Abstract
Abstract
Oral cancer represents a significant health burden worldwide while periodontitis is a common chronic infection of the periodontium. Many studies have suggested the association between periodontal disease and oral cancer. Studies have shown that biofilms on oral cancer lesions are rich in anaerobic bacteria, known to be associated with periodontal disease. This establishes that periodontal bacteria are present in the oral cancer microenvironment and likely directly interact with cancer cells. Therefore, it is vital to understand the interactions between the oral bacteria and cancer cells in order to improve treatment outcomes. The aim of this study was to investigate the effect of periodontal bacteria on oral cancer cells. Three oral cancer cell lines (OQ01, BHY and HN) were polyinfected with 4 bacteria associated with chronic periodontitis (Tanneralla forsynthia, Treponema denticola, Porphyromonas gingivalis and Fusobacterium nucleatum). Likely because BHY and HN already have a high baseline level of IL-8, OQ01 alone showed significantly enhanced IL-8 secretion (P< 0.05) but enhanced TFG-β secretion was detected in all cell lines tested. Polybacterial infection of oral cancer cells also upregulated mRNA for MMP1 (40 fold) and MMP9 (more than 60 fold), which are known to enhance cancer cell invasiveness. In addition, the expression of ZEB1 (4 fold higher), an oncogene known to induce epithelial mesenchymal transition in cancer cells, and MYC, JAK1 and STAT3, oncogenes involved in cell survival, were all significantly enhanced in polybacterial infected cancer cells. Further analysis using OQ01 cells in a single bacterial infection showed that F. nucleatum alone had the same or greater effect (4 fold higher IL-8 secretion) as the polybacterial infection with all 4 bacteria. All three strains of F. nucleatum tested enhanced the invasiveness of the oral cancer cells in vitro. Interestingly, Fusobacterial supernatant alone was enough to induce the same invasive phenotype as live bacteria in OQ01. These results suggest that F. nucleatum is the main periodontal pathogen responsible for inducing an invasive phenotype in these oral cancer cells. For in vivo studies, we used a mouse model of infection-associated oral tumorigenesis, which included the induction of chronic periodontitis by P. gingivalis and F. nucleatum and the administration of an oral carcinogen 4-nitroquinoline-1-oxide (4NQO). The results demonstrated that infection with Fusobacteria and P. gingivalis promoted oral cancer progression and enhanced invasion compared to controls. Our data also showed that Fusobacteria enhanced both survival and invasiveness of oral cancer cells. Collectively, this is the first study revealing the interaction between oral cancer cells and multiple periodontal bacteria. The modulation of the tumor microenvironment by oral bacteria has the potential to identify target genes for cancer treatment and improve patients’ prognosis.
Citation Format: Amani Harrandah, Sasanka S. Chukkapalli, William JR Dunn, Ann Progulske-Fox, Edward K. Chan. Modulation of oral cancer cells survival and invasiveness by fusobacteria [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2824.