Fusobacterium nucleatum: a new player in regulation of cancer development and therapeutic response

Abstract

A dysbiosis in microbial diversity or functionality can promote disease development. Emerging preclinical and clinical evidence emphasizes the interplay between microbiota and both disease evolution and the treatment response of different cancers. One bacterium that has garnered much attention in a few cancer microbiota studies is Fusobacterium nucleaum (Fn). To provide updated knowledge of the functional role of Fn in cancer prevention and management, this review summarizes the relationship among Fn, cancer, and chemoimmunotherapy response, with the potential mechanisms of action also intensively discussed, which will benefit the development of strategies to prevent or treat cancer via Fn-based therapeutic interventions.

Keywords: Fusobacterium nucleatum; chemoresistance; immune evasion; metastasis; tumor microenvironment.

Figure 1

Different cancers associated with Fn. Fn is a Gram-negative anaerobic bacillus that exists, among others, in the human oral cavity and the gastrointestinal tract. For carcinogenesis, the high abundance of Fn is associated with head and neck cancer, esophageal cancer, pancreatic cancer, prostatic cancer, cervical carcinoma, and breast cancer. Relative events reported in each cancer are listed in the rectangles. Fn: Fusobacterium nucleaum.

Figure 2

The mechanisms by which Fn initiates and promotes carcinogenesis and enhances disease progression. Fn plays an important role in the whole process of cancer carcinogenesis and progression, supporting the notion that Fn may have a causative role in different states of cancer rather than being a consequence of cancer development. (A,B) Mechanisms of FadA and Fap2 on host cell adherence and invasion. (C-E) Host responses for cancer initiation and promotion including DNA damage, antitumor immune evasion, and pro-inflammatory environment. (F,G) Fn-induced tumor invasion and metastasis for cancer progression. Fn: Fusobacterium nucleaum.

Figure 3

Specific mechanisms of drug resistance induced by Fn. The research on Fn-mediated drug resistance mainly focuses on autophagy activation (A,B) and apoptosis blockade (C-F). (A) Fn modulates endogenous LC3 and ATG7 expression to induce chemoresistance against 5-FU, CDDP, and docetaxel in ESCC. (B) Fn intervention induces a selective loss of miR-4802 and miR-18a*, leading to TLR4/MYD88-dependent autophagy activation and a CRC chemotherapeutic response to OXA and 5-FU. (C) Fn-mediated TLR4/MYD88/NF-κB pathway activation induces upregulation of BIRC3, which consequently cripples the level of cleaved caspase 3 and cleaved PARP caused by 5-FU. (D) In colon cancer cells, the apoptosis effects induced by OXA and 5-FU could be prevented by Fn-induced ANO1 upregulation. (E) Fn-induced overexpression of ANXA1 confers 5-FU resistance in colon cancer cells, but the specific mechanism needs further investigation. (F) Fn may downregulate p53 expression through the non-canonical Wnt/NFAT pathway to inhibit CDDP-induced apoptosis and migration in OSCC cells. Fn: Fusobacterium nucleaum; 5-FU: 5-fluorouracil; OXA: oxaliplatin; CRC: colorectal cancer; CDDP: cisplatin; ESCC: esophageal squamous cell carcinoma; BIRC3: baculoviral IAP repeat-containing protein 3; ANO1: Anoctamin-1; ANXA1: Annexin A1; OSCC: oral squamous cell carcinoma; PARP: poly ADP-ribose polymerase.