The Role of Fusobacterium nucleatum in Oral and Colorectal Carcinogenesis

Abstract

In recent years, several studies have suggested a strong association of microorganisms with several human cancers. Two periodontopathogenic species in particular have been mentioned frequently: Fusobacterium nucleatum (F. nucleatum) and Porphyromonas gingivalis. Chronic periodontal disease has been reported to be a risk factor for oral squamous cell carcinoma (OSCC), colorectal cancer (CRC) and pancreatic cancer. F. nucleatum is a Gram-negative anaerobic bacterium that lives in the oral cavity, urogenital, intestinal and upper digestive tract. It plays a significant role as a co-aggregation factor, with almost all bacterial species that participate in oral plaque formation acting as a bridge between early and late colonizers. F. nucleatum, gives an important inflammatory contribution to tumorigenesis progression and is associated with epithelial-derived malignancies, such as OSCC and CRC. F. nucleatum produces an adhesion protein, FadA, which binds to VE-cadherin on endothelial cells and to E-cadherins on epithelial cells. The last binding activates oncogenic pathways, such as Wnt/βcatenin, in oral and colorectal carcinogenesis. F. nucleatum also affects immune response because its Fap2 protein interacts with an immune receptor named TIGIT present on some T cells and natural killer cells inhibiting immune cells activities. Morover, F. nucleatum release outer membrane vesicles (OMVs), which induce the production of proinflammatory cytokines and initiating inflammation. F. nucleatum migrates from the oral cavity and reaches the colon hematogenously but it is not known if in the bloodstream it reaches the CRC as free, erythrocyte-bound bacteria or in OMV. F. nucleatum abundance in CRC tissue has been inversely correlated with overall survival (OS). The prevention and treatment of periodontal disease through the improvement of oral hygiene should be included in cancer prevention protocols. FadA virulence factors may also serve as novel targets for therapeutic intervention of oral and colorectal cancer.

Keywords: Wnt/βcatenin; colorectal cancer; immune response; oral microbiota; oral squamous cell carcinoma; periodontal bacteria.

Figure 1

Activation of Wnt/β-catenin pathway by F. nucleatum. F. nucleatum activates the oncogenic Wnt pathway by binding of FadA with E-cadherin. In OSCC occurrence and progression, F. nucleatum is reported to stimulate the binding of Wnt5a with its receptor Frizzled, thereby activating β-catenin. Image created with BioRender (https://biorender.com; last accessed on 28 July 2023).

Figure 2

F. nucleatum in the tumor microenvironment. In tumor cells without F.nucleatum infection, TILs are able to recognize and eliminate tumor cells also with the help of cytotoxic granules released containing granzymes and perforins. In the presence of F.nucleatum, its Fap2 protein specifically targets the inhibitory receptor TIGIT, thus protecting tumor cells from immune cell attack. Image created with BioRender (https://biorender.com; last accessed on 28 July 2023).