Fusobacterium nucleatum Promotes Colorectal Carcinogenesis by Modulating E-Cadherin/β-Catenin Signaling via its FadA Adhesin

Colorectal cancer (CRC) is one of the most frequent and deadly neoplasms worldwide. Genetic factors, lifestyle habits, and inflammation are important risk factors associated with CRC development. In recent years, growing evidence has supporting the significant role of the intestinal microbiome in CRC carcinogenesis. Disturbances in the healthy microbial balance, known as dysbiosis, are frequently observed in these patients. Pathogenic microorganisms that induce intestinal dysbiosis have become an important target to determine the role of bacterial infection in tumorigenesis. Interestingly, the presence of different bacterial strains, such as Fusobacterium nucleatum, has been detected in tissue and stool from patients with CRC and associated with substantial clinical and molecular features, as well as with patient therapy response. Therefore, understanding how the presence and levels of F. nucleatumstrains in the gut affect the risk of CRC onset and progression may inform suitable candidates for interventions focused on modulation of this bacteria. Here we review new insights into the role of gut microbiota in CRC carcinogenesis and the clinical utility of using the detection of F. nucleatum in different settings such as screening, prognosis, and microbiota modulation as a means to prevent cancer, augment therapies, and reduce adverse effects of treatment.

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The Intestinal Microbiota and Colorectal Cancer

Frontiers in Immunology ◽

10.3389/fimmu.2020.615056 ◽

2020 ◽

Vol 11 ◽

Author(s):

Yiwen Cheng ◽

Zongxin Ling ◽

Lanjuan Li

Keyword(s):

Oxidative Stress ◽

Colorectal Cancer ◽

Escherichia Coli ◽

Intestinal Microbiota ◽

Pathogenic Bacteria ◽

Large Population ◽

Fusobacterium Nucleatum ◽

Colorectal Carcinogenesis ◽

Complex Relationship ◽

Streptococcus Bovis

The intestinal microbiota, composed of a large population of microorganisms, is often considered a “forgotten organ” in human health and diseases. Increasing evidence indicates that dysbiosis of the intestinal microbiota is closely related to colorectal cancer (CRC). The roles for intestinal microorganisms that initiated and facilitated the CRC process are becoming increasingly clear. Hypothesis models have been proposed to illustrate the complex relationship between the intestinal microbiota and CRC. Recent studies have identified Streptococcus bovis, enterotoxigenic Bacteroides fragilis, Fusobacterium nucleatum, Enterococcus faecalis, Escherichia coli, and Peptostreptococcus anaerobius as CRC candidate pathogens. In this review, we summarized the mechanisms involved in microbiota-related colorectal carcinogenesis, including inflammation, pathogenic bacteria, and their virulence factors, genotoxins, oxidative stress, bacterial metabolites, and biofilm. We also described the clinical values of intestinal microbiota and novel strategies for preventing and treating CRC.

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Low Abundance Fusobacterium Nucleatum Supports Early Pregnancy Development – An In Vitro Study

Frontiers in Immunology ◽

10.3389/fimmu.2021.698045 ◽

2021 ◽

Vol 12 ◽

Author(s):

Martha Heusler ◽

Rebekka Einenkel ◽

Jens Ehrhardt ◽

Damián Oscar Muzzio ◽

Marek Zygmunt

Keyword(s):

Cell Lines ◽

Reproductive Tract ◽

Bacterial Species ◽

Embryo Implantation ◽

In Vitro Study ◽

Fusobacterium Nucleatum ◽

Trophoblastic Cell ◽

Local Conditions ◽

E Cadherin

Pregnancy success depends greatly on a balanced immune homeostasis. The detection of bacterial components in the upper reproductive tract in non-pregnant and pregnant women raised questions on its possible beneficial role in reproductive health. The local conditions that allow the presence of bacteria to harmonize with the establishment of pregnancy are still unknown. Among the described bacterial species in endometrial and placental samples, Fusobacterium nucleatum was found. It has been observed that F. nucleatum can induce tumorigenesis in colon carcinoma, a process that shares several features with embryo implantation. We propose that low concentrations of F. nucleatum may improve trophoblast function without exerting destructive responses. Inactivated F. nucleatum and E. coli were incubated with the trophoblastic cell lines HTR8/SVneo, BeWo, and JEG-3. Viability, proliferation, migratory capacity, invasiveness and the secretion of chemokines, other cytokines and matrix metalloproteinases were assessed. The presence of F. nucleatum significantly induced HTR8/SVneo invasion, accompanied by the secretion of soluble mediators (CXCL1, IL-6 and IL-8) and metalloproteinases (MMP-2 and MMP-9). However, as concentrations of F. nucleatum increased, these did not improve invasiveness, hindered migration, reduced cell viability and induced alterations in the cell cycle. Part of the F. nucleatum effects on cytokine release were reverted with the addition of a TLR4 blocking antibody. Other effects correlated with the level of expression of E-cadherin on the different cell lines tested. Low amounts of F. nucleatum promote invasion of HTR8/SVneo cells and induce the secretion of important mediators for pregnancy establishment. Some effects were independent of LPS and correlated with the expression of E-cadherin on trophoblasts.

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ROS-mediated lipid peroxidation as a result of Cu(ii) interaction with FomA protein fragments of F. nucleatum: relevance to colorectal carcinogenesis

Metallomics ◽

10.1039/c9mt00179d ◽

2019 ◽

Vol 11 (12) ◽

pp. 2066-2077 ◽

Cited By ~ 2

Author(s):

Monika Katarzyna Lesiów ◽

Urszula Katarzyna Komarnicka ◽

Agnieszka Kyzioł ◽

Alina Bieńko ◽

Piotr Pietrzyk

Keyword(s):

Reactive Oxygen Species ◽

Lipid Peroxidation ◽

Reactive Oxygen ◽

Fusobacterium Nucleatum ◽

Colorectal Carcinogenesis ◽

Oxygen Species ◽

Protein Fragments

The ability of Cu(ii) complexes with FomA protein fragments of Fusobacterium nucleatum (Fn) to produce reactive oxygen species (ROS) was determined.

