Colorectal carcinogenesis, colorectal cancer development and Fusobacterium nucleatum

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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Conversion from epithelial to partial-EMT phenotype by Fusobacterium nucleatum infection promotes invasion of oral cancer cells

Scientific Reports ◽

10.1038/s41598-021-94384-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Wenhua Shao ◽

Natsumi Fujiwara ◽

Yasuhiro Mouri ◽

Satoru Kisoda ◽

Kayo Yoshida ◽

...

Keyword(s):

Gene Expression ◽

Colorectal Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Fusobacterium Nucleatum ◽

Cancer Development ◽

Mesenchymal Transition ◽

Epithelial Phenotype ◽

Oral Cancer Cells ◽

Metastatic Risk

Abstract The ability of cancer cells to undergo partial-epithelial mesenchymal transition (p-EMT), rather than complete EMT, poses a higher metastatic risk. Although Fusobacterium nucleatum mainly inhabits in oral cavity, attention has been focused on the F. nucleatum involvement in colorectal cancer development. Here we examined the p-EMT regulation by F. nucleatum in oral squamous cell carcinoma (OSCC) cells. We cultured OSCC cells with epithelial, p-EMT or EMT phenotype with live or heat-inactivated F. nucleatum. Expression of the genes involved in epithelial differentiation, p-EMT and EMT were examined in OSCC cells after co-culture with F. nucleatum by qPCR. Cell growth and invasion of OSCC cells were also examined. Both live and heat-inactivated F. nucleatum upregulated the expression of p-EMT-related genes in OSCC cells with epithelial phenotype, but not with p-EMT or EMT phenotype. Moreover, F. nucleatum promoted invasion of OSCC cells with epithelial phenotype. Co-culture with other strains of bacteria other than Porphyromonas gingivalis did not alter p-EMT-related genes in OSCC cells with epithelial phenotype. F. nucleatum infection may convert epithelial to p-EMT phenotype via altering gene expression in OSCC. Oral hygiene managements against F. nucleatum infection may contribute to reduce the risk for an increase in metastatic ability of OSCC.

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Both endogenous and exogenous miR-139–5p inhibit Fusobacterium nucleatum-related colorectal cancer development

European Journal of Pharmacology ◽

10.1016/j.ejphar.2020.173459 ◽

2020 ◽

Vol 888 ◽

pp. 173459

Author(s):

Yuyu Zhao ◽

Qianying Tao ◽

Shaoyu Li ◽

Peiyong Zheng ◽

Jianwen Liu ◽

...

Keyword(s):

Colorectal Cancer ◽

Fusobacterium Nucleatum ◽

Cancer Development

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Promoter Methylation Precedes Chromosomal Alterations in Colorectal Cancer Development

Analytical Cellular Pathology ◽

10.1155/2006/846251 ◽

2006 ◽

Vol 28 (5-6) ◽

pp. 247-257 ◽

Cited By ~ 1

Author(s):

Sarah Derks ◽

Cindy Postma ◽

Peter T. M. Moerkerk ◽

Sandra M. van den Bosch ◽

Beatriz Carvalho ◽

...

Keyword(s):

