The role of Fusobacterium nucleatum in colorectal cancer: from carcinogenesis to clinical management

Liquid biopsy, which generally refers to the analysis of biological components such as circulating nuclear acids and circulating tumor cells in body fluids, particularly in peripheral blood, has shown good capacity to overcome several limitations faced by conventional tissue biopsies. Emerging evidence in recent decades has confirmed the promising role of liquid biopsy in the clinical management of various cancers, including colorectal cancer, which is one of the most prevalent cancers and the second leading cause of cancer-related deaths worldwide. Despite the challenges and poor clinical outcomes, patients with metastatic colorectal cancer can expect potential clinical benefits with liquid biopsy. Therefore, in this review, we focus on the clinical prospects of liquid biopsy in metastatic colorectal cancer, specifically with regard to the recently discovered various biomarkers identified on liquid biopsy. These biomarkers have been shown to be potentially useful in multiple aspects of metastatic colorectal cancer, such as auxiliary diagnosis of metastasis, prognosis prediction, and monitoring of therapy response.

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Metabolic and Community Synergy of Oral Bacteria in Colorectal Cancer

mSphere ◽

10.1128/msphere.00102-16 ◽

2016 ◽

Vol 1 (3) ◽

Cited By ~ 62

Author(s):

Kaitlin J. Flynn ◽

Nielson T. Baxter ◽

Patrick D. Schloss

Keyword(s):

Colorectal Cancer ◽

Fusobacterium Nucleatum ◽

Oral Bacteria ◽

Oral Microbiota ◽

Community Members ◽

Content Type ◽

Bacterial Physiology ◽

Oral Biofilms ◽

Two Factors

ABSTRACT The oral periodontopathic bacterium Fusobacterium nucleatum has been repeatedly associated with colorectal tumors. Molecular analysis has identified specific virulence factors that promote tumorigenesis in the colon. However, other oral community members, such as members of the Porphyromonas spp., are also found with F. nucleatum on colonic tumors, and thus, narrow studies of individual pathogens do not take community-wide virulence properties into account. A broader view of oral bacterial physiology and pathogenesis identifies two factors that could promote colonization and persistence of oral bacterial communities in the colon. The polymicrobial nature of oral biofilms and the asaccharolytic metabolism of many of these species make them well suited to life in the microenvironment of colonic lesions. Consideration of these two factors offers a novel perspective on the role of oral microbiota in the initiation, development, and treatment of colorectal cancer.

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The Role of Fecal Fusobacterium nucleatum and pks+ Escherichia coli as Early Diagnostic Markers of Colorectal Cancer

Disease Markers ◽

10.1155/2021/1171239 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Kaixi Liu ◽

Xinran Yang ◽

Mi Zeng ◽

Yumeng Yuan ◽

Jianhong Sun ◽

...

Keyword(s):

Colorectal Cancer ◽

Escherichia Coli ◽

Characteristic Curve ◽

Fusobacterium Nucleatum ◽

Diagnostic Value ◽

Diagnostic Efficiency ◽

Serum Samples ◽

Accurate Analysis ◽

E Coli

Background. Accurate analysis of intestinal microbiota will facilitate establishment of an evaluating system for assessing colorectal cancer (CRC) risk and prognosis. This study evaluates the potential role of Fusobacterium nucleatum (F. nucleatum) and Escherichia coli with a pks gene (pks+ E. coli) in early CRC diagnosis. Methods. We recruited 139 patients, including CRC ( n = 60 ), colorectal adenomatous polyposis (CAP) ( n = 37 ), and healthy individuals ( n = 42 ) based on their colonoscopy examinations. We collected stool and serum samples from the participants and measured the relative abundance of F. nucleatum and pks+ E. coli in fecal samples by quantitative PCR. Receiver operating characteristic curve (ROC) analyses were used to analyze the diagnostic value of single or combined biomarkers. Results. Fecal F. nucleatum and pks+ E. coli levels were higher in the CRC group in either the CAP group or healthy controls ( P = 0.02 ; 0.01). There was no statistical difference in the distribution of F. nucleatum and pks+ E. coli in patients with different tumor sites ( P > 0.05 ). The combination of F. nucleatum+pks+ E. coli+CEA+CA19-9+FOBT was chosen as the optimal panel in differentiating both CRC and CAP from the controls. The combination of F. nucleatum, pks+ E. coli, and FOBT improved diagnostic efficiency. However, there was difficulty in differentiating CRC from CAP. Conclusion. Our results suggested that combining bacterial markers with conventional tumor markers improves the diagnostic efficiency for noninvasive diagnosis of CRC.

