Salivary Biomarkers for Oral Squamous Cell Carcinoma Diagnosis and Follow-Up: Current Status and Perspectives

Abstract

Oral cancer is the sixth most common cancer type in the world, and 90% of it is represented by oral squamous cell carcinoma (OSCC). Despite progress in preventive and therapeutic strategies, delay in OSCC diagnosis remains one of the major causes of high morbidity and mortality; indeed the majority of OSCC has been lately identified in the advanced clinical stage (i.e., III or IV). Moreover, after primary treatment, recurrences and/or metastases are found in more than half of the patients (80% of cases within the first 2 years) and the 5-year survival rate is still lower than 50%, resulting in a serious issue for public health. Currently, histological investigation represents the "gold standard" of OSCC diagnosis; however, recent studies have evaluated the potential use of non-invasive methods, such as "liquid biopsy," for the detection of diagnostic and prognostic biomarkers in body fluids of oral cancer patients. Saliva is a biofluid containing factors such as cytokines, DNA and RNA molecules, circulating and tissuederived cells, and extracellular vesicles (EVs) that may be used as biomarkers; their analysis may give us useful information to do early diagnosis of OSCC and improve the prognosis. Therefore, the aim of this review is reporting the most recent data on saliva biomarker detection in saliva liquid biopsy from oral cancer patients, with particular attention to circulating tumor DNA (ctDNA), EVs, and microRNAs (miRNAs). Our results highlight that saliva liquid biopsy has several promising clinical uses in OSCC management; it is painless, accessible, and low cost and represents a very helpful source of diagnostic and prognostic biomarker detection. Even if standardized protocols for isolation, characterization, and evaluation are needed, recent data suggest that saliva may be successfully included in future clinical diagnostic processes, with a considerable impact on early treatment strategies and a favorable outcome.

Saliva—Friend and Foe in the COVID-19 Outbreak

“…Saliva also represents an attractive biofluid source option for the detection of SARS-CoV-2, due to being non-invasive, easy-to-access, and low-cost, as well as having the ability to "mirror" systemic and local disease status [50]. It is well-known that saliva harbors a wide range of circulatory components (Figure 2), such as pro-inflammatory cytokines [51,52], chemokines [53], matrix metalloproteinases [54,55], mitochondrial DNA [56], genomic DNA [57], bacteria [58], SARS-CoV and SARS-CoV-2 virus [30,31,59], SARS-CoV antibodies [59], miRNAs [60], and extracellular vesicles (EVs) [61]. Furthermore, saliva samples can be stored at -80 • C for several years with little degradation [62].…”

Body Fluid Biomarkers for Alzheimer’s Disease—An Up-To-Date Overview

“…In contrast to blood, saliva is a matrix that can be collected easily and non-invasively, at all ages and many times per day, and assessed through different assays [ 139 , 141 , 142 , 143 , 144 ], which is promising for its future clinical application in the timely detection, diagnosis, prognosis and monitoring of neurological disorders [ 142 , 145 ]. In this regard, a novel term has been introduced, salivaomics, which encompasses all biomarkers discovered within the genome, microbiome, epigenome, transcriptome, proteome and metabolome for the development of translational and clinical tools for diagnosis [ 145 , 146 ].…”

Current Understanding of the HIF-1-Dependent Metabolism in Oral Squamous Cell Carcinoma

“…Since the induction of several signal transduction pathways is an early event in oral carcinogenesis prior to detectable clinical features, such as TNM and grading, potential biomarkers in tissue specimens as well as in whole saliva are urgently needed for the early detection of this disease [ 14 ]. In this context, it is noteworthy that the HIF pathway and HIF-dependent target proteins are involved in the progression and clinical outcome of OSCC [ 15 , 16 , 17 , 18 , 19 ].…”