Role of Porphyromonas gingivalis in oral and orodigestive squamous cell carcinoma

Abstract

Oral and esophageal squamous cell carcinomas harbor a diverse microbiome that differs compositionally from precancerous and healthy tissues. Though causality is yet to be definitively established, emerging trends implicate periodontal pathogens such as Porphyromonas gingivalis as associated with the cancerous state. Moreover, infection with P. gingivalis correlates with a poor prognosis, and P. gingivalis is oncopathogenic in animal models. Mechanistically, properties of P. gingivalis that have been established in vitro and could promote tumor development include induction of a dysbiotic inflammatory microenvironment, inhibition of apoptosis, increased cell proliferation, enhanced angiogenesis, activation of epithelial-to-mesenchymal transition, and production of carcinogenic metabolites. The microbial community context is also relevant to oncopathogenicity, and consortia of P. gingivalis and Fusobacterium nucleatum are synergistically pathogenic in oral cancer models in vivo. In contrast, oral streptococci, such as Streptococcus gordonii, can antagonize protumorigenic epithelial cell phenotypes induced by P. gingivalis, indicating functionally specialized roles for bacteria in oncogenic communities. Consistent with the notion of the bacterial community constituting the etiologic unit, metatranscriptomic data indicate that functional, rather than compositional, properties of the tumor-associated communities have more relevance to cancer development. A consistent association of P. gingivalis with oral and orodigestive carcinoma could have diagnostic potential for early detection of these conditions that have a high incidence and low survival rates.

Keywords: community; gingivalis; squamous cell carcinoma.

FIGURE 1

Potential tumorigenic activity of Porphyromonas gingivalis in oral squamous cell carcinoma. A, Effector molecules of P. gingivalis that have been associated with a tumorigenic function. B, Tumorigenic effects of P. gingivalis on the oral epithelium. Green font denotes components that are activated or increased in messenger RNA or protein amounts. Red font denotes components that are suppressed or decreased in messenger RNA or protein amounts. EMT, epithelial-mesenchymal transition; LPS, lipopolysaccharide; NDK, nucleoside diphosphate kinase

FIGURE 2

Impact of Porphyromonas gingivalis on pathways associated with epithelial-mesenchymal transition and the mitigating effect of Streptococcus gordonii. Transcription factors upregulated by P. gingivalis are shown, although the pathways have not been defined in all cases. MMPs, metalloproteinases. P indicates phosphorylation

FIGURE 3

Interplay between Porphyromonas gingivalis and Streptococcus gordonii in the activation of Notch1 signaling and upregulation of olfactomedin 4 (OLFM4). Activation of Notch signaling is induced through increased expression of the Notch1 receptor and the Jagged1 (Jag1) agonist. In addition, Jagged1 is released in response to P. gingivalis, leading to paracrine activation. Following Jagged1-Notch1 engagement, the Notch1 extracellular domain is cleaved by P. gingivalis gingipain proteases. Antagonism by S. gordonii involves inhibition of gingipain activity by secreted hydrogen peroxide. Olfactomedin 4 is involved in epithelial cell migratory, proliferative and inflammatory responses to P. gingivalis. ICD: intracellular domain