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Fusobacterium nucleatum Acts as a Pro-carcinogenic Bacterium in Colorectal Cancer: From Association to Causality

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.710165 ◽

2021 ◽

Vol 9 ◽

Author(s):

Shuang Wang ◽

Yang Liu ◽

Jun Li ◽

Lei Zhao ◽

Wei Yan ◽

...

Keyword(s):

Colorectal Cancer ◽

Tumor Microenvironment ◽

Tumor Tissue ◽

Symbiotic Bacterium ◽

Fusobacterium Nucleatum ◽

Future Studies ◽

The Past ◽

Common Cancer ◽

Research Gap

Colorectal cancer (CRC) is a common cancer worldwide with complex etiology. Fusobacterium nucleatum (F. nucleatum), an oral symbiotic bacterium, has been linked with CRC in the past decade. A series of gut microbiota studies show that CRC patients carry a high abundance of F. nucleatum in the tumor tissue and fecal, and etiological studies have clarified the role of F. nucleatum as a pro-carcinogenic bacterium in various stages of CRC. In this review, we summarize the biological characteristics of F. nucleatum and the epidemiological associations between F. nucleatum and CRC, and then highlight the mechanisms by which F. nucleatum participates in CRC progression, metastasis, and chemoresistance by affecting cancer cells or regulating the tumor microenvironment (TME). We also discuss the research gap in this field and give our perspective for future studies. These findings will pave the way for manipulating gut F. nucleatum to deal with CRC in the future.

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Fusobacterium nucleatum Promotes the Progression of Colorectal Cancer Through Cdk5-Activated Wnt/β-Catenin Signaling

Frontiers in Microbiology ◽

10.3389/fmicb.2020.545251 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xiang Li ◽

Jiepeng Huang ◽

Tingting Yu ◽

Xiaoting Fang ◽

Liqin Lou ◽

...

Keyword(s):

Colorectal Cancer ◽

Signaling Pathway ◽

Fusobacterium Nucleatum ◽

Underlying Mechanism ◽

Valuable Insight ◽

Direct Role ◽

Cellular Processes ◽

And Migration

Background/AimsGrowing evidence supports the direct link of Fusobacterium nucleatum with colorectal cancer (CRC). However, to date, the underlying mechanism of action remains poorly understood. In this study, we examined the effects of F. nucleatum on the progression of CRC and investigated whether cyclin-dependent kinase 5 (Cdk5) is involved in the effect through activating the Wnt/β-catenin signaling pathway.Materials and MethodsCRC tissues and matched histologically normal specimens were collected from patients who were diagnosed with CRC and underwent surgical treatment in our hospital between January 2018 and January 2019. Two human CRC cell lines, including DLD-1 and SW480, were utilized mainly for in vitro mechanistic investigations.ResultsThe abundance of F. nucleatum was significantly greater in CRC tissues than in cancer-free specimens, which was significantly correlated with the progression of CRC. In vitro investigations revealed that F. nucleatum significantly enhanced the proliferation and migration of CRC cells. Furthermore, F. nucleatum significantly induced the expression of Cdk5 and activation of the Wnt/β-catenin signaling pathway. Notably, knockdown of Cdk5 significantly abrogated the effects of F. nucleatum on cellular processes and Wnt/β-catenin signaling in relation to the progression of CRC.ConclusionThe results of this study demonstrate that F. nucleatum orchestrates a molecular network involving the direct role of Cdk5 in activating Wnt/β-catenin signaling to modulate CRC progression. Thus, in-depth investigations of F. nucleatum-associated molecular pathways may offer valuable insight into the pathogenesis of CRC, which may help further the development of treatment for this disease.

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Potential Use of Biotherapeutic Bacteria to Target Colorectal Cancer-Associated Taxa

International Journal of Molecular Sciences ◽

10.3390/ijms21030924 ◽

2020 ◽

Vol 21 (3) ◽

pp. 924 ◽

Cited By ~ 1

Author(s):

Garreth W. Lawrence ◽

Máire Begley ◽

Paul D. Cotter ◽

Caitriona M. Guinane

Keyword(s):

Colorectal Cancer ◽

Fusobacterium Nucleatum ◽

Host Immunity ◽

Associated Bacteria ◽

Health And Disease ◽

Inflammatory Bowel ◽

Key Drivers ◽

Potential Use

The role of the gut microbiome in human health and disease is the focus of much attention. It has been widely agreed upon that our gut bacteria play a role in host immunity, nutrient absorption, digestion, metabolism, and other key drivers of health. Furthermore, certain microbial signatures and specific taxa have also been associated with the development of diseases, such as obesity; inflammatory bowel disease; and, indeed, colorectal cancer (CRC), which is the focus of this review. By extension, such taxa represent potential therapeutic targets. In particular, the emerging human pathogen Fusobacterium nucleatum represents an important agent in CRC development and its control within the gastrointestinal tract is desirable. This paper reviews the principal bacterial pathogens that have been associated with CRC to date and discusses the in vitro and human studies that have shown the potential use of biotherapeutic strains as a means of targeting CRC-associated bacteria.

