Nuclear Magnetic Resonance Metabolomics Biomarkers for Identifying High Risk Patients with Extranodal Extension in Oral Squamous Cell Carcinoma

Abstract

Extranodal extension (ENE) is an independent adverse prognostic factor in oral squamous cell carcinoma (OSCC), and is difficult to identify preoperatively. We aimed to discover biomarkers for high risk patients with ENE. Tandem tissue, plasma, and urine samples of 110 patients with OSCC were investigated through 600-MHz nuclear magnetic resonance (NMR) metabolomics analysis. We found that the levels of creatine, creatine phosphate, glycine, and tyramine in plasma significantly decreased in stage IV ENE positive OSCC compared with stage IV ENE negative OSCC. To understand the underlying mechanism behind the alteration of plasma metabolites, our tissue analysis revealed that the carnitine level significantly increased in tumors but significantly decreased in the adjacent normal tissue in advanced stage OSCC, in addition to decreased levels of alanine and pyruvate in tumor tissues. The global metabolomics analysis on tumor tissues also showed that stage IV tumors with an ENE positive status demonstrated higher levels of aspartate, butyrate, carnitine, glutamate, glutathione, glycine, glycolate, guanosine, and sucrose but lower levels of alanine, choline, glucose, isoleucine, lactate, leucine, myo-inositol, O-acetylcholine, oxypurinol, phenylalanine, pyruvate, succinate, tyrosine, valine, and xanthine than tumors with an ENE negative status. We concluded that metabolomics alterations in tumor tissues correspond to an increase in the tumor stage and are detectable in plasma samples. Metabolomic alterations of OSCC can serve as potential diagnostic markers and predictors of ENE in patients with stage IV OSCC.

Untargeted Metabolomics Identify a Panel of Urinary Biomarkers for the Diagnosis of Urothelial Carcinoma of the Bladder, as Compared to Urolithiasis with or without Urinary Tract Infection in Dogs

“…Amino acid catabolism is a crucial component for cancer cell proliferation and progression, as it is involved in various processes such as nucleotide synthesis, lipogenesis, metastasis, epigenetic modifications, and evasion of tumor recognition by the immune system [ 25 ]. Phenylalanine is one of the essential amino acids, and the importance of phenylalanine metabolism has been identified in several human cancers, including colorectal cancer [ 26 ] and oral squamous cell [ 27 ] and non-small cell lung carcinoma, whereas phenylalanine restriction was associated with decreased tumor invasion in melanoma [ 28 ]. This study identified N-Acetylphenylalanine, an N-acetylated form of phenylalanine (Pubchem, [ 12 ]), to be significantly upregulated in the UC group, indicating a probable role of this metabolite in canine UC.…”

The Practicality of the Use of Liquid Biopsy in Early Diagnosis and Treatment Monitoring of Oral Cancer in Resource-Limited Settings

“…NF-κB-dependent cytokines, matrix metalloproteinases (MMPs) and pro-inflammatory cytokines in saliva may be involved in the relationship between oral malignancies and aging, involving the senescence-associated secretory phenotype (SASP), and inflammatory diseases, such as oral mucosal ulcers and periodontitis [ 42 ]. Metabolome biomarkers in OSCC were also investigated using nuclear magnetic resonance (NMR) metabolomics to detect high-risk patients with an extranodal extension [ 43 ]. Recent research has revealed that EVs, including exosomes (small vesicles) and bigger vesicles, are released into the saliva from oral cancer lesions and/or oral tissues [ 44 ].…”

Organoids and Liquid Biopsy in Oral Cancer Research

“…Metabolome biomarkers in OSCC were also examined to identify high-risk patients with extranodal extension by using Nuclear Magnetic Resonance (NMR) metabolomics [ 16 ].…”