Chronic Inflammation as a Link between Periodontitis and Carcinogenesis

Abstract

Periodontitis is characterized by a chronic inflammation produced in response to a disease-associated multispecies bacterial community in the subgingival region. Although the inflammatory processes occur locally in the oral cavity, several studies have determined that inflammatory mediators produced during periodontitis, as well as subgingival species and bacterial components, can disseminate from the oral cavity, contributing therefore, to various extraoral diseases like cancer. Interestingly, carcinogenesis associated with periodontal species has been observed in both the oral cavity and in extra oral sites. In this review, several studies were summarized showing a strong association between orodigestive cancers and poor oral health, presence of periodontitis-associated bacteria, tooth loss, and clinical signs of periodontitis. Proinflammatory pathways were also summarized. Such pathways are activated either by mono- or polymicrobial infections, resulting in an increase in the expression of proinflammatory molecules such as IL-6, IL-8, IL-1β, and TNF-α. In addition, it has been shown that several periodontitis-associated species induce the expression of genes related to cell proliferation, cell cycle, apoptosis, transport, and immune and inflammatory responses. Intriguingly, many of these pathways are linked to carcinogenesis. Among them, the activation of Toll-like receptors (TLRs) and antiapoptotic pathways (such as the PI3K/Akt, JAK/STAT, and MAPK pathways), the reduction of proapoptotic protein expression, the increase in cell migration and invasion, and the enhancement in metastasis are addressed. Considering that periodontitis is a polymicrobial disease, it is likely that mixed species promote carcinogenesis both in the oral cavity and in extra oral tissues and probably-as observed in periodontitis-synergistic and/or antagonistic interactions occur between microbes in the community. To date, a good amount of studies has allowed us to understand how monospecies infections activate pathways involved in tumorigenesis; however, more studies are needed to determine the combined effect of oral species in carcinogenesis.

Figure 1

Association of periodontal bacteria with orodigestive cancer. Periodontitis has been associated with orodigestive cancers through the chronic inflammation generated in the oral cavity and the concomitant mobilization of inflammatory mediators to distal sites in the human body, as well as a direct carcinogenic effect mediated by periodontitis-associated bacterial species either directly in oral cells or by migrating from the oral cavity.

Figure 2

Host response mechanisms of cellular transformation induced by periodontal bacteria. Inhibition of apoptosis, epithelial-mesenchymal transition (EMT), invasion and migration, metastasis, and proliferation are triggered through the activation of prooncogenic pathways by P. gingivalis (red arrows), T. denticola (purple arrows), F. nucleatum (yellow arrow), and P. gingivalis+F. nucleatum coinfection (orange arrows).