Colorectal Cancer ◽

Promoter Methylation ◽

Chromosomal Abnormalities ◽

Methylation Status ◽

Colorectal Carcinogenesis ◽

Cancer Development ◽

Comparative Genomic ◽

Early Event ◽

Chromosomal Alterations ◽

Normal Tissues

Background: Colorectal cancers are characterized by genetic and epigenetic alterations. This study aimed to explore the timing of promoter methylation and relationship with mutations and chromosomal alterations in colorectal carcinogenesis. Methods: In a series of 47 nonprogressed adenomas, 41 progressed adenomas (malignant polyps), 38 colorectal carcinomas and 18 paired normal tissues, we evaluated promoter methylation status of hMLH1, O6MGMT, APC, p14ARF, p16INK4A, RASSF1A, GATA-4, GATA-5, and CHFR using methylation-specific PCR. Mutation status of TP53, APC and KRAS were studied by p53 immunohistochemistry and sequencing of the APC and KRAS mutation cluster regions. Chromosomal alterations were evaluated by comparative genomic hybridization. Results: Our data demonstrate that nonprogressed adenomas, progressed adenomas and carcinomas show similar frequencies of promoter methylation for the majority of the genes. Normal tissues showed significantly lower frequencies of promoter methylation of APC, p16INK4A, GATA-4, and GATA-5 (P-values: 0.02, 0.02, 1.1×10−5 and 0.008 respectively). P53 immunopositivity and chromosomal abnormalities occur predominantly in carcinomas (P values: 1.1×10−5 and 4.1×10−10). Conclusions: Since promoter methylation was already present in nonprogressed adenomas without chromosomal alterations, we conclude that promoter methylation can be regarded as an early event preceding TP53 mutation and chromosomal abnormalities in colorectal cancer development.

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The Four Horsemen in Colon Cancer

Journal of Oncology ◽

10.1155/2019/5636272 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Marco Antonio Hernández-Luna ◽

Sergio López-Briones ◽

Rosendo Luria-Pérez

Keyword(s):

Colorectal Cancer ◽

Escherichia Coli ◽

Gastrointestinal Tract ◽

Salmonella Enterica ◽

Bacteroides Fragilis ◽

Fusobacterium Nucleatum ◽

Cancer Development ◽

Gastrointestinal Neoplasms ◽

Intestinal Dysbiosis ◽

Incidence And Mortality

Worldwide, neoplasms of the gastrointestinal tract have a very high incidence and mortality. Among these, colorectal cancer, which includes colon and rectum malignancies, representing both highest incidence and mortality. While gallbladder cancer, another neoplasm associated to gastrointestinal tract occurs less frequently. Genetic factors, inflammation and nutrition are important risk factors associated with colorectal cancer development. Likewise, pathogenic microorganisms inducing intestinal dysbiosis have become an important scope to determine the role of bacterial infection on tumorigenesis. Interestingly, in human biopsies of different types of gastrointestinal tract cancer, the presence of different bacterial strains, such as Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis and Salmonella enterica have been detected, and it has been considered as a high-risk factor to cancer development. Therefore, pathogens infection could contribute to neoplastic development through different mechanisms; including intestinal dysbiosis, inflammation, evasion of tumoral immune response and activation of pro-tumoral signaling pathways, such as β catenin. Here, we have reviewed the suggested bacterial molecular mechanisms and their possible role on development and progression of gastrointestinal neoplasms, focusing mainly on colon neoplasms, where the bacteria Fusobacterium nucleatum, Escherichia coli, Bacteroides fragilis and Salmonella enterica infect.

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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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A prospective interventional trial on the effect of periodontal treatment on Fusobacterium nucleatum abundance in patients with colorectal tumours

Scientific Reports ◽

10.1038/s41598-021-03083-4 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Tsutomu Yoshihara ◽

Mitomu Kioi ◽

Junichi Baba ◽

Haruki Usuda ◽

Takaomi Kessoku ◽

...

Keyword(s):

Colorectal Cancer ◽

Fusobacterium Nucleatum ◽

Periodontal Treatment ◽

Cancer Development ◽

Low Grade ◽

Before And After ◽

Group A ◽

Stool Samples ◽

Low Grade Dysplasia ◽

Colorectal Tumours

AbstractFusobacterium nucleatum is associated with the progression of colorectal cancer. Thus, the possibility of preventing colorectal cancer or its progression by targeting F. nucleatum has been explored. As F. nucleatum is associated with periodontitis, we analysed whether treating periodontitis could influence F. nucleatum abundance in the colon. Patients with colorectal tumours who underwent colonoscopy were recruited. Patients diagnosed with periodontitis by a dentist were treated for approximately 3 months. Endoscopic resection of colorectal tumours was performed after periodontitis treatment, and resected tumours were pathologically classified as high-(HGD) or low-grade dysplasia (LGD). Saliva and stool samples were collected before and after the treatment. Of the 58 patients with colorectal tumours, 31 were included in the study, 16 showed improvement in periodontitis, and 11 showed no improvement. Stool F. nucleatum levels before treatment were significantly lower in the LGD group than in the HGD group. A significant decrease in faecal F. nucleatum levels was observed in patients who underwent successful treatment but not in those whose treatment failed. Salivary F. nucleatum levels were not altered in patients despite periodontal treatment. Thus, successful periodontitis treatment reduces stool F. nucleatum levels and may aid research on periodontitis and suppression of colorectal cancer development.

