Periodontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model
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Adi Binder Gallimidi1,2, Stuart Fischman2, Brurya Revach1, Raanan Bulvik1, Alina Maliutina2, Ariel M. Rubinstein1, Gabriel Nussbaum2,*, Michael Elkin1,*
1Sharett Oncology Institute, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
2Institute of Dental Sciences, Hebrew University-Hadassah Faculty of Dental Medicine, Jerusalem, Israel
*These authors have contributed equally to this work
Michael Elkin, e-mail: email@example.com
Gabriel Nussbaum, e-mail: firstname.lastname@example.org
Keywords: oral cancer, TLR2, STAT3, IL-6, periodontitis
Received: April 16, 2015 Accepted: May 26, 2015 Published: June 08, 2015
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.
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