Esophageal Squamous Cell Carcinoma Is Accompanied by Local and Systemic Changes in L-arginine/NO Pathway.

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 ( = 61) and benign conditions ( = 62) using LC-QTOF-MS and enzyme expression in esophageal tumors and matched noncancerous samples ( = 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 , , , and but had downregulated , , and . Except for markedly higher and lower 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 s in addition to and and the pathway link with stemness-promoting cytokines warrants further investigation.