Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model.

// Adi Binder Gallimidi 1, 2 , Stuart Fischman 2 , Brurya Revach 1 , Raanan Bulvik 1 , Alina Maliutina 2 , Ariel M. Rubinstein 1 , Gabriel Nussbaum 2, * , Michael Elkin 1, * 1 Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel 2 Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel * These authors have contributed equally to this work Correspondence to: Michael Elkin, e-mail: melkin@hadassah.org.il Gabriel Nussbaum, e-mail: gabrieln@ekmd.huji.ac.il Keywords: oral cancer, TLR2, STAT3, IL-6, periodontitis Received: April 16, 2015      Accepted: May 26, 2015      Published: June 08, 2015 ABSTRACT Oral squamous cell carcinoma (OSCC) is a lethal disease whose incidence is increasing. Epidemiologic studies demonstrate an association between periodontitis and oral cancer, and periodontal pathogens are implicated in the pathogenesis of numerous disorders, including rheumatoid arthritis, cardiovascular diseases, diabetes and gastrointestinal malignancies. Nevertheless, a causal role for periodontal pathogens in OSCC has not been shown, partly due to the lack of an appropriate animal model. Here, utilizing a newly-established murine model of periodontitis-associated oral tumorigenesis, we report that chronic bacterial infection promotes OSCC, and that augmented signaling along the IL-6-STAT3 axis underlies this effect. Our results indicate that periodontal pathogens P. gingivalis and F. nucleatum stimulate tumorigenesis via direct interaction with oral epithelial cells through Toll-like receptors. Furthermore, oral pathogens stimulate human OSCC proliferation and induce expression of key molecules implicated in tumorigenesis. To the best of our knowledge, these findings represent the first demonstration of a mechanistic role for oral bacteria in chemically induced OSCC tumorigenesis. These results are highly relevant for the design of effective prevention and treatment strategies for OSCC.