Replication Study: Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma.
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ABSTRACT:
SUBMITTER: Repass J
PROVIDER: S-EPMC5849410 | biostudies-literature | 2018 Mar
REPOSITORIES: biostudies-literature
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Project description:An estimated 15% or more of the cancer burden worldwide is attributable to known infectious agents. We screened colorectal carcinoma and matched normal tissue specimens using RNA-seq followed by host sequence subtraction and found marked over-representation of Fusobacterium nucleatum sequences in tumors relative to control specimens. F. nucleatum is an invasive anaerobe that has been linked previously to periodontitis and appendicitis, but not to cancer. Fusobacteria are rare constituents of the fecal microbiota, but have been cultured previously from biopsies of inflamed gut mucosa. We obtained a Fusobacterium isolate from a frozen tumor specimen; this showed highest sequence similarity to a known gut mucosa isolate and was confirmed to be invasive. We verified overabundance of Fusobacterium sequences in tumor versus matched normal control tissue by quantitative PCR analysis from a total of 99 subjects (p = 2.5 × 10(-6)), and we observed a positive association with lymph node metastasis.
| S-EPMC3266037 | biostudies-literature
Project description:ImportanceEvidence indicates a complex link between gut microbiome, immunity, and intestinal tumorigenesis. To target the microbiota and immunity for colorectal cancer prevention and therapy, a better understanding of the relationship between microorganisms and immune cells in the tumor microenvironment is needed. Experimental evidence suggests that Fusobacterium nucleatum may promote colonic neoplasia development by downregulating antitumor T cell-mediated adaptive immunity.ObjectiveTo test the hypothesis that a greater amount of F nucleatum in colorectal carcinoma tissue is associated with a lower density of T cells in tumor tissue.Design, setting, and participantsA cross-sectional analysis was conducted on 598 rectal and colon carcinoma cases in 2 US nationwide prospective cohort studies with follow-up through 2006, the Nurses' Health Study (participants enrolled in 1976) and the Health Professionals Follow-up Study (participants enrolled in 1986). Tissue collection and processing were performed from 2002 through 2008, and immunity assessment, 2008 through 2009. From 2013 through 2014, the amount of F nucleatum in colorectal carcinoma tissue was measured by quantitative polymerase chain reaction assay; we equally dichotomized positive cases (high vs low). Multivariable ordinal logistic regression analysis was conducted in 2014 to assess associations of the amount of F nucleatum with densities (quartiles) of T cells in tumor tissue, controlling for clinical and tumor molecular features, including microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 (LINE-1) methylation, and KRAS, BRAF, and PIK3CA mutation status. We adjusted the 2-sided α level to .013 for multiple hypothesis testing.Main outcomes and measuresDensities of CD3+, CD8+, CD45RO (protein tyrosine phosphatase receptor type C [PTPRC])+, and FOXP3+ T cells in tumor tissue, determined by means of tissue microarray immunohistochemical analysis and computer-assisted image analysis.ResultsF nucleatum was detected in colorectal carcinoma tissue in 76 (13%) of 598 cases. Compared with F nucleatum-negative cases, F nucleatum-high cases were inversely associated with the density of CD3+ T cells (for a unit increase in quartile categories of CD3+ T cells as an outcome: multivariable odds ratio, 0.47 [95% CI, 0.26-0.87]; P for trend = .006). The amount of F nucleatum was not significantly associated with the density of CD8+, CD45RO+, or FOXP3+ T cells (P fortrend = .24, .88, and .014, respectively).Conclusions and relevanceThe amount of tissue F nucleatum is inversely associated with CD3+ T-cell density in colorectal carcinoma tissue. On validation, our human population data may provide an impetus for further investigations on potential interactive roles of Fusobacterium and host immunity in colon carcinogenesis.