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Detection of Fusobaterium nucleatum in feces and colorectal mucosa as a risk factor for colorectal cancer: a systematic review and meta-analysis

Systematic Reviews ◽

10.1186/s13643-020-01526-z ◽

2020 ◽

Vol 9 (1) ◽

Author(s):

Amal Idrissi Janati ◽

Igor Karp ◽

Claudie Laprise ◽

Hisham Sabri ◽

Elham Emami

Keyword(s):

Colorectal Cancer ◽

Systematic Review ◽

Systematic Reviews ◽

Meta Analysis ◽

Positive Association ◽

Fusobacterium Nucleatum ◽

Relevant Information ◽

Colorectal Carcinogenesis ◽

Qualitative Synthesis ◽

Tissue Samples

Abstract Background Colorectal cancer (CRC) is a major cause of cancer deaths worldwide. Accumulating evidence suggests a potentially important role of colorectal infection with Fusobacterium nucleatum (F. nucleatum) in colorectal carcinogenesis. We conducted a systematic review, including both a qualitative synthesis and a meta-analysis, to synthesize the evidence from the epidemiological literature on the association between F. nucleatum detection in the colon/rectum and CRC. Methods A systematic literature search of Ovid MEDLINE(R), Embase, Web of Science Core Collection, EBM Reviews—Cochrane Database of Systematic Reviews, and CINAHL Plus with Full Text was conducted using earliest inclusive dates up to 4 October 2020. Eligible studies were original, comparative observational studies that reported results on colorectal F. nucleatum detection and CRC. Two independent reviewers extracted the relevant information. Odds ratio (OR) estimates were pooled across studies using the random effects model. Newcastle-Ottawa scale was used to critically appraise study quality. Results Twenty-four studies were included in the systematic review, of which 12 were included in the meta-analysis. Studies investigated F. nucleatum in feces, colorectal tissue samples, or both. In most studies included in the systematic review, the load of F. nucleatum was higher, on average, in specimens from CRC patients than in those from CRC-free controls. Meta-analysis showed a positive association between F. nucleatum detection in colorectal specimens and CRC (OR = 8.3; 95% confidence interval (95% CI) 5.2 to 13.0). Conclusions The results of this systematic review suggest that F. nucleatum in the colon/rectum is associated with CRC. Systematic review registration This systematic review protocol has been registered with the International Prospective Register of Systematic Reviews (PROSPERO) on July 10, 2018 (registration number CRD42018095866).

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Relationship between Fusobacterium nucleatum, inflammatory mediators and microRNAs in colorectal carcinogenesis

World Journal of Gastroenterology ◽

10.3748/wjg.v24.i47.5351 ◽

2018 ◽

Vol 24 (47) ◽

pp. 5351-5365 ◽

Cited By ~ 21

Author(s):

Marcela Alcântara Proença ◽

Joice Matos Biselli ◽

Maysa Succi ◽

Fábio Eduardo Severino ◽

Gustavo Noriz Berardinelli ◽

...

Keyword(s):

Inflammatory Mediators ◽

Fusobacterium Nucleatum ◽

Colorectal Carcinogenesis

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Role of the β-Catenin/REG Iα Axis in the Proliferation of Sessile Serrated Adenoma/Polyps Associated with Fusobacterium nucleatum

Pathogens ◽

10.3390/pathogens10040434 ◽

2021 ◽

Vol 10 (4) ◽

pp. 434

Author(s):

Heihachiro Nishimura ◽

Hirokazu Fukui ◽

Xuan Wang ◽

Nobuhiko Ebisutani ◽

Takashi Nakanishi ◽

...

Keyword(s):

Nuclear Translocation ◽

Fusobacterium Nucleatum ◽

Colorectal Carcinogenesis ◽

Cell Nuclei ◽

Sessile Serrated Adenoma ◽

Serrated Adenoma ◽

Reg Iα ◽

The Relationship

Although sessile serrated adenoma/polyps (SSA/Ps) may arise through a pathway different from the traditional adenoma–carcinoma sequence, details of SSA/P tumorigenesis still remain unclear. Fusobacterium nucleatum (Fn) is frequently detected in colorectal cancer (CRC) tissues and may play a pivotal role in colorectal carcinogenesis. Here, we investigated the relationship between Fn and the β-catenin/REG Iα axis in SSA/Ps and their involvement in the proliferation of these lesions. Fn was detected in SSA/Ps by fluorescence in situ hybridization using a Fn-targeted probe, and expression of β-catenin, REG Iα and Ki67 was examined using immunohistochemistry. Sixteen of 30 SSA/P lesions (53.3%) were positive for Fn. Eighteen SSA/P lesions (60%) showed β-catenin immunoreactivity in the tumor cell nuclei. A significant majority of Fn-positive lesions showed nuclear expression of β-catenin (87.5%) and higher REG Iα scores and Ki67 labeling indices relative to Fn-negative lesions. The SSA/P lesions expressing β-catenin in nuclei had significantly higher REG Iα scores and Ki67 labeling indices than those expressing β-catenin on cytomembranes. The REG Iα score was positively correlated with the Ki67 labeling index in SSA/P lesions. The treatment with Wnt agonist SKL2001 promoted nuclear β-catenin translocation and enhanced REG Ia expression in Caco2 cells. Fn may play a role in the proliferation of SSA/P lesions through promotion of β-catenin nuclear translocation and REG Iα expression.

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