Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway
TL;DR: The presence of F. nucleatum was identified in premalignant colorectal lesions regardless of histopathology but was more frequently associated with CIMP‐high lesions, and its positivity increased according to histological grade, suggesting that it may contribute to the progression of coloreCTal neoplasia.
Abstract: Human gut microbiota is being increasingly recognized as a player in colorectal cancers (CRCs). Evidence suggests that Fusobacterium nucleatum (F. nucleatum) may contribute to disease progression and is associated with CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in CRCs; however, to date, there are no reports about the relationship between F. nucleatum and molecular features in the early stage of colorectal tumorigenesis. Therefore, we investigated the presence of F. nucleatum in premalignant colorectal lesions. In total, 465 premalignant lesions (343 serrated lesions and 122 non-serrated adenomas) and 511 CRCs were studied. We determined the presence of F. nucleatum and analyzed its association with molecular features including CIMP, MSI and microRNA-31 status. F. nucleatum was detected in 24% of hyperplastic polyps, 35% of sessile serrated adenomas (SSAs), 30% of traditional serrated adenomas (TSAs) and 33% of non-serrated adenomas. F. nucleatum was more frequently detected in CIMP-high premalignant lesions than in CIMP-low/zero lesions (p = 0.0023). In SSAs, F. nucleatum positivity increased gradually from sigmoid colon to cecum (p = 0.042). F. nucleatum positivity was significantly higher in CRCs (56%) than in premalignant lesions of any histological type (p < 0.0001). In conclusion, F. nucleatum was identified in premalignant colorectal lesions regardless of histopathology but was more frequently associated with CIMP-high lesions. Moreover, F. nucleatum positivity increased according to histological grade, suggesting that it may contribute to the progression of colorectal neoplasia. Our data also indicate that F. nucleatum positivity in SSAs may support the "colorectal continuum" concept.
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TL;DR: Col colonization of human colorectal cancers with Fusobacterium and its associated microbiome—including Bacteroides, Selenomonas, and Prevotella species—is maintained in distal metastases, demonstrating microbiome stability between paired primary and metastatic tumors.
Abstract: Colorectal cancers comprise a complex mixture of malignant cells, nontransformed cells, and microorganisms. Fusobacterium nucleatum is among the most prevalent bacterial species in colorectal cancer tissues. Here we show that colonization of human colorectal cancers with Fusobacterium and its associated microbiome—including Bacteroides , Selenomonas , and Prevotella species—is maintained in distal metastases, demonstrating microbiome stability between paired primary and metastatic tumors. In situ hybridization analysis revealed that Fusobacterium is predominantly associated with cancer cells in the metastatic lesions. Mouse xenografts of human primary colorectal adenocarcinomas were found to retain viable Fusobacterium and its associated microbiome through successive passages. Treatment of mice bearing a colon cancer xenograft with the antibiotic metronidazole reduced Fusobacterium load, cancer cell proliferation, and overall tumor growth. These observations argue for further investigation of antimicrobial interventions as a potential treatment for patients with Fusobacterium -associated colorectal cancer.
861 citations
TL;DR: The amount of F. nucleatum DNA in colorectal cancer tissue is associated with shorter survival, and may potentially serve as a prognostic biomarker, which may have implications in developing cancer prevention and treatment strategies through targeting GI microflora by diet, probiotics and antibiotics.
Abstract: 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 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.
659 citations
TL;DR: Large-cohort multi-omics data indicate that shifts in the microbiome and metabolome occur from the very early stages of the development of colorectal cancer, which is of possible etiological and diagnostic importance.
Abstract: In most cases of sporadic colorectal cancers, tumorigenesis is a multistep process, involving genomic alterations in parallel with morphologic changes. In addition, accumulating evidence suggests that the human gut microbiome is linked to the development of colorectal cancer. Here we performed fecal metagenomic and metabolomic studies on samples from a large cohort of 616 participants who underwent colonoscopy to assess taxonomic and functional characteristics of gut microbiota and metabolites. Microbiome and metabolome shifts were apparent in cases of multiple polypoid adenomas and intramucosal carcinomas, in addition to more advanced lesions. We found two distinct patterns of microbiome elevations. First, the relative abundance of Fusobacterium nucleatum spp. was significantly (P < 0.005) elevated continuously from intramucosal carcinoma to more advanced stages. Second, Atopobium parvulum and Actinomyces odontolyticus, which co-occurred in intramucosal carcinomas, were significantly (P < 0.005) increased only in multiple polypoid adenomas and/or intramucosal carcinomas. Metabolome analyses showed that branched-chain amino acids and phenylalanine were significantly (P < 0.005) increased in intramucosal carcinomas and bile acids, including deoxycholate, were significantly (P < 0.005) elevated in multiple polypoid adenomas and/or intramucosal carcinomas. We identified metagenomic and metabolomic markers to discriminate cases of intramucosal carcinoma from the healthy controls. Our large-cohort multi-omics data indicate that shifts in the microbiome and metabolome occur from the very early stages of the development of colorectal cancer, which is of possible etiological and diagnostic importance. Colorectal cancer stages are associated with distinct microbial and metabolomic profiles that could shed light on cancer progression.
599 citations
TL;DR: Fusobacterium nucleatum increased proliferation and invasive activities of CRC cell lines compared with control cells and levels of F nucleatum DNA and miR21 were increased in tumor tissues compared with non-tumor colon tissues from patients.