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The Role of the Gut Microbiota in Colorectal Cancer Causation

International Journal of Molecular Sciences ◽

10.3390/ijms20215295 ◽

2019 ◽

Vol 20 (21) ◽

pp. 5295 ◽

Cited By ~ 15

Author(s):

Alhinai ◽

Walton ◽

Commane

Keyword(s):

Colorectal Cancer ◽

Microbial Community ◽

Gut Microbiota ◽

Fusobacterium Nucleatum ◽

Colorectal Carcinogenesis ◽

Cell Behaviour ◽

Streptococcus Gallolyticus ◽

Chemically Induced ◽

Carcinogenic Process

Here, we reviewed emerging evidence on the role of the microbial community in colorectal carcinogenesis. A healthy gut microbiota promotes intestinal homeostasis and can exert anti-cancer effects; however, this microbiota also produces a variety of metabolites that are genotoxic and which can negatively influence epithelial cell behaviour. Disturbances in the normal microbial balance, known as dysbiosis, are frequently observed in colorectal cancer (CRC) patients. Microbial species linked to CRC include certain strains of Bacteroides fragilis, Escherichia coli, Streptococcus gallolyticus, Enterococcus faecalis and Fusobacterium nucleatum, amongst others. Whether these microbes are merely passive dwellers exploiting the tumour environment, or rather, active protagonists in the carcinogenic process is the subject of much research. The incidence of chemically-induced tumours in mice models varies, depending upon the presence or absence of these microorganisms, thus strongly suggesting influences on disease causation. Putative mechanistic explanations differentially link these strains to DNA damage, inflammation, aberrant cell behaviour and immune suppression. In the future, modulating the composition and metabolic activity of this microbial community may have a role in prevention and therapy.

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A Tale of Two Colons and Two Cancers

Swiss Surgery ◽

10.1024/1023-9332.9.1.3 ◽

2003 ◽

Vol 9 (1) ◽

pp. 3-7 ◽

Cited By ~ 5

Author(s):

Gervaz ◽

Bühler ◽

Scheiwiller ◽

Morel

Keyword(s):

Colorectal Cancer ◽

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Splenic Flexure ◽

Chromosomal Instability ◽

Proximal Colon ◽

Colorectal Carcinogenesis ◽

Physiological Data ◽

Central Hypothesis ◽

Group Stratification

The central hypothesis explored in this paper is that colorectal cancer (CRC) is a heterogeneous disease. The initial clue to this heterogeneity was provided by genetic findings; however, embryological and physiological data had previously been gathered, showing that proximal (in relation to the splenic flexure) and distal parts of the colon represent distinct entities. Molecular biologists have identified two distinct pathways, microsatellite instability (MSI) and chromosomal instability (CIN), which are involved in CRC progression. In summary, there may be not one, but two colons and two types of colorectal carcinogenesis, with distinct clinical outcome. The implications for the clinicians are two-folds; 1) tumors originating from the proximal colon have a better prognosis due to a high percentage of MSI-positive lesions; and 2) location of the neoplasm in reference to the splenic flexure should be documented before group stratification in future trials of adjuvant chemotherapy in patients with stage II and III colon cancer.

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Increased serum MMP-2, MMP-7, MMP-9, TIMP-1 and TIMP-2 levels in colorectal cancer development

Zeitschrift für Gastroenterologie ◽

10.1055/s-0031-1278460 ◽

2011 ◽

Vol 49 (05) ◽

Author(s):

I Hritz ◽

Z Varga ◽

M Juhász ◽

P Miheller ◽

Z Tulassay ◽

...

Keyword(s):

Colorectal Cancer ◽

Cancer Development

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