| S-EPMC4537376 | biostudies-literature
Project description:OBJECTIVE:Accumulating evidence links the intestinal microbiota and colorectal carcinogenesis. Fusobacterium nucleatum may promote colorectal tumour growth and inhibit T cell-mediated immune responses against colorectal tumours. Thus, we hypothesised that the amount of F. nucleatum in colorectal carcinoma might be associated with worse clinical outcome. DESIGN:We used molecular pathological epidemiology database of 1069 rectal and colon cancer cases in the Nurses' Health Study and the Health Professionals Follow-up Study, and measured F. nucleatum DNA in carcinoma tissue. Cox proportional hazards model was used to compute hazard ratio (HR), controlling for potential confounders, including microsatellite instability (MSI, mismatch repair deficiency), CpG island methylator phenotype (CIMP), KRAS, BRAF, and PIK3CA mutations, and LINE-1 hypomethylation (low-level methylation). RESULTS:Compared with F. nucleatum-negative cases, multivariable HRs (95% CI) for colorectal cancer-specific mortality in F. nucleatum-low cases and F. nucleatum-high cases were 1.25 (0.82 to 1.92) and 1.58 (1.04 to 2.39), respectively, (p for trend=0.020). The amount of F. nucleatum was associated with MSI-high (multivariable odd ratio (OR), 5.22; 95% CI 2.86 to 9.55) independent of CIMP and BRAF mutation status, whereas CIMP and BRAF mutation were associated with F. nucleatum only in univariate analyses (p<0.001) but not in multivariate analysis that adjusted for MSI status. CONCLUSIONS:The amount of F. nucleatum DNA in colorectal cancer tissue is associated with shorter survival, and may potentially serve as a prognostic biomarker. Our data may have implications in developing cancer prevention and treatment strategies through targeting GI microflora by diet, probiotics and antibiotics.
| S-EPMC4769120 | biostudies-literature
Project description:ObjectivesEvidence suggests a possible role of Fusobacterium nucleatum in colorectal carcinogenesis, especially in right-sided proximal colorectum. Considering a change in bowel contents and microbiome from proximal to distal colorectal segments, we hypothesized that the proportion of colorectal carcinoma enriched with F. nucleatum might gradually increase along the bowel subsites from rectum to cecum.MethodsA retrospective, cross-sectional analysis was conducted on 1,102 colon and rectal carcinomas in molecular pathological epidemiology databases of the Nurses' Health Study and the Health Professionals Follow-up Study. We measured the amount of F. nucleatum DNA in colorectal tumor tissue using a quantitative PCR assay and equally dichotomized F. nucleatum-positive cases (high vs. low). We used multivariable logistic regression analysis to examine the relationship of a bowel subsite variable (rectum, rectosigmoid junction, sigmoid colon, descending colon, splenic flexure, transverse colon, hepatic flexure, ascending colon, and cecum) with the amount of F. nucleatum.ResultsThe proportion of F. nucleatum-high colorectal cancers gradually increased from rectal cancers (2.5%; 4/157) to cecal cancers (11%; 19/178), with a statistically significant linear trend along all subsites (P<0.0001) and little evidence of non-linearity. The proportion of F. nucleatum-low cancers was higher in rectal, ascending colon, and cecal cancers than in cancers of middle segments.ConclusionsThe proportion of F. nucleatum-high colorectal cancers gradually increases from rectum to cecum. Our data support the colorectal continuum model that reflects pathogenic influences of the gut microbiota on neoplastic and immune cells and challenges the prevailing two-colon (proximal vs. distal) dichotomy paradigm.
| S-EPMC5543402 | biostudies-literature
Project description:Colorectal cancer (CRC) is an important threat to human health and the fourth leading cause of mortality worldwide. Accumulating evidence indicates that the composition of the intestinal flora is associated with the occurrence of CRC. Fusobacterium nucleatum (Fn), one of the highly enriched bacteria in CRC tissues, invades the mucosa with adhesion factors and virulence proteins, interacts with the host immune system and promotes the occurrence and development of CRC and chemoresistance. Fn infection is prevalent in human colorectal carcinoma, although the infection rate varies in different regions. Fn may be used as a prognostic indicator of CRC. It is important to understand the multi-pathway carcinogenic mechanisms associated with CRC in order to develop novel antibacterial drugs against Fn. The current review summarizes the role of Fn and relevant research concerning CRC published in recent years, focusing on Fn infection in CRC, pathogenesis of Fn, Fn-positive CRC treatment, screening and prevention strategies against Fn-positive CRC.
