The Roles and Interactions of Porphyromonas gingivalis and Fusobacterium nucleatum in Oral and Gastrointestinal Carcinogenesis: A Narrative Review

Abstract

Epidemiological studies have spotlighted the intricate relationship between individual oral bacteria and tumor occurrence. Porphyromonas gingivalis and Fusobacteria nucleatum, which are known periodontal pathogens, have emerged as extensively studied participants with potential pathogenic abilities in carcinogenesis. However, the complex dynamics arising from interactions between these two pathogens were less addressed. This narrative review aims to summarize the current knowledge on the prevalence and mechanism implications of P. gingivalis and F. nucleatum in the carcinogenesis of oral squamous cell carcinoma (OSCC), colorectal cancer (CRC), and pancreatic ductal adenocarcinoma (PDAC). In particular, it explores the clinical and experimental evidence on the interplay between P. gingivalis and F. nucleatum in affecting oral and gastrointestinal carcinogenesis. P. gingivalis and F. nucleatum, which are recognized as keystone or bridging bacteria, were identified in multiple clinical studies simultaneously. The prevalence of both bacteria species correlated with cancer development progression, emphasizing the potential impact of the collaboration. Regrettably, there was insufficient experimental evidence to demonstrate the synergistic function. We further propose a hypothesis to elucidate the underlying mechanisms, offering a promising avenue for future research in this dynamic and evolving field.

Keywords: bateria–host interactions; colorectal cancers; microbial interaction; oral squamous cell carcinomas; pancreatic ductal carcinomas; periodontitis.

Figure 1

Multiple pathways employed by P. gingivalis in tumor induction: (1) P2X7 activation via ATP is blocked, leading to the stimulation of IL-1β, which promotes tumorigenesis, and the induction of ROS, which fosters a pro-inflammatory microenvironment. (2) Facilitation of immune evasion occurs through the activation of B7-H1 and B7-DC receptors, contributing to a (partial) circumvention of the immune system. Immune evasion is facilitated through the activation of B7-H1 and B7-DC receptors, contributing to a (partial) evasion of the immune system. (3) Activation of FimA results in the downregulation of p53, enhancing the host cell’s cell cycle while simultaneously suppressing apoptosis. The JAK/STAT axis is also implicated in the downregulation of apoptosis. (4) Additionally, P. gingivalis stimulates invasion through PAR2 activation via gingipains, activating NF-κB signaling, which leads to the formation of MMP-9, thereby enhancing P. gingivalis invasion. Upon invasion, pro-MMP-9 undergoes upregulation facilitated by ERK1/2 and ETS1, along with activation of p38 and HSP27. Abbreviations: ATP—adenosine triphosphate; ERK1/2—extracellular signal-regulated kinase 1/2; ETS1—protein; FimA—protein; HSP27—heat shock protein 27; IL-1β—interleukin-1β; JAK—Janus kinase 1; MMP-9—matrix metalloproteinase-9; NF-κB—nuclear factor kappa B; P2X7—purinergic receptor; pro-MMP-9—pro-matrix metalloproteinase-9; p38, p53—protein; ROS—reaction oxygen species; STAT—signal transducer and activator of transcription.

Figure 2

The potential mechanisms of F. nucleatum in cancer: (1) The virulence factor FadA binds to E-cadherin, subsequently activating β-catenin. This activation, in turn, triggers the transcription factor Myc, leading to the activation of cyclin-D. The activation of cyclin-D stimulates host cell survival and proliferation. (2) F. nucleatum enhances invasion by activating p38, Etk, p70, and RhoA, resulting in the upregulation of MMP-13. Abbreviations: Etk—tyrosine kinase; FadA—Fusobacterium adhesin A; MMP-13—matrix metalloproteinase-13; p38—protein kinase; p70—S6 kinase; RhoA—kinase.