Fusobacterium nucleatum infection correlates with two types of microsatellite alterations in colorectal cancer and triggers DNA damage.
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ABSTRACT:
SUBMITTER: Okita Y
PROVIDER: S-EPMC7526104 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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<i>Fusobacterium nucleatum</i> infection correlates with two types of microsatellite alterations in colorectal cancer and triggers DNA damage.
Okita Yoshiki Y Koi Minoru M Takeda Koki K Ross Ryan R Mukherjee Bhramar B Koeppe Erika E Stoffel Elena M EM Galanko Joseph A JA McCoy Amber N AN Keku Temitope O TO Okugawa Yoshinaga Y Kitajima Takahito T Toiyama Yuji Y Martens Eric E Carethers John M JM
Gut pathogens 20200929
<i>Fusobacterium nucleatum</i> (<i>Fn</i>) is frequently found in colorectal cancers (CRCs). High loads of <i>Fn</i> DNA are detected in CRC tissues with microsatellite instability-high (MSI-H), or with the <i>CpG</i> island hypermethylation phenotype (CIMP). <i>Fn</i> infection is also associated with the inflammatory tumor microenvironment of CRC. A subtype of CRC exhibits inflammation-associated microsatellite alterations (IAMA), which are characterized by microsatellite instability-low (MSI- ...[more]
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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:Fusobacterium nucleatum (Fn) has been frequently detected in colorectal cancer. A high load of Fn has been associated with subtypes of colorectal cancers, located in the proximal colon, exhibiting microsatellite instability-high (MSI-H), MLH1 promoter hypermethylation, the CpG island hypermethylation phenotype-high, or BRAF mutation in some studies. Although these features characterize the sessile serrated pathway (SSP) of colon cancers, other studies have shown that Fn infection is associated with KRAS mutations mainly characteristic of non-serrated neoplasia. It is also not clear at what point the association of Fn infection with these genomic alterations is established during colorectal carcinogenesis. Here we show that MSI-H, MLH1 hypermethylation, BRAF mutation or KRAS mutations were independently associated with Fn infection in colorectal cancer. On the other hand, increasing Fn copy number in tissues was associated with increased probability to exhibit MSI-H, MLH1 hypermethylation or BRAF mutations but not KRAS mutations in colorectal cancer. We also show that Fn load was significantly less than that of colorectal cancer and no association was detected between BRAF/KRAS mutations or MLH1 hypermethylation and Fn infection in adenomas. Our combined data suggest that increasing loads of Fn during and/or after adenomacarcinoma transition might promote SSP but not KRAS-driven colorectal carcinogenesis. Alternatively, Fn preferentially colonizes colorectal cancers with SSP and KRAS mutations but can expand more in colorectal cancers with SSP.SignificanceThe authors demonstrated that Fn is enriched in colorectal cancers exhibiting the SSP phenotype, and in colorectal cancers carrying KRAS mutations. Fn infection should be considered as a candidate risk factor specific to colorectal cancers with the SSP phenotype and with KRAS mutations.
| S-EPMC10530411 | biostudies-literature
Project description:The presence of Fusobacterium nucleatum (F. nucleatum) in colorectal carcinoma tissue has been associated with microsatellite instability (MSI), lower-level T-cell infiltrates, and poor clinical outcomes. Considering differences in the tumor-immune microenvironment between MSI-high and non-MSI-high carcinomas, we hypothesized that the association of F. nucleatum with immune response might differ by tumor MSI status. Using samples from 1,041 rectal and colon cancer patients within the Nurses' Health Study and Health Professionals Follow-up Study, we measured F. nucleatum DNA in tumor tissue by a quantitative polymerase chain reaction assay. Multivariable logistic regression models were used to examine the association between F. nucleatum status and histopathologic lymphocytic reactions or density of CD3+ cells, CD8+ cells, CD45RO (PTPRC)+ cells, or FOXP3+ cells in strata of tumor MSI status. We adjusted for potential confounders, including CpG island methylator phenotype; LINE-1 methylation; and KRAS, BRAF, and PIK3CA mutations. The association of F. nucleatum with tumor-infiltrating lymphocytes (TIL) and intratumoral periglandular reaction differed by tumor MSI status (P interaction = 0.002). The presence of F. nucleatum was negatively associated with TIL in MSI-high tumors [multivariable odds ratio (OR), 0.45; 95% confidence interval (CI), 0.22-0.92], but positively associated with TIL in non-MSI-high tumors (multivariable OR 1.91; 95% CI, 1.12-3.25). No significant differential association was observed for peritumoral lymphocytic reaction, Crohn-like lymphoid reaction, or T-cell densities. In conclusion, the association of F. nucleatum with immune response to colorectal carcinoma differs by tumor MSI status, suggesting that F. nucleatum and MSI status interact to affect antitumor immune reactions. Cancer Immunol Res; 6(11); 1327-36. ©2018 AACR See related Spotlight on p. 1290.
| S-EPMC6215508 | 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:ObjectiveAccumulating 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.DesignWe 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).ResultsCompared 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.ConclusionsThe 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: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: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:BackgroundGlobally, 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.MethodsC57BL/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.ResultsFusobacterium 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.ConclusionsIn 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.
| S-EPMC7523382 | 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
Project description:BackgroundFusobacterium nucleatum (Fn) acts as a procarcinogenic bacterium in colorectal carcinoma (CRC) by regulating the inflammatory tumor microenvironment (TME). Neutrophil extracellular traps (NETs), which can be generated by persistent inflammation, have been recently considered to be significant contributors in promoting cancer progression. However, whether NETs are implicated in Fn-related carcinogenesis is still poorly characterized. Here, we explored the role of NETs in Fn-related CRC as well as their potential clinical significance.MethodsFn was measured in tissue specimens and feces samples from CRC patients. The expression of NET markers were also detected in tissue specimens, freshly isolated neutrophils and blood serum from CRC patients, and the correlation of circulating NETs levels with Fn was evaluated. Cell-based experiments were conducted to investigate the mechanism by which Fn modulates NETs formation. In addition, we clarified the functional mechanism of Fn-induced NETs on the growth and metastasis of CRC in vitro and in vivo experiments.ResultsTissue and blood samples from CRC patients, particularly those from Fn-infected CRC patients, exhibited greater neutrophil infiltration and higher NETs levels. Fn infection induced abundant NETs production in in vitro studies. Subsequently, we demonstrated that Fn-induced NETs indirectly accelerated malignant tumor growth through angiopoiesis, and facilitated tumor metastasis, as manifested by epithelial-mesenchymal transition (EMT)-related cell migration, matrix metalloproteinase (MMP)-mediated basement membrane protein degradation, and trapping of CRC cells. Mechanistically, the Toll-like receptor (TLR4)-reactive oxygen species (ROS) signaling pathway and NOD-like receptor (NOD1/2)-dependent signaling were responsible for Fn-stimulated NETs formation. More importantly, circulating NETs combined with carcinoembryonic antigen (CEA) could predict CRC occurrence and metastasis, with areas under the ROC curves (AUCs) of 0.92 and 0.85, respectively.ConclusionsOur findings indicated that Fn-induced NETs abundance by activating TLR4-ROS and NOD1/2 signalings in neutrophils facilitated CRC progression. The combination of circulating NETs and CEA was identified as a novel screening strategy for predicting CRC occurrence and metastasis.
| S-EPMC10492297 | biostudies-literature