Periodontal pathogens promote cancer aggressivity via TLR/MyD88 triggered activation of Integrin/FAK signaling that is therapeutically reversible by a probiotic bacteriocin.

Pachiyappan Kamarajan,Islam Ateia,Ana Chang,Richard Darveau,Yvonne L Kapila,Jae M Shin,J Christopher Fenno,Charles Le,Ling Zhan,Renée M Tsolis

doi:10.1371/journal.ppat.1008881

Abstract

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.

Highlights

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and it is a major health burden [1,2,3]
Risk factors, including smoking, alcohol consumption and human papilloma virus (HPV) infection alone have not been sufficient in explaining the incidence and aggressive behaviors of Oral squamous cell carcinoma (OSCC)
We test whether periodontal pathogens promote oral cancer tumorigenesis, and whether bacteriocin/nisin treatment may modulate these responses

Summary

Introduction

Head and neck squamous cell carcinoma (HNSCC) is one of the most common cancers worldwide and it is a major health burden [1,2,3]. Oral squamous cell carcinoma (OSCC), a subset of HNSCC, is the most common malignant oral neoplasm. As risk factors, smoking, alcohol consumption and human papilloma virus (HPV) infection have been implicated [5,6,7]. These risk factors alone have not been sufficient in explaining the incidence and aggressive behaviors of OSCC. Other factors, such as oral dysbiosis may play an important role in OSCC tumor development, progression and metastasis, yet this has not been well explored

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