Abstract
The L-arginine/NO pathway holds promise as a source of potential therapy target and biomarker; yet, its status and utility in esophageal squamous cell carcinoma (ESCC) is unclear. We aimed at quantifying pathway metabolites in sera from patients with ESCC (n = 61) and benign conditions (n = 62) using LC-QTOF-MS and enzyme expression in esophageal tumors and matched noncancerous samples (n = 40) using real-time PCR with reference to ESCC pathology and circulating immune/inflammatory mediators, quantified using Luminex xMAP technology. ESCC was associated with elevated systemic arginine and asymmetric dimethylarginine. Citrulline decreased and arginine bioavailability increased along with increasing ESCC advancement. Compared to adjacent tissue, tumors overexpressed ODC1, NOS2, PRMT1, and PRMT5 but had downregulated ARG1, ARG2, and DDAH1. Except for markedly higher NOS2 and lower ODC1 in tumors from M1 patients, the pathology-associated changes in enzyme expression were subtle and present also in noncancerous tissue. Both the local enzyme expression level and systemic metabolite concentration were related to circulating inflammatory and immune mediators, particularly those associated with eosinophils and those promoting viability and self-renewal of cancer stem cells. Metabolic reprogramming in ESCC manifests itself by the altered L-arginine/NO pathway. Upregulation of PRMTs in addition to NOS2 and ODC1 and the pathway link with stemness-promoting cytokines warrants further investigation.
Highlights
Squamous cell carcinoma of the esophagus (ESCC) is the dominant type of esophageal cancerand one of the deadliest and understudied malignancies worldwide
Our preliminary research has shown that esophageal squamous cell carcinoma (ESCC) might be locally characterized by upregulated expression of genes encoding glucose transporter 1 (GLUT1) as well as inducible nitric oxide synthase (NOS) and ornithine decarboxylase (ODC) of the L-arginine/nitric oxide (NO)/polyamine pathway [6]
The present study provides a comprehensive overview of pathway status in ESCC, including local enzyme expression and systemic metabolites, with reference to a broad spectrum of inflammatory, immune, and angiogenic mediators
Summary
Squamous cell carcinoma of the esophagus (ESCC) is the dominant type of esophageal cancerand one of the deadliest and understudied malignancies worldwide. The etiology of ESCC differs by geographic region with smoking and heavy alcohol consumption considered synergistic primary causes in Western European countries. New potential factors, such as polycyclic aromatic hydrocarbons; diet—low in antioxidants and contaminated with mycotoxins and nitrosamines; and the oral microbiome, are still emerging. The approach, referred to as “precision/personalized medicine“, is only starting to be implemented in ESCC, and first potential therapy targets have recently been identified using next-generation sequencing (NGS) [3]
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