysis of Plasma and Tissue Reveals a Prognostic Risk Score System and Metabolic Dysregulation in Esophageal Squamous Cell Carcinoma

et al. 2020

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“…Still, IDO1 is a useful marker for progression of in oral squamous cell carcinoma (41). In esophageal squamous cell carcinoma, progression and metastasis correlates with strong inflammation at the tumors' invasive front and disturbed TRP metabolism (42). These cumulative data highlight the biological relevance of the KP in malignancies and may explain why IDO1 is barely detectable upon long-term in vitro culture.…”

Section: Discussionmentioning

confidence: 98%

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

et al. 2020

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Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated.

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“…It has been reported that Trp hydroxylase facilitates the biotransformation of approximately 5% Trp by TPH2. Via the KP, the degradation of the other 95% of Trp is converted to kynurenine, and the regulation of this primarily occurs with IDO1 (Cheng et al, ). In this study, we found that the mRNA expression level of IDO1 was significantly increased in DE rats, while TPH2 did not change significantly.…”

Section: Discussionmentioning

confidence: 99%

Quantitative profiling of neurotransmitter abnormalities in brain, cerebrospinal fluid, and serum of experimental diabetic encephalopathy male rat

Han

Min

Wang

et al. 2017

J of Neuroscience Research

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Diabetic encephalopathy (DE), one of the most prevalent chronic complications of diabetes mellitus, is short of effective prevention and formidable therapeutic strategies. The aim of the present study is to reveal the imbalance of tryptophan (Trp) and its metabolites in streptozotocin (STZ)-induced experimental DE rats to underscore their critical values in clinical diagnosis of the disease.For this purpose, we first developed an accurate and appropriate simultaneous method for measuring Trp and its metabolites using liquid chromatography-tandem mass spectrometry, which was in accordance with the requirements of biological sample analysis. Secondly, a single STZ intraperitoneal injection was administered to male Sprague-Dawley rats, and their cognitive function was detected by Morris water maze tests. Cerebrospinal fluid (CSF), serum, and brain tissue were then collected for the determination of Trp and its metabolites. Compared with age-matched control rats, the levels of neuroprotective serotonin decreased significantly in the samples of cortices, hippocampi, striatum, CSF, and serums in the STZ-induced DE rats, while the levels of neurotoxic 3-hydroxykynurenine increased significantly. Moreover, analogous changes of both compounds were found in the central nervous system and peripheral blood of the STZ-induced DE rats. In conclusion, we established a quantitative method for the simultaneous detection of Trp and its metabolites, and we also present a critical elucidation of the nervous system dysfunction in DE.

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Disturbed tryptophan metabolism correlating to progression and metastasis of esophageal squamous cell carcinoma

Cited by 30 publications

References 23 publications

Combined Metabolomic Analysis of Plasma and Tissue Reveals a Prognostic Risk Score System and Metabolic Dysregulation in Esophageal Squamous Cell Carcinoma

Combined Metabolomic Analysis of Plasma and Tissue Reveals a Prognostic Risk Score System and Metabolic Dysregulation in Esophageal Squamous Cell Carcinoma

Activation of the Kynurenine Pathway in Human Malignancies Can Be Suppressed by the Cyclin-Dependent Kinase Inhibitor Dinaciclib

Quantitative profiling of neurotransmitter abnormalities in brain, cerebrospinal fluid, and serum of experimental diabetic encephalopathy male rat

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