| S-EPMC6607099 | biostudies-literature
Project description:Colorectal cancer (CRC) is the third most prevalent cancer and second in terms of mortality. Emerging evidence from recent studies suggests a potential role of Fusobacterium nucleatum in the development of CRC. In this article, we review studies from different geographical regions examining the association between F. nucleatum and CRC, the detection methods and the tumorigenic mechanisms. Furthermore, we discuss the potential clinical impact of F. nucleatum in CRC and suggest future study directions.
| S-EPMC6618585 | biostudies-literature
Project description:Background: This study aimed to clarify the relationship between F. nucleatum levels and the prognosis of CRC, which is still controversial. Methods: Relevant articles were searched on PubMed, Web of Science, PMC and Embase up to April 7, 2020. Outcomes of interest included clinical characteristics, molecular characteristic and survival analysis. HR (OR), odds ratios (OR) and 95% confidence interval (CI) were calculated to explore the prognostic value and relationship of clinical characteristics of Fusobacterium nucleatum in CRC. Results: A total of 3626 CRC patients from 13 eligible studies were included. High levels of F. nucleatum were associated with worse prognosis, as such parameters as overall survival (OS) (hazard ratio [HR] = 1.40, 95% confidence interval [CI]: 1.40 - 1.63, P < 0.0001), disease-free survival (DFS) (HR = 1.71, 95% CI: 1.29-2.26, P = 0.0002), and cancer-specific survival (OR= 1.93, 95% CI: 1.42-2.62, P <0.0001). F. nucleatum levels were related with T3-T4 stage (OR = 2.20, 95% CI: 1.66-2.91, P < 0.00001), M1 stage (OR = 2.11, 95% CI: 1.25-3.56, P = 0.005), poor tumor differentiation (OR = 1.83, 95% CI: 1.11-3.03, P =0.02), microsatellite instability-high (OR = 2.53, 95% CI: 1.53-4.20, P = 0.0003), and KRAS mutation (OR =1.27, 95% CI: 1.00-1.61, P=0.05) showed. Conclusions: High levels of F. nucleatum suggest a poor prognosis and are associated with tumor growth, distant metastasis, poor differentiation, MSI-high, and KRAS mutation in CRC patients.
| S-EPMC7890333 | biostudies-literature
Project description:Gut microbiota are linked to chronic inflammation and carcinogenesis. Chemotherapy failure is the major cause of recurrence and poor prognosis in colorectal cancer patients. Here, we investigated the contribution of gut microbiota to chemoresistance in patients with colorectal cancer. We found that Fusobacterium (F.) nucleatum was abundant in colorectal cancer tissues in patients with recurrence post chemotherapy, and was associated with patient clinicopathological characterisitcs. Furthermore, our bioinformatic and functional studies demonstrated that F. nucleatum promoted colorectal cancer resistance to chemotherapy. Mechanistically, F. nucleatum targeted TLR4 and MYD88 innate immune signaling and specific microRNAs to activate the autophagy pathway and alter colorectal cancer chemotherapeutic response. Thus, F. nucleatum orchestrates a molecular network of the Toll-like receptor, microRNAs, and autophagy to clinically, biologically, and mechanistically control colorectal cancer chemoresistance. Measuring and targeting F. nucleatum and its associated pathway will yield valuable insight into clinical management and may ameliorate colorectal cancer patient outcomes.
