Abstract
Simple SummaryThe early detection of oral cancer is a high priority, as improvements in this area could lead to greater cure rates and reduced disability due to extensive surgery. Oral cancer is very difficult to detect in over 70% of cases as it develops unseen until quite advanced, sometimes rapidly. Therefore, the development of markers in body fluids (liquid biopsies) indicative of cancerous changes have a high priority. We show here that small molecules called metabolites can distinguish between non-diseased oral cells and two types of cells found in oral cells on the road to cancer. Although our investigation is preliminary, some of the metabolites have already been detected in the saliva (split) of oral cancer patients, and could eventually help detect oral cancer development at an earlier stage.Premalignant oral lesions (PPOLs) which bypass senescence (IPPOL) have a much greater probability of progressing to malignancy, but pre-cancerous fields also contain mortal PPOL keratinocytes (MPPOL) that possess tumour-promoting properties. To identify metabolites that could potentially separate IPPOL, MPPOL and normal oral keratinocytes non-invasively in vivo, we conducted an unbiased screen of their conditioned medium. MPPOL keratinocytes showed elevated levels of branch-chain amino acid, lipid, prostaglandin, and glutathione metabolites, some of which could potentially be converted into volatile compounds by oral bacteria and detected in breath analysis. Extracellular metabolites were generally depleted in IPPOL, and only six were elevated, but some metabolites distinguishing IPPOL from MPPOL have been associated with progression to oral squamous cell carcinoma (OSCC) in vivo. One of the metabolites elevated in IPPOL relative to the other groups, citrate, was confirmed by targeted metabolomics and, interestingly, has been implicated in cancer growth and metastasis. Although our investigation is preliminary, some of the metabolites described here are detectable in the saliva of oral cancer patients, albeit at a more advanced stage, and could eventually help detect oral cancer development earlier.
Highlights
Oral cancer, predominantly squamous cell carcinoma (OSCC), is the sixth most common cancer worldwide and the management of this cancer has barely improved in decades
Extracellular metabolites were generally depleted in IPPOL, and only six were elevated, but some metabolites distinguishing IPPOL from mortal PPOL keratinocytes (MPPOL) have been associated with progression to oral squamous cell carcinoma (OSCC) in vivo
HR IPPOL lines D19, D20, and D35 were of additional interest as the patients from which they were derived from progressed to OSCC within 5 years of being biopsied [12]
Summary
Predominantly squamous cell carcinoma (OSCC), is the sixth most common cancer worldwide and the management of this cancer has barely improved in decades. One of the problems in treating OSCC is that they frequently develop from a field of genetically and phenotypically diverse cells that are histologically undetectable [1]. Even some high-risk PPOL (HR-PPOL), have extensive gene copy number variations [6] and develop genetic heterogeneity and, the platform for drug resistance [7]. Recent evidence suggests that this genetic heterogeneity [8] and the induction of cellular senescence [9] develops prior to most OSCCs becoming visible [8] and immortal keratinocytes with extensive gene copy number variations have been demonstrated in PPOLs of low histological grade [5]. It has long been known that even advanced OSCCs contain both mortal and immortal keratinocytes [10,11], sometimes mixtures of the two [11], and the same is true of PPOLs [5,12]
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