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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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FadA promotes DNA damage and progression of Fusobacterium nucleatum-induced colorectal cancer through up-regulation of chk2

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01677-w ◽

2020 ◽

Vol 39 (1) ◽

Cited By ~ 1

Author(s):

Pin Guo ◽

Zibin Tian ◽

Xinjuan Kong ◽

Lin Yang ◽

Xinzhi Shan ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Damage ◽

Fusobacterium Nucleatum ◽

Immunofluorescence Assay ◽

S Phase ◽

Polyposis Coli ◽

Tumor Number ◽

E Cadherin

Abstract Background Globally, colorectal cancer (CRC) affects more than 1 million people each year. In addition to non-modifiable and other environmental risk factors, Fusobacterium nucleatum infection has been linked to CRC recently. In this study, we explored mechanisms underlying the role of Fusobacterium nucleatum infection in the progression of CRC in a mouse model. Methods C57BL/6 J-Adenomatous polyposis coli (APC) Min/J mice [APC (Min/+)] were treated with Fusobacterium nucleatum (109 cfu/mL, 0.2 mL/time/day, i.g., 12 weeks), saline, or FadA knockout (FadA−/−) Fusobacterium nucleatum. The number, size, and weight of CRC tumors were determined in isolated tumor masses. The human CRC cell lines HCT29 and HT116 were treated with lentiviral vectors overexpressing chk2 or silencing β-catenin. DNA damage was determined by Comet assay and γH2AX immunofluorescence assay and flow cytometry. The mRNA expression of chk2 was determined by RT-qPCR. Protein expression of FadA, E-cadherin, β-catenin, and chk2 were determined by Western blot analysis. Results Fusobacterium nucleatum treatment promoted DNA damage in CRC in APC (Min/+) mice. Fusobacterium nucleatum also increased the number of CRC cells that were in the S phase of the cell cycle. FadA−/− reduced tumor number, size, and burden in vivo. FadA−/− also reduced DNA damage, cell proliferation, expression of E-cadherin and chk2, and cells in the S phase. Chk2 overexpression elevated DNA damage and tumor growth in APC (Min/+) mice. Conclusions In conclusion, this study provided evidence that Fusobacterium nucleatum induced DNA damage and cell growth in CRC through FadA-dependent activation of the E-cadherin/β-catenin pathway, leading to up-regulation of chk2.

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The Contemporary Role of Resection and Ablation in Colorectal Cancer Liver Metastases

Digestive Disease Interventions ◽

10.1055/s-0040-1715816 ◽

2020 ◽

Vol 04 (03) ◽

pp. 291-302

Author(s):

Mariam F. Eskander ◽

Christopher T. Aquina ◽

Aslam Ejaz ◽

Timothy M. Pawlik

Keyword(s):

Colorectal Cancer ◽

Portal Vein ◽

Surgical Oncology ◽

Portal Vein Ligation ◽

Safe Alternative ◽

Colorectal Cancer Liver Metastases ◽

Liver Remnant ◽

New Era ◽

Ablation Therapy

AbstractAdvances in the field of surgical oncology have turned metastatic colorectal cancer of the liver from a lethal disease to a chronic disease and have ushered in a new era of multimodal therapy for this challenging illness. A better understanding of tumor behavior and more effective systemic therapy have led to the increased use of neoadjuvant therapy. Surgical resection remains the gold standard for treatment but without the size, distribution, and margin restrictions of the past. Lesions are considered resectable if they can safely be removed with tumor-free margins and a sufficient liver remnant. Minimally invasive liver resections are a safe alternative to open surgery and may offer some advantages. Techniques such as portal vein embolization, association of liver partition with portal vein ligation for staged hepatectomy, and radioembolization can be used to grow the liver remnant and allow for resection. If resection is not possible, nonresectional ablation therapy, including radiofrequency and microwave ablation, can be performed alone or in conjunction with resection. This article presents the most up-to-date literature on resection and ablation, with a discussion of current controversies and future directions.

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The Critical Role of the miR-21-MEG2 Axis in Colorectal Cancer

Critical Reviews in Eukaryotic Gene Expression ◽

10.1615/critreveukaryotgeneexpr.2020036484 ◽

2020 ◽

Vol 30 (6) ◽

pp. 509-518

Author(s):

Zengtao Bao ◽

Shanting Gao ◽

Baoming Zhang ◽

Wenchao Shi ◽

Aimin Li ◽

...

Keyword(s):

Colorectal Cancer ◽

Critical Role

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