From Beyond the Pale to the Pale Riders: The Emerging Association of Bacteria with Oral Cancer

Abstract

Oral cancer, predominantly oral squamous cell carcinoma (OSCC), is the eighth-most common cancer worldwide, with a 5-y survival rate <50%. There are numerous risk factors for oral cancer, among which periodontal disease is gaining increasing recognition. The creation of a sustained dysbiotic proinflammatory environment by periodontal bacteria may serve to functionally link periodontal disease and oral cancer. Moreover, traditional periodontal pathogens, such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola, are among the species most frequently identified as being enriched in OSCC, and they possess a number of oncogenic properties. These organisms share the ability to attach and invade oral epithelial cells, and from there each undergoes its own unique molecular dialogue with the host epithelium, which ultimately converges on acquired phenotypes associated with cancer, including inhibition of apoptosis, increased proliferation, and activation of epithelial-to-mesenchymal transition leading to increased migration of epithelial cells. Additionally, emerging properties of structured bacterial communities may increase oncogenic potential, and consortia of P. gingivalis and F. nucleatum are synergistically pathogenic within in vivo oral cancer models. Interestingly, however, some species of oral streptococci can antagonize the phenotypes induced by P. gingivalis, indicating functionally specialized roles for bacteria in oncogenic communities. Transcriptomic data support the concept that functional, rather than compositional, properties of oral bacterial communities have more relevance to cancer development. Collectively, the evidence is consistent with a modified polymicrobial synergy and dysbiosis model for bacterial involvement in OSCC, with driver mutations generating a conducive microenvironment on the epithelial boundary, which becomes further dysbiotic by the synergistic action of bacterial communities.

Keywords: F. nucleatum; OSCC; P. gingivalis; S. gordonii; T. denticola; polymicrobial synergy and dysbiosis.

Figure 1.

Potential mechanisms by which Porphyromonas gingivalis could affect cancer-associated processes in gingival epithelial cells. Peach: healthy epithelial cells. Blue: epithelial cells that have acquired an antiapoptotic phenotype. Purple: epithelial cells that have acquired an accelerated proliferation phenotype. Green: epithelial cells that have undergone epithelial-to-mesenchymal transition and have acquired an invasive phenotype. Note that for simplicity other contributing host and environmental factors are not depicted.

Figure 2.

Antagonistic interactions of Streptococcus gordonii on Porphyromonas gingivalis through activation of the TAK1-NLK host kinase cascade. P. gingivalis can dephosphorylate FOXO1 on serine residues, which prevents translocation from the nucleus to the cytoplasm, thus enhancing activity. When S. gordonii is present, the TAK1-NLK1 pathway is activated, which supersedes the effect of P. gingivalis and increases phosphorylation of FOXO1 on Ser329, thus allowing translocation of FOXO1 to the cytoplasm, where it is inactive. EMT, epithelial-to-mesenchymal transition.

Figure 3.

Schematic representation of polymicrobial synergy and dysbiosis model for oral squamous cell carcinoma. In health, the host responses to homeostatic communities are a eubiotic balance of proliferation with programmed cell death. Driver mutations lead to dysregulation of host processes, which can also be manipulated by organisms associated with a dysbiotic community. As the tumor microenvironment is established, anaerobic, gram-negative organisms are enriched as a result of hypoxic proinflammatory conditions. As organisms such as Porphyromonas gingivalis, Fusobacterium nucleatum, and Treponema denticola accumulate, the tumor cells can acquire an invasive phenotype through epithelial-to-mesenchymal transition, as well as increased resistance to chemotherapeutic drugs.