Oral microbiota in the oral-genitourinary axis: identifying periodontitis as a potential risk of genitourinary cancers

Abstract

Periodontitis has been proposed as a novel risk factor of genitourinary cancers: although periodontitis and genitourinary cancers are two totally distinct types of disorders, epidemiological and clinical studies, have established associations between them. Dysbiosis of oral microbiota has already been established as a major factor contributing to periodontitis. Recent emerging epidemiological evidence and the detection of oral microbiota in genitourinary organs indicate the presence of an oral-genitourinary axis and oral microbiota may be involved in the pathogenesis of genitourinary cancers. Therefore, oral microbiota provides the bridge between periodontitis and genitourinary cancers. We have carried out this narrative review which summarizes epidemiological studies exploring the association between periodontitis and genitourinary cancers. We have also highlighted the current evidence demonstrating the capacity of oral microbiota to regulate almost all hallmarks of cancer, and proposed the potential mechanisms of oral microbiota in the development of genitourinary cancers.

Keywords: Kidney neoplasms; Oral microbiota; Oral-genitourinary axis; Periodontitis; Prostatic neoplasms; Urinary bladder neoplasms; Urogenital neoplasms.

Fig. 1

Oral microbiota in periodontal health (left) and disease (right). The predominant bacteria identified by Human Microbiome project or NGS-based studies in periodontal health (left) and periodontal disease (right) are shown in the figure. F. nucleatum acts as a mutualist in healthy periodontal tissue. In periodontitis, F. nucleatum turns into an opportunistic pathogen and functions as a bridge organism to bind P. gingivalis through the fusobacterial adhesins RadD, Fap2 and FomA. NGS next-generation sequencing

Fig. 2

Main effects of individual members of the oral microbiota on hallmarks of cancer. Selected examples of oral microbiota and their molecular mechanisms are shown to be modulating each of the cancer hallmarks, including sustaining proliferative signaling (a), evading growth suppressors (b), resisting cell death (c), enabling replicative immortality (d), activating invasion and metastasis (e), reprogramming of energy metabolism (f), promoting genome instability (g), inducing angiogenesis (h), inducing tumor-promoting inflammation (i), and evading immune destruction (j). DSBs double-strand breaks, ERK extracellular regulated protein kinases, F. nucleatum Fusobacterium nucleatum, H₂S hydrogen sulfide, LPS lipopolysaccharide, miR-21 MicroRNA 21, MMP-9 matrix metalloproteinase-9, MSI microsatellite instability, OMP outer membrane protein, OMVs outer membrane vesicles, OXPHOS oxidative phosphorylation, P. gingivalis Porphyromonas gingivalis, PAD peptidyl arginine deaminase, PI3K phosphatidylinositol 3-kinase, Sp1 specificity protein 1, TCF transcription factor, TERT telomerase reverse transcriptase, TIGIT T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain, TLR4 toll-like receptor 4, VEGF-A vascular endothelial growth factor-A

Fig. 3

Potential molecular mechanisms by which oral microbiota promote genitourinary cancers. a Oral bacteria, bacterial metabolites, and inflammatory factors enter into human blood. b Oral bacteria, bacterial metabolites, and inflammatory are delivered via blood vessels. c Oral bacteria may colonize the urinary system through blood vessel. Subsequently, the structural components of bacteria (e.g., LPS, FadA) and bacterial metabolites (e.g., gingipains) promote the development of bladder, prostate and kidney cancer. Meanwhile, the long-term presence of inflammatory cells and inflammatory molecules in the systemic circulation is associated with the early formation of primary epithelial tumors in bladder, kidney, and prostate cancers, and promote the excessive proliferation, invasiveness, and angiogenesis of cancer cells. A. actinomycetemcomitans Aggregatibacter actinomycetemcomitans, F. nucleatum Fusobacterium nucleatum, P. gingivalis Porphyromonas gingivalis