Saliva – a pivotal player in the pathogenesis of oropharyngeal cancer

Abstract

Oropharyngeal (OP) cancer, which is usually squamous cell carcinoma, is the most common head and neck malignancy and accounts for 2 -4% of all new cancers. It is primarily induced by exposure to tobacco. The paradigm of cigarette smoke (CS)-induced OP cancer's pathogenesis is based on the assumption that a constant direct attack of various CS carcinogens causes widespread accumulating cellular and DNA aberrations in the OP mucosal cells, in turn eventually resulting in malignant transformation. However, there is never a direct contact between CS and the OP mucosa. Saliva, bathing the mucosa from the oral cavity to the larynx, always intervenes, and CS must first interact with saliva before it reaches the mucosa. The current study investigated the role of saliva in the pathogenesis of OP cancer. A synergistic effect of CS and saliva on oral cancer cells was demonstrated. This synergism is based on the reaction between redox active metals in saliva and low reactive free radicals in CS, which results in the production of highly active hydroxyl free radicals. Thus, when exposed to CS, salivary behavior is reversed and the saliva loses its antioxidant capacity and becomes a potent prooxidant milieu. The devastating role of CS-borne aldehydes was demonstrated as well. Based on these results and on our recent reports demonstrating that CS destroys various salivary components, including protective ones such as peroxidase, the most important salivary antioxidant enzyme, a comprehensive view of the pivotal role of saliva in the pathogenesis of CS-induced OP cancer is suggested. Oropharyngeal (OP) cancer, which is usually squamous cell carcinoma, is the most common head and neck malignancy, having a worldwide incidence of over 300 000 new cases each year and accounting for 2 -4% of all new cancers (Bross and Coombes, 1976;McGinnis and Foege, 1993;Collins et al, 1994;Ko et al, 1995;Piyathilake et al, 1995;Zheng et al, 1997;Nagler et al, 1999; Lippman and Hong, 2001). The commonly accepted paradigm for cigarette smoke (CS)-induced OP cancer pathogenesis is based on the assumption that a constant and direct attack of various CS carcinogens causes widespread accumulating cellular and DNA aberrations in the OP mucosa eventually leading to malignant transformation and cancer development. The CS-borne carcinogens are often thought to be free radicals. The process is initially expressed by dysplastic mucosal lesions which are then transformed into in situ carcinoma lesions, eventually resulting in fullblown infiltrating and metastasising OP cancer (Holleb et al, 1991). Chen et al (2002) demonstrated that chewing tobacco (areca quid) resulted in the formation of ROS in the oral cavity causing oxidative DNA damage to the surrounding tissues. Further support can be found in a report demonstrating that premalignant mucosal lesions and low-grade carcinomas express DNA aberrations following a pathway of exposure to free radicals (Sudb et al, 2001). Moreover, Bloching et al (2001) recently found increased genotoxic activity in the saliv...

Evaluation of salivary and serum lipid peroxidation, and glutathione in oral leukoplakia and oral squamous cell carcinoma

“…Further credence of saliva as an anticarcinogenic medium was demonstrated by Dayan et al, who conducted an animal study where he found that desalivated group of rats were more affected with pathological changes in shorter duration, as compared to controls on administration of 4-Nitroquinoline 1-oxide (4NQO), which is a local carcinogen. Thus, it can be concluded that saliva, detoxifies 4NQO and benzopyrene and protects against carcinogenesis (46).…”

The Effect of Tobacco Smoking on Salivation

“…Recent research confirms that smoking negatively affects the quality of saliva. Substances from cigarette smoke destroy protective macromolecules of saliva, enzymes and proteins, and thus saliva loses its protective role and becomes an agent in carcinogenesis and development of oral and oropharyngeal cancer (10)(11)(12).…”

The Dual Role of Saliva in Oral Carcinogenesis

“…Based on the results obtained and on the well-known observation that OSCC mostly occurs in oral epithelial cells exposed to tobacco and always in the presence of saliva, a comprehensive view of the pathogenesis of OSCC was suggested. It was also based on the recent studies mentioned [14, 15, 46, 48] which demonstrate an inhibition induced by CS of various salivary components. Of those components, the most important are those of the salivary protective machinery, such as peroxidase (the saliva-related indirect pathway).…”

“…Most interestingly, a new phenomenon was recently discovered in which a lethal synergistic effect of CS and saliva on oral cancer cells was demonstrated for the first time [48]. Its importance is due both to its novelty and to its possible biological and pathological significance.…”