Fusobacterium nucleatum and oral cancer: a critical review

Abstract

There is a growing level of interest in the potential role inflammation has on the initiation and progression of malignancy. Notable examples include Helicobacter pylori-mediated inflammation in gastric cancer and more recently Fusobacterium nucleatum-mediated inflammation in colorectal cancer. Fusobacterium nucleatum is a Gram-negative anaerobic bacterium that was first isolated from the oral cavity and identified as a periodontal pathogen. Biofilms on oral squamous cell carcinomas are enriched with anaerobic periodontal pathogens, including F. nucleatum, which has prompted hypotheses that this bacterium could contribute to oral cancer development. Recent studies have demonstrated that F. nucleatum can promote cancer by several mechanisms; activation of cell proliferation, promotion of cellular invasion, induction of chronic inflammation and immune evasion. This review provides an update on the association between F. nucleatum and oral carcinogenesis, and provides insights into the possible mechanisms underlying it.

Keywords: Carcinogenesis; F. nucleatum; Fusobacteria; OSCC; Oral cancer.

Fig. 1

Oncogenic role of STAT3. STAT3 controls various tumour-associated genes which can influence proliferation, angiogenesis, invasion and metastasis. *Genes (in bold) known to be upregulated as a result of STAT3 activation in oral cancer cells infected with F. nucleatum

Fig. 2

Hallmarks of cancer influenced my F. nucleatum infection. (1) Production of reactive oxygen species (ROS) and cytokines by F. nucleatum causes DNA damage resulting in genomic instability. (2) F. nucleatum infection in HNSCC causes hypermethylation of CpG islands located in the promoter regions of tumour suppressor genes LXN and SMARCA2 resulting in their inactivation. Downregulation of p27, Ku70 and p53 tumour suppressor genes in OSCC results in weakened cell repair ability and increased cell proliferation. (3) LPS/TLR4 signalling results in cytokine production and NF-κB activation which is responsible for tumour-promoting inflammation. Activation of STAT3 upregulates multiple genes responsible for cell proliferation, invasion and metastasis. Upregulated expression of microRNA-21 promotes proliferation of cancer cells. (4) Fusobacterial FadA binds to E-cadherin resulting in decreased phosphorylation of β-catenin. Subsequently, β-catenin translocates to the nucleus, resulting in cell proliferation with increased expression of oncogenic and inflammatory genes. (5) Fusobacterial Fap2 can protect tumours from immune cell attack by inhibiting T-cells and Natural Killer cells. Figure created with BioRender.com