Is Salivary Exosome the Answer to Early Detection of Oral Cancer?

Muy-Teck Teh, BSc, PhD

Centre for Clinical and Diagnostic Oral Sciences Barts and The London School of Medicine and Dentistry Queen Mary University of London The Blizard Building 4 Newark Street London E1 2AT England, UK; Tel. +44 (0) 20 7882 7140; Fax: +44 (0) 20 7882 7137; E-mail: m.t.teh@qmul.ac.uk

The presence of exosomesin almost all bodily fluidsincluding saliva¹ represents a promising surrogate approach to investigate tumour markers. This has important clinical implications for developing non-invasive salivary diagnostics and therapeutics.² Human saliva is an ideal fluid for developing non-invasive diagnostics and salivary biomarkers have been demonstrated in clinical studies showing promising diagnostic potentials but lacking in sensitivity mostly due to complexity of saliva.^2,3 Hence, this led to the emerging interests on exosomes which are membrane-bound extracellular vesicles carrying specific membrane proteins with numerous types of nucleic acids4 and protein cargos,^2,5,6 well protected from degradation by extracellular enzymes. Their size (50-150 nm diameter) is an advantage for purification and reducing the overall complexity ofsaliva.² Most of the salivary exosome studies to date have been restricted to characterization of normal healthy samples.² Emerging studies began looking at biochemical properties of disease-derived saliva exosomes.^2,5,6 So, itseems no brainer thatsalivary exosome serves asthe perfect target for finding a biomarker that could enable early oral cancer detection by means of a simple saliva test.

As oral cancer itself is a complex heterogeneous disease, a number of factors should be considered when investigating oral cancer exosomes in saliva. Site of tumour may have profound impact on the route where cancer exosomes enter. For example, comparing a patient with tonsillar tumour whereby its cancer exosomes may not be detectable in the patient’s saliva compared to a patient with buccal or tongue tumour. Given the anatomical complexity of the oral compartment, coupled with presumably very low abundance of cancer exosomes at early stages of tumour development, and in a chemically fluctuating salivary environment, the challenges researchers are facing would be analogy to detecting an individual’s cells in the sewage system.

The main challenge remains in finding a cancer specific marker(s) that represents early development of oral cancer. Many studies are restricted to comparing normal and clinically visible tumour samples which led to the identification of cancer markers that are not representative and/or detectable at early stages of tumour development. Nevertheless, a recent study has shown a promising outlook if one could identify a cancer exosome-specific marker. The group demonstrated that pancreatic tumour secretes unique cancer exosomes carrying Glypican-1 (GPC1) into the bloodstream which could be used as a biomarker for detecting early pancreatic cancer in patients.⁷ However, oral cancer is a highly complex, multi-staged, multi-factorial and highly heterogeneous disease, it is unlikely that it could be represented by a single biomarker throughout tumourigenesis.^8,9 The future of early oral cancer detection studies may lie in longitudinal sampling of individuals (ideally from conception!) to provide comprehensive and progressive clinical record and biological data in the hope to identify a predictive signature(s) indicative of oral cancer development. As for the question whether oral cancer exosomes could be the answer for early oral cancer detection, the answer may lie in the identification of a unique early oral cancer-specific exosomal marker, if there is one.

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7. Melo SA, Luecke LB, Kahlert C, et al. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature. 2015. doi: 10.1038/nature14581

8. Teh MT. FOXM1 coming of age: Time for translation into clinical benefits? Frontiers in Oncology. 2012; 2(146): 1-6. doi: 10.3389/ fonc.2012.00146

9. Teh MT. Cells brainwashed by FOXM1: Do they have potential as biomarkers of cancer? Biomark Med. 2012; 6(4): 499-501. doi: 10.2217/bmm.12.33