555 citations
TL;DR: The role of microorganisms in colorectal carcinogenesis, and the potential clinical translation of the gut microbiota as a biomarker for CRC diagnosis and prognosis are described, and as an approach for disease prevention and to improve therapy are described.
Abstract: Colorectal cancer (CRC) accounts for about 10% of all new cancer cases globally. Located at close proximity to the colorectal epithelium, the gut microbiota comprises a large population of microorganisms that interact with host cells to regulate many physiological processes, such as energy harvest, metabolism and immune response. Sequencing studies have revealed microbial compositional and ecological changes in patients with CRC, whereas functional studies in animal models have pinpointed the roles of several bacteria in colorectal carcinogenesis, including Fusobacterium nucleatum and certain strains of Escherichia coli and Bacteroides fragilis. These findings give new opportunities to take advantage of our knowledge on the gut microbiota for clinical applications, such as gut microbiota analysis as screening, prognostic or predictive biomarkers, or modulating microorganisms to prevent cancer, augment therapies and reduce adverse effects of treatment. This Review aims to provide an overview and discussion of the gut microbiota in colorectal neoplasia, including relevant mechanisms in microbiota-related carcinogenesis, the potential of utilizing the microbiota as CRC biomarkers, and the prospect for modulating the microbiota for CRC prevention or treatment. These scientific findings will pave the way to clinically translate the use of gut microbiota for CRC in the near future.
549 citations
References
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01 Jan 2010
TL;DR: WHO Classification of Tumours of the Digestive System - Libros de Medicina - Gastroenterologia oncologica - 128,25
Abstract: WHO Classification of Tumours of the Digestive System - Libros de Medicina - Gastroenterologia oncologica - 128,25
4,643 citations
TL;DR: It is suggested that a holistic approach to studying the microbiota that goes beyond characterization of community composition and encompasses dynamic interactions between all components of the microbiota and host tissue over time will be crucial for building predictive models for diagnosis and treatment of diseases linked to imbalances in the microbiota.
2,832 citations
TL;DR: The large-scale dynamics of the microbiome can be described by many of the tools and observations used in the study of population ecology, andiphering the metagenome and its aggregate genetic information can also be used to understand the functional properties of the microbial community.
Abstract: Interest in the role of the microbiome in human health has burgeoned over the past decade with the advent of new technologies for interrogating complex microbial communities. The large-scale dynamics of the microbiome can be described by many of the tools and observations used in the study of population ecology. Deciphering the metagenome and its aggregate genetic information can also be used to understand the functional properties of the microbial community. Both the microbiome and metagenome probably have important functions in health and disease; their exploration is a frontier in human genetics.
2,650 citations
TL;DR: Data suggest that, through recruitment of tumor-infiltrating immune cells, fusobacteria generate a proinflammatory microenvironment that is conducive for colorectal neoplasia progression, and this work finds that F.nucleatum does not exacerbate colitis, enteritis, or inflammation-associated intestinal carcinogenesis.
1,704 citations
"Association of Fusobacterium nuclea..." refers background or result in this paper
...nucleatum expression increases with disease progression from colorectal adenoma to CRC.(7,12,47) However, no previous studies have investigated F....
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...J. Cancer: 137, 1258–1268 (2015) VC 2015 UICC International Journal of Cancer IJC Colorectal carcinogenesis represents a heterogeneous process associated with various sets of somatic molecular alterations, which are influenced by diet and environmental and microbial exposures.1–3 The human intestinal microbiota inhabits a complex and diverse environment populated by hundreds of different bacterial species.4–6 Recently, metagenomic analyses involving whole-genome sequencing, transcriptome sequencing and 16S ribosomal RNA gene DNA sequencing have demonstrated enrichment of Fusobacterium nucleatum (F. nucleatum) in colorectal cancer (CRC) tissues.7,8 Previous studies have reported that F. nucleatum induces mucosal inflammation in colorectal disease, including CRC.7,9–11 Moreover, increased levels of F. nucleatum are related to patient survival12 and to specific molecular subsets of CRCs such as the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI).13 Therefore, accumulating evidence indicates that F. nucleatum may play a role in the progression of CRC.4–8,12–17 Premalignant colorectal neoplastic lesions appear to be important precursor lesions in the pathogenesis of CRC....
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...nucleatum is more likely to be present in tumor tissue compared to normal tissue in CRCs.(7,12,47) Thus, our current data appears to be consistent with these reports....
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...To identify the role in the early stage of tumorigenesis, we investigated the pres- ence of F. nucleatum in colorectal lesions using a database of 976 patients with colorectal serrated lesions, non-serrated adenoma or CRC....
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...Inflammation is a well-known risk factor for CRC. F. nucleatum has been reported to be associated not only with CRC7,9–11 but also with inflammatory disorders, such as periodontitis,36 acute appendicitis37 and inflammatory bowel disease (IBD).38,39 Inflammation and reactive oxygen species (ROS) can reduce the enzymatic activity of mismatch repair (MMR) proteins and cause epigenetic silencing of the MMR protein, MLH1....
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TL;DR: Overabundance of Fusobacterium sequences in tumor versus matched normal control tissue is verified by quantitative PCR analysis from a total of 99 subjects, and a positive association with lymph node metastasis is observed.
Abstract: 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.
1,535 citations
"Association of Fusobacterium nuclea..." refers background or methods in this paper
...nucleatum) in colorectal cancer (CRC) tissues.(7,8) Previous studies have reported that F....
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...nucleatum were normalized to prostaglandin transporter (PGT) in each reaction as previously described.(8,31) Details on the PCR mix and PCR conditions have been described in our recent report....
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