Abstract
Oral squamous cell carcinoma (OSCC) is the most common type of oral cancer. Its development has been associated with diverse factors such as tobacco smoking and alcohol consumption. In addition, it has been suggested that microorganisms are risk factors for oral carcinogenesis. Epstein–Barr virus (EBV), which establishes lifelong persistent infections and is intermittently shed in the saliva, has been associated with several lymphomas and carcinomas that arise in the oral cavity. In particular, it has been detected in a subset of OSCCs. Moreover, its presence in patients with periodontitis has also been described. Porphyromonas gingivalis (P. gingivalis) is an oral bacterium in the development of periodontal diseases. As a keystone pathogen of periodontitis, P. gingivalis is known not only to damage local periodontal tissues but also to evade the host immune system and eventually affect systemic health. Persistent exposure to P. gingivalis promotes tumorigenic properties of oral epithelial cells, suggesting that chronic P. gingivalis infection is a potential risk factor for OSCC. Given that the oral cavity serves as the main site where EBV and P. gingivalis are harbored, and because of their oncogenic potential, we review here the current information about the participation of these microorganisms in oral carcinogenesis, describe the mechanisms by which EBV and P. gingivalis independently or synergistically can collaborate, and propose a model of interaction between both microorganisms.
Highlights
Oral cancer develops in the lips, cheeks, floor of the mouth, mobile tongue, and hard palate, buccal alveolar bone, retromolar trigone, and soft palate [1]
Both pathogenic and mutualistic bacteria coevolve together to maintain oral homeostasis [76]. Under certain conditions, such as smoking, obesity, stress, diabetes, or even the presence of specific microorganism, the balance of the oral ecosystem is altered, allowing an increase in the number of pathogenic bacteria that produce damage in the tissue because of the expression of their virulence factors and the consequent host immune response [77]. This is called the theory of polymicrobial synergy and dysbiosis (PDS), which proposes that the loss of homeostasis is caused by keystone pathogens that communicate with the accessory pathogens, acting synergistically to support the virulence of the disease-associated organism and facilitating the progression toward pathogenesis [78]
Many studies have identified overexpressed or mutated genes related to oral tumorigenesis, among which are those involved in proliferation (PI3K/Akt/mTOR, NOTCH, H-ras), apoptosis regulation (Bcl2, Bax), cell-cycle control (p53, cyclin D, CDKN2), leading to increased migration and invasion (Zeb, Vimentin, Slug, Snail) (Figure 1) [109,110,111]
Summary
Oral cancer develops in the lips, cheeks, floor of the mouth, mobile tongue, and hard palate, buccal alveolar bone, retromolar trigone, and soft palate [1]. Tobacco smoking (TS) and alcohol consumption are often considered as the major risk factors for oral cancer [14,15]. Among smokers who never drink alcohol, there is a two-fold risk estimate for oral cavity and oropharyngeal cancer, which increases with frequency and duration of smoking, while drinking among non-smokers seems unrelated to oral cancer risk [16,17]. The risks of oral cancer increase at least five-fold in those subjects who both smoke tobacco and drink alcohol [15,16,17]. The purpose of this review is to describe the role of EBV and the periodontitis-associated bacteria, P. gingivalis, in the development of oral cancer, as well as to revise the current literature regarding the interaction between these two microorganisms
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