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

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.

Simultaneous LC-MS/MS-Based Quantification of Free 3-Nitro-l-tyrosine, 3-Chloro-l-tyrosine, and 3-Bromo-l-tyrosine in Plasma of Colorectal Cancer Patients during Early Postoperative Period

“…It also corroborates findings of an inverse relationship between tumor infiltration by eosinophils and the metastatic potential of colorectal cancer as well as the progression from adenoma to carcinoma (reviewed in [41]). The 3-NT is considered a footprint of NOS2 activity [5], and NOS2 expression in tumors of the digestive tract is elevated [8][9][10]. Therefore, the inverse 3-NT correlation with lymph node and distant metastasis observed here seems counterintuitive.…”

“…The macrophage NOS2 has been implicated in cancer promotion [6,7]. Local NOS2 overexpression has been shown in the digestive tract tumors [8,9], including those in the colon and rectum [10], predicting poor prognosis [11].…”

Altered L-Arginine Metabolic Pathways in Gastric Cancer: Potential Therapeutic Targets and Biomarkers

“…SDMA was also correlated with stroma-derived (SCF), the signaling of which is involved in viability and self-renewing properties of cancer stem cells [36]. The interrelationship between intermediates of arginine metabolic pathways and stemness-promoting cytokines, recurring in various cancers [9], is intriguing and worth exploration.…”

“…L-arginine (Arg) metabolic pathways are among those repeatedly found to be deregulated [7][8][9]. Pharmacological manipulation of pathway enzymes is viewed as an attractive therapeutic approach while monitoring enzyme activity and/or metabolite concentration may aid cancer diagnosis and treatment [10][11][12][13].…”

Arginine Methylation in Brain Tumors: Tumor Biology and Therapeutic Strategies

“…It was recently discovered that type I PRMT inhibition significantly suppressed proliferation and induced apoptosis of colorectal cancer cell lines [ 101 ]. PRMT gene expression was also implicated in tumorigenesis in a study examining the L-arginine/NO pathway in esophageal squamous cell carcinoma [ 102 ]. In comparison to adjacent healthy tissue, tumors overexpressed PRMT1 , PRMT5 , and other genes involved in the L-arginine/NO pathway.…”