Prognostic Significance of Serum Free Amino Acids in Head and Neck Cancers

Abstract

Despite distinctive advances in the field of head and neck squamous cell cancer (HNSCC) biomarker discovery, the spectrum of clinically useful prognostic serum biomarkers is limited. As metabolic activities in highly proliferative transformed cells are fundamentally different from those in non-transformed cells, specific shifts in concentration of different metabolites may serve as diagnostic or prognostic markers. Blood amino acids have been identified as promising biomarkers in different cancers before, but little is known about this field in HNSCC. Blood amino acid profiles of 140 HNSCC patients were examined using high-performance liquid chromatography. Cox proportional hazards regression model was used to assess the prognostic value of amino acid concentrations in serum. Colony forming assay was used to identify the effect of amino acids that were significant in Cox proportional hazards regression models on colony forming ability of FaDu and Detroit 562 cell lines. In the multivariable Cox regression model for overall survival (OS), palliative treatment was associated with an unfavourable prognosis while high serum levels of methionine have had a positive prognostic impact. In the relapse-free survival (RFS) multivariable model, methionine was similarly identified as a positive prognostic factor, along with tumor localization in the oropharynx. Oral cavity localization and primary radio(chemo)therapy treatment strategy have been linked to poorer RFS. 1mM serine was shown to support the forming of colonies in both tested HNSCC cell lines. Effect of methionine was exactly the opposite.

Circulating Tumor Cells and Circulating Tumor DNA Detection in Potentially Resectable Metastatic Colorectal Cancer: A Prospective Ancillary Study to the Unicancer Prodige-14 Trial

“…Lastly, newly developed circulating biomarkers such as free serum amino acids [38] could be compared to CTC or ctDNA detection for their prognostic value. Similarly, circulating extracellular matrix components have been evaluated as biomarkers for cancer diagnosis and prognosis in various tumor types [39].…”

Targeting Cellular Metabolism Modulates Head and Neck Oncogenesis

“…For example, methionine-derivative S-adenosyl methionine (SAM) is a cofactor acting mainly as a methyl donor to cytosine in DNA during epigenetic modification [136]. A recent study found a reduced oral mucositis after an oral D-methionine treatment in patients with grade 3/4 HNSCCs [137]; an in vitro study showed that the administration of methionine could also downregulate the proliferative capacity in HNSCC cells; it was also reported that there was a positive correlation of high methionine serum levels with greater overall and relapse-free survival rates [121,138]. These findings suggest that methionine could be tumor-suppressive and that the methionine content might serve as a prognostic factor for HNSCC patients, although one must still mechanistically clarify the way in which methionine regulates epigenetic modification in HNSCC development.…”

Prognostic Role of Serum Amino Acids in Head and Neck Cancer

“…Various factors can influence serum AA pattern in cancer, depending on the type and the stage of the disease: muscle wasting, malnutrition, systemic inflammation, and insulin resistance [ 20 , 21 ]. To our knowledge, only one study has specifically addressed the link between the basal serum AA levels and long-term prognosis in HNC patients [ 15 ]. Our study was done on a larger number of patients, with a less unbalanced female/male patient ratio, measuring a wider panel of serum AAs and evaluating the impact of AA profiles on both the OS and the risk of advanced stage.…”

“…Glycine uptake and catabolism promote tumorigenesis and malignancy [ 30 ], and its biosynthesis is deemed as a central process in sustaining rapid proliferation [ 11 , 28 ]; serine serves as a central hub in the metabolic network for many aspects of cancer cell survival and proliferation [ 28 ]. Higher concentrations of glycine and serine have been detected in the malignant head and neck squamous cell carcinoma tissue samples compared to surrounding normal tissues [ 15 , 31 ].…”

“…Because of these important roles in tumor metabolism, there continues to be significant interest in studying AA metabolism for cancer marker detection. Several investigators have reported changes in peripheral blood AAs in various types of cancer patients, including lung, ovarian, and also HNC patients [ 14 , 15 ]. The only study which specifically addressed the link between the basal serum AA levels and long-term prognosis in HNC patients concluded that increased serum levels of methionine had a favourable prognostic impact in terms of overall survival (OS) and relapse-free survival, while increased serine showed borderline significance as a negative prognostic factor for OS [ 15 ].…”