The role of Fusobacteria in oral cancer and immune evasion.

PURPOSE OF REVIEW: There is growing evidence that suggests a possible role for bacteria in the progression of cancer. Fusobacteria have been detected in different types of cancers, including colorectal and oral cancers. Fusobacteria are common opportunistic oral bacteria known to cause various infections. In this review, we focus on the association between Fusobacteria and cancer, specifically oral cancer, and provide insight into the role of Fusobacteria in carcinogenesis and immune evasion. RECENT FINDINGS: Recently, it has been suggested that Fusobacteria are among the bacteria that contribute to the progression of cancer and might affect disease prognosis and treatment outcome. Moreover, Fusobacteria might alter tumor microenvironment and have an impact on tumor immune response. Thus, understanding the effect of Fusobacteria on cancer cells and tumor microenvironment is crucial to improve treatment outcome. SUMMERY: Recent evidences suggest that Fusobacteria not only have an impact on tumor progression, but might also affect tumor immune response. Moreover, Fusobacteria presence in the tumor microenvironment might have an impact on treatment outcome and might be used as a prognostic factor.

Fusobacterium is enriched in oral cancer and promotes induction of programmed death-ligand 1 (PD-L1).

Recently, increased number of studies have demonstrated a relationship between the oral microbiome and development of head and neck cancer, however, there are few studies to investigate the role of oral bacteria in the context of the tumor microenvironment in a single head and neck subsite. Here, paired tumor and adjacent normal tissues from thirty-seven oral tongue squamous cell carcinoma (SCC) patients were subjected to 16S rRNA gene sequencing and whole exome sequencing (WES), in addition to RNA sequencing for tumor samples. We observed that Fusobacterium was significantly enriched in oral tongue cancer and that Rothia and Streptococcus were enriched in adjacent normal tissues. A decrease in alpha diversity was found in tumor when compared to adjacent normal tissues. While increased Fusobacterium in tumor samples was not associated with changes in immune cell infiltration, it was associated with increased PD-L1 mRNA expression. Therefore, we examined the effects of Fusobacterium on PD-L1 expression in head and neck SCC cell lines. We demonstrated that infection with Fusobacterium species can increase both PD-L1 mRNA and surface PD-L1 protein expression on head and neck cancer cell lines. The correlation between Fusobacterium and PD-L1 expression in oral tongue SCC, in conjunction with the ability of the bacterium to induce PD-L1 expression in vitro suggests a potential role for Fusobacterium on modulation of the tumor immune microenvironment in head and neck cancer.

Fusobacteria modulate oral carcinogenesis and promote cancer progression.

Background: Evidence suggest periodontal bacterial infection can contribute to oral cancer initiation and progression. Aim: To investigate the effects of periodontal bacteria on oral cancer cell behavior using a cell-based system and a mouse carcinogenesis model. Methods: Oral cancer cell lines were polyinfected with four periodontal bacteria. Cytokine levels and relative changes in oncogene mRNA expression were determined post-infection. Oral tumours in mice induced by 4-nitroquinoline-1-oxide (4NQO) were compared with and without administrating periodontal bacteria. Results: Polyinfected oral cancer cells had upregulated MMP1, MMP9, and IL-8. The expression of cell survival markers MYC, JAK1, and STAT3 and epithelial-mesenchymal transition markers ZEB1 and TGF-ß were also significantly elevated. Monoinfections showed F. nucleatum alone had comparable or greater effects than the four bacteria together. Fusobacterial culture supernatant, primarily LPS, was sufficient to induce IL-8 secretion, demonstrating that direct contact of live Fusobacteria with cancer cells might not be required to exert changes in cancer cell behaviour. In the 4NQO-induced oral tumour model, mice infected with bacteria developed significantly larger and more numerous lesions compared to those not infected. Conclusion: This study demonstrated that Fusobacteria could potentially enhance cancer cell invasiveness, survival, and EMT when presented in the oral tumour microenvironment. Abbreviations: 4NQO, 4-nitroquinoline-1-oxide; ELISA, enzyme-linked immunosorbent assay; EMT, epithelial-mesenchymal transition; IL-8, interleukin-8; JAK1, Janus kinase 1; LPS, lipopolysaccharide; MMP, matrix metalloproteinase; OSCCs, oral squamous cell carcinomas; PK, proteinase K; PMB, Polymyxin B; qRT-PCR, quantitative real-time polymerase chain reaction; STAT3, signal transducer and activator of transcription 3; TGF-ß, transforming growth factor beta; ZEB1, zinc finger E-Box binding homeobox 1.

Emerging microRNAs in cancer diagnosis, progression, and immune surveillance.

MicroRNAs (miRNAs) are small noncoding RNAs that function in post-transcriptional regulation of gene expression. Dysregulation of miRNAs has been reported in different stages of cancer development and progression. This dysregulation results in different miRNA profiles between cancer and normal tissues. Many studies have shown a significant correlation between miRNA profile and cancer diagnosis and prognosis. Additionally, since a single miRNA regulates multiple mRNA targets, miRNAs dysregulation can affect several pathways involved in cancer development. Finally, due to their regulatory role in immune cell development, many recent studies have reported that certain miRNAs play key roles in cancer immunology. In this brief review, we discuss the role of miR-21 and miR-375 in the RAS pathway as well as their role in cancer diagnosis and progression, along with the role of other select miRNAs in cancer immune surveillance.

MicroRNA-375 as a biomarker for malignant transformation in oral lesions.

OBJECTIVE: Malignant transformation of oral premalignant lesions is the key process in the progression to oral squamous cell carcinoma (OSCC). Previously, we identified miR-7 and miR-21 as candidate oncogenes and miR-375 and miR-494 as candidate tumor suppressors in OSCC. We aim to evaluate these microRNAs as biomarkers of malignant transformation in oral premalignant lesions. STUDY DESIGN: Formalin-fixed, paraffin-embedded samples from progressive premalignant lesions and paired sequential OSCC tumors at the same site were obtained from same patients (n = 31). Total RNA was extracted and analyzed for microRNA levels using real-time polymerase chain reaction. RESULTS: MiR-375 expression in progressive lesions was clearly lower than in nonprogressive control lesions (average eightfold difference, P = .0004). Furthermore, the expression of miR-375 decreased significantly after the progression from premalignant lesion to OSCC (P < .0001). Receiver operating characteristic curve analysis revealed that miR-375 was able to differentiate between progressive and nonprogressive premalignant lesions (P < .0001). CONCLUSIONS: MiR-375 downregulation in oral premalignant lesions is associated with a higher risk of malignant transformation.