| S-EPMC5767127 | biostudies-literature
Project description:Aspirin is a chemopreventive agent for colorectal adenoma and cancer (CRC) that, like many drugs inclusive of chemotherapeutics, has been investigated for its effects on bacterial growth and virulence gene expression. Given the evolving recognition of the roles for bacteria in CRC, in this work, we investigate the effects of aspirin with a focus on one oncomicrobe-Fusobacterium nucleatum We show that aspirin and its primary metabolite salicylic acid alter F. nucleatum strain Fn7-1 growth in culture and that aspirin can effectively kill both actively growing and stationary Fn7-1. We also demonstrate that, at levels that do not inhibit growth, aspirin influences Fn7-1 gene expression. To assess whether aspirin modulation of F. nucleatum may be relevant in vivo, we use the ApcMin/+ mouse intestinal tumor model in which Fn7-1 is orally inoculated daily to reveal that aspirin-supplemented chow is sufficient to inhibit F. nucleatum-potentiated colonic tumorigenesis. We expand our characterization of aspirin sensitivity across other F. nucleatum strains, including those isolated from human CRC tissues, as well as other CRC-associated microbes, enterotoxigenic Bacteroides fragilis, and colibactin-producing Escherichia coli Finally, we determine that individuals who use aspirin daily have lower fusobacterial abundance in colon adenoma tissues, as determined by quantitative PCR performed on adenoma DNA. Together, our data support that aspirin has direct antibiotic activity against F. nucleatum strains and suggest that consideration of the potential effects of aspirin on the microbiome holds promise in optimizing risk-benefit assessments for use of aspirin in CRC prevention and management.IMPORTANCE There is an increasing understanding of the clinical correlations and potential mechanistic roles of specific members of the gut and tumoral microbiota in colorectal cancer (CRC) initiation, progression, and survival. However, we have yet to parlay this knowledge into better CRC outcomes through microbially informed diagnostic, preventive, or therapeutic approaches. Here, we demonstrate that aspirin, an established CRC chemopreventive, exhibits specific effects on the CRC-associated Fusobacterium nucleatum in culture, an animal model of intestinal tumorigenesis, and in human colonic adenoma tissues. Our work proposes a potential role for aspirin in influencing CRC-associated bacteria to prevent colorectal adenomas and cancer, beyond aspirin's canonical anti-inflammatory role targeting host tissues. Future research, such as studies investigating the effects of aspirin on fusobacterial load in patients, will help further elucidate the prospect of using aspirin to modulate F. nucleatum in vivo for improving CRC outcomes.
| S-EPMC8092249 | biostudies-literature
Project description:Fusobacterium nucleatum (Fn), a bacterium present in the human oral cavity and rarely found in the lower gastrointestinal tract of healthy individuals1, is enriched in human colorectal cancer (CRC) tumours2-5. High intratumoural Fn loads are associated with recurrence, metastases and poorer patient prognosis5-8. Here, to delineate Fn genetic factors facilitating tumour colonization, we generated closed genomes for 135 Fn strains; 80 oral strains from individuals without cancer and 55 unique cancer strains cultured from tumours from 51 patients with CRC. Pangenomic analyses identified 483 CRC-enriched genetic factors. Tumour-isolated strains predominantly belong to Fn subspecies animalis (Fna). However, genomic analyses reveal that Fna, considered a single subspecies, is instead composed of two distinct clades (Fna C1 and Fna C2). Of these, only Fna C2 dominates the CRC tumour niche. Inter-Fna analyses identified 195 Fna C2-associated genetic factors consistent with increased metabolic potential and colonization of the gastrointestinal tract. In support of this, Fna C2-treated mice had an increased number of intestinal adenomas and altered metabolites. Microbiome analysis of human tumour tissue from 116 patients with CRC demonstrated Fna C2 enrichment. Comparison of 62 paired specimens showed that only Fna C2 is tumour enriched compared to normal adjacent tissue. This was further supported by metagenomic analysis of stool samples from 627 patients with CRC and 619 healthy individuals. Collectively, our results identify the Fna clade bifurcation, show that specifically Fna C2 drives the reported Fn enrichment in human CRC and reveal the genetic underpinnings of pathoadaptation of Fna C2 to the CRC niche.
| S-EPMC11006615 | biostudies-literature