Periodontitis and risk of cancer: Mechanistic evidence

Abstract

This review aims to critically analyze the pathways of interaction and the pathogenic mechanisms linking periodontitis and oral bacteria with the initiation/progression of cancer at different body compartments. A higher risk of head and neck cancer has been consistently associated with periodontitis. This relationship has been explained by the local promotion of dysbiosis, chronic inflammation, immune evasion, and direct (epi)genetic damage to epithelial cells by periodontal pathobionts and their toxins. Epidemiological reports have also studied a possible link between periodontitis and the incidence of other malignancies at distant sites, such as lung, breast, prostate, and digestive tract cancers. Mechanistically, different pathways have been involved, including the induction of a chronic systemic inflammatory state and the spreading of oral pathobionts with carcinogenic potential. Indeed, periodontitis may promote low-grade systemic inflammation and phenotypic changes in the mononuclear cells, leading to the release of free radicals and cytokines, as well as extracellular matrix degradation, which are all mechanisms involved in carcinogenic and metastatic processes. Moreover, the transient hematogenous spill out or micro-aspiration/swallowing of periodontal bacteria and their virulence factors (i.e., lipopolysaccharides, fimbriae), may lead to non-indigenous bacterial colonization of multiple microenvironments. These events may in turn replenish the tumor-associated microbiome and thus influence the molecular hallmarks of cancer. Particularly, specific strains of oral pathobionts (e.g., Porphyromonas gingivalis and Fusobacterium nucleatum) may translocate through the hematogenous and enteral routes, being implicated in esophageal, gastric, pancreatic, and colorectal tumorigenesis through the modulation of the gastrointestinal antitumor immune system (i.e., tumor-infiltrating T cells) and the increased expression of pro-inflammatory/oncogenic genes. Ultimately, the potential influence of common risk factors, relevant comorbidities, and upstream drivers, such as gerovulnerability to multiple diseases, in explaining the relationship cannot be disregarded. The evidence analyzed here emphasizes the possible relevance of periodontitis in cancer initiation/progression and stimulates future research endeavors.

Keywords: epidemiology; neoplasms; periodontal disease; periodontal medicine; risk factors; systemic health/disease.

FIGURE 1

The proposed routes for a periodontitis signature in relation to the cancer hallmarks and enabling characteristics, described by Hanahan (2022). The presence and thickness of the arrows reflect the available amount of evidence.

FIGURE 2

(A) Proposed principal routes of periodontal inflammation and oral bacteria in cancer development. (B) In head and neck cancer, periodontal bacteria act by: 1. direct action of virulence factors; 2. epigenetic and gene expression modulation; 3. chronic inflammation via pathogen‐associated molecular patterns (PAMPs) and reactive oxygen species (ROS); 4. epithelial barrier dysfunction; and 5. immune evasion. (C) In pancreatic cancer, Fusobacterium nucleatum (Fn) and Porphyromonas gingivalis (Pg) may induce genetic damage and reduction of p53 triggering antiapoptotic characteristics within the intratumoral bacteriome, whereas their lipopolysaccharide may activate TLR‐4 and NF‐κB signaling, promoting inflammation. These bacteria also exert immune evasive effects on natural killer (NK) cells and promote elastase release from tumor‐associated polymorphonuclear cells (PMN). (D) In colorectal cancer, Fn may promote cell proliferation via FadA adhesin‐E‐cadherin interaction, a pro‐carcinogenic environment via miRNA‐mediated activation of TLR2/TLR4, and immune evasion by suppressing NK and effector T cells via the Fap2‐T‐cell immunoglobulin and ITIM domain (TIGIT) interaction.