L-Arginine/NO Pathway Metabolites in Colorectal Cancer: Relevance as Disease Biomarkers and Predictors of Adverse Clinical Outcomes Following Surgery

Abstract

The L-Arginine/NO pathway is involved in carcinogenesis and immunity. Its diagnostic and prognostic value in colorectal cancer (CRC) was determined using tandem mass spectrometry in 199 individuals (137 with CRC) and, during a three-day follow up, in 60 patients undergoing colorectal surgery. Citrulline was decreased and asymmetric (ADMA) and symmetric (SDMA) dimethylarginines and dimethylamine (DMA) were increased in CRC. The DMA increase corresponded with CRC advancement while arginine, ADMA, and SDMA levels were higher in left-sided cancers. Arginine, citrulline, ADMA, and DMA dropped and SDMA increased post incision. Females experienced a more substantial drop in arginine. The arginine and ADMA dynamics depended on blood loss. The initial SDMA increase was higher in patients requiring transfusions. Postoperative dynamics in arginine and dimethylarginines differed in robot-assisted and open surgery. Concomitant SDMA, citrulline, and DMA quantification displayed a 92% accuracy in detecting CRC. Monitoring changes in arginine, ADMA, and SDMA in the early postoperative period predicted postoperative ileus with 84% and surgical site infections with 90% accuracy. Changes in ADMA predicted operative morbidity with 90% and anastomotic leakage with 77% accuracy. If positively validated, L-arginine/NO pathway metabolites may facilitate CRC screening and surveillance, support differential diagnosis, and assist in clinical decision-making regarding patients recovering from colorectal surgery.

L-Arginine/Nitric Oxide Pathway Is Altered in Colorectal Cancer and Can Be Modulated by Novel Derivatives from Oxicam Class of Non-Steroidal Anti-Inflammatory Drugs

“…Cancer metabolic reprogramming is believed to hold a great potential as a source of novel biomarkers and molecular targets for chemoprevention and treatment [ 5 ]. Altered concentration of L-arginine/NO pathway metabolites at systemic level and their utility as diagnostic and prognostic tools in CRC has already been demonstrated [ 7 ]. An accumulation of arginine, citrulline, ADMA, and SDMA in colorectal cancer tissue has been shown as well [ 10 , 33 , 34 ].…”

“…Metabolite concentration in cell cultures was quantified using a method recently developed [ 85 ] and routinely used in our laboratory [ 6 , 7 , 86 , 87 , 88 ] with small modifications.…”

“…We have recently demonstrated that CRC, as well as the disease-promoting conditions [ 6 ], is associated with systemic changes in metabolites of L-arginine/nitric oxide (NO) pathway, potentially applicable as CRC biomarkers and predictors of adverse clinical events after curative tumor resection [ 7 ]. In the present study, we aimed at transcriptional profiling of the underlying alterations in pathway enzymes as a follow-up.…”

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

“…In the present study, we conducted a comprehensive analysis of the L-arginine/NO pathway status at the local transcriptomic and systemic metabolic level, in order to screen for potential molecular therapy targets and biomarkers, respectively. Alterations in the pathway metabolites as well as their suitability as diagnostic tools have recently been demonstrated by our group in colorectal cancer (CRC) [ 7 ] and inflammatory bowel disease, the condition associated with increased CRC risk [ 8 ].…”

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

“…Surgery evokes the stress response, encompassing the release of cytokines and affecting inflammation and immunity, the degree of which depends on the extent of trauma [57]. Accordingly, we and others have repeatedly shown that compared to the classic open approach, robot-assisted colorectal surgery is associated with attenuated inflammatory and beneficial immune response, which translates into favorable clinical outcomes [58][59][60][61][62][63]. No significant difference in plasma 3-NT with respect to the invasiveness of the procedure observed here is in line with previous observations concerning minilaparotomy cholecystectomy and laparoscopy cholecystectomy [64].…”