Periodontal pathogens promote cancer aggressivity via TLR/MyD88 triggered activation of Integrin/FAK signaling that is therapeutically reversible by a probiotic bacteriocin
Open accessAbstract
Epidemiological studies reveal significant associations between periodontitis and oral cancer. However, knowledge about the contribution of periodontal pathogens to oral cancer and potential regulatory mechanisms involved is limited. Previously, we showed that nisin, a bacteriocin and commonly used food preservative, reduced oral cancer tumorigenesis and extended the life expectancy in tumor-bearing mice. In addition, nisin has antimicrobial effects on key periodontal pathogens. Thus, the purpose of this study was to test the hypothesis that key periodontal pathogens (Porphyromonas gingivalis, Treponema denticola, and Fusobacterium nucleatum) promote oral cancer via specific host-bacterial interactions, and that bacteriocin/nisin therapy may modulate these responses. All three periodontal pathogens enhanced oral squamous cell carcinoma (OSCC) cell migration, invasion, tumorsphere formation, and tumorigenesis in vivo, without significantly affecting cell proliferation or apoptosis. In contrast, oral commensal bacteria did not affect OSCC cell migration. Pathogen-enhanced OSCC cell migration was mediated via integrin alpha V and FAK activation, since stably blocking alpha V or FAK expression abrogated these effects. Nisin inhibited these pathogen-mediated processes. Further, Treponema denticola induced TLR2 and 4 and MyD88 expression. Stable suppression of MyD88 significantly inhibited Treponema denticola-induced FAK activation and abrogated pathogen-induced migration. Together, these data demonstrate that periodontal pathogens contribute to a highly aggressive cancer phenotype via crosstalk between TLR/MyD88 and integrin/FAK signaling. Nisin can modulate these pathogen-mediated effects, and thus has therapeutic potential as an antimicrobial and anti-tumorigenic agent.
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Nisin was demonstrated in vitro to mitigate pathogen-mediated oral tumorigenesis, cancer cell migration, and cell invasion of oral squamous cell carcinoma, suggesting an anti-cancer role for commensal species.
“In addition, nisin was recently demonstrated in vitro to mitigate pathogen‐mediated oral tumorigenesis, cancer cell migration, and cell invasion of oral squamous cell carcinoma in vitro, thus suggesting an anti‐cancer role for commensal species.167”
From The oral microbiome: Role of key organisms and complex networks in oral health and disease (2021) · cites this paper as [167]
A mechanistic understanding of this was attributed to crosstalk between oral pathogens and integrin/focal adhesion kinase and toll-like receptor/Myd88 signaling pathways.
“Moreover, a mechanistic understanding of this was attributed to crosstalk between oral pathogens and integrin/focal adhesion kinase and toll‐like receptor/Myd88 signaling pathways.”
From The oral microbiome: Role of key organisms and complex networks in oral health and disease (2021) · cites this paper as [167]
T denticola, P gingivalis, and F nucleatum enhance cell migration, invasiveness, stemness, and oral tumorigenesis of oral squamous cell carcinomas but have little effect on cell proliferation and apoptosis.
“Their findings demonstrate that T denticola, P gingivalis, and F nucleatum enhance cell migration, invasiveness, stemness, and oral tumorigenesis of oral squamous cell carcinomas but have little effect on cell proliferation and apoptosis.167”
From The oral microbiome: Role of key organisms and complex networks in oral health and disease (2021) · cites this paper as [167]
These interactions were reversed by treatment with the bacteriocin nisin.
“Interestingly, these interactions were reversed by treatment with the bacteriocin, nisin.167”
From The oral microbiome: Role of key organisms and complex networks in oral health and disease (2021) · cites this paper as [167]
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References 151 · Cited by 134
- Authors
- Kamarajan, P., Ateia, I., Shin, J. M., Fenno, J. C., Le, C., Zhan, L., Chang, A., Darveau, R., & Kapila, Y. L.
- Affiliations
- University of California, San Francisco (US)
- Mansoura University (EG)
- University of Michigan (US)
- University of Washington (US)
- Corresponding author
- Kapila, Yvonne L.
- ORCID
- Venue
- PLOS Pathogens
- Publisher
- Public Library of Science (PLoS)
- Published
- 2020-10-01
- Volume
- 16
- Issue
- 10
- Pages
- e1008881
- ISSN
- 1553-7366 (ISSN-L)
- 1553-7374
- PMC
- PMC7529280
- OpenAlex
- W3091269252
- Cited by
- 134
- References
- 151
- Citations by year
- 2026: 23 · 2025: 29 · 2024: 20 · 2023: 20 · 2022: 24 · 2021: 17 · 2020: 1
- FWCI
- 15.80
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Pathogens (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute of Dental and Craniofacial Research (R01 DE025225, T32 DE 7057-38)
- International Association for Dental Research
- AAP-Sunstar
- Ministry of Higher Education, Egypt
- Topics
- Health Sciences › Dentistry › Periodontics › Oral microbiology and periodontitis research
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biotechnology › Cancer Research and Treatments
- Keywords
- periodontal pathogens, oral squamous cell carcinoma, nisin, Porphyromonas gingivalis, Treponema denticola, Fusobacterium nucleatum, ITGAV, focal adhesion kinase, TLR2, TLR4, tumor cell migration, tumor invasion, carcinogenesis, host-pathogen interaction, oral commensal bacteria
- MeSH terms
- Animals, Carcinoma, Squamous Cell, Cell Movement, Humans, Mice, Nude, Mouth Neoplasms, Periodontitis, Tumor Cells, Cultured, Integrins, Bacteroidaceae Infections, Porphyromonas gingivalis, Apoptosis, Probiotics, Xenograft Model Antitumor Assays, Cell Proliferation, Toll-Like Receptor 2, Mice, Focal Adhesion Kinase 1, Myeloid Differentiation Factor 88
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