Relationship between Fusobacterium nucleatum and antitumor immunity in colorectal cancer liver metastasis.
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ABSTRACT:
SUBMITTER: Sakamoto Y
PROVIDER: S-EPMC8586672 | biostudies-literature |
REPOSITORIES: biostudies-literature
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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:The enrichment of Fusobacterium nucleatum (Fn) has been identified in CRC patients and associated with worse outcomes. However, whether Fn was involved in the metastasis of CRC was not well determined. Here, we found that the abundance of Fn was significantly increased in CRC patients with lymph nodes metastasis. To further clarify the role of Fn in CRC metastasis, we performed transwell and wound healing assays after incubating CRC cell lines with or without Fn and injected Fn-treated or untreated CRC cells into nude mice via tail vein. The results indicated that Fn infection promoted CRC cells migration in vitro, as well as lung metastasis in vivo. Interestingly, colonization of Fn was detected in metastatic lung lesions of nude mice by fluorescence in situ hybridization. Mechanistically, RNA sequencing and validation study revealed that Fn significantly upregulated the expression of long non-coding RNA Keratin7-antisense (KRT7-AS) and Keratin7 (KRT7) in CRC cells. Importantly, Fn-induced CRC lung metastasis was attenuated by the depletion of KRT7-AS. In addition, KRT7-AS facilitated CRC cells migration by upregulating KRT7. Subsequently, we found that NF-κB signaling pathway was involved in the upregulation of KRT7-AS upon Fn infection. In conclusion, Fn infection upregulated KRT7-AS/KRT7 by activating NF-κB pathway, which promoted CRC cell migration in vitro and metastasis in vivo.
| S-EPMC7524269 | 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:Colorectal cancer (CRC) is one of the most common malignant tumors and is associated with Fusobacterium nucleatum (F. nucleatum, Fn) infection. In this study, we explored the role of F. nucleatum in the CRC metastasis. Our results showed that the abundance of F. nucleatum was enriched in the feces and tumors of patients with CRC and tended to increase in stage IV compared to stage I in patients with metastatic CRC. Tumor-derived CCL20 activated by F. nucleatum not only increases CRC metastasis, but also participates in the reprograming of the tumor microenvironment. F. nucleatum promoted macrophage infiltration through CCL20 activation and simultaneously induced M2 macrophage polarization, enhancing the metastasis of CRC. In addition, we identified using database prediction and luciferase activity hat miR-1322, a candidate regulatory micro-RNA, could bind to CCL20 directly. F. nucleatum infection decreased the expression of miR-1322 by activating the NF-κB signaling pathway in CRC cells. In conclusion, F. nucleatum promotes CRC metastasis through the miR-1322/CCL20 axis and M2 polarization.
| S-EPMC8510564 | 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
Project description:Fusobacterium nucleatum, a Gram-negative oral anaerobe, is a significant contributor to colorectal cancer. Using an in vitro cancer progression model, we discover that F. nucleatum stimulates the growth of colorectal cancer cells without affecting the pre-cancerous adenoma cells. Annexin A1, a previously unrecognized modulator of Wnt/?-catenin signaling, is a key component through which F. nucleatum exerts its stimulatory effect. It is specifically expressed in proliferating colorectal cancer cells and involved in activation of cyclin D1. Annexin A1 expression level in colon cancer is a predictor of poor prognosis independent of cancer stage, grade, age and sex. The FadA adhesin from F. nucleatum up-regulates Annexin A1 expression through E-cadherin. A positive feedback loop between FadA and Annexin A1 is identified in the cancerous cells, absent in the non-cancerous cells. We therefore propose a "two-hit" model in colorectal carcinogenesis, with somatic mutation(s) as the first hit, and F. nucleatum as the second hit exacerbating cancer progression after benign cells become cancerous. This model extends the "adenoma-carcinoma" model and identifies microbes such as F. nucleatum as cancer "facilitators".
| S-SCDT-EMBOR-2018-47638V1 | biostudies-other
Project description:Fusobacterium nucleatum is supposed to play a critical role in the development of colorectal cancer. The species has also been associated with ulcerative colitis (UC) that can progress into colorectal cancer, however, the involvement of bacteria in this process remains unclear. We analysed 177 colon biopsies obtained from patients during screening, including 20 healthy controls, 56 UC cases and 69 cases at different stages of progression to colitis-associated cancer (CAC); 32 samples of sporadic colorectal carcinoma (sCRC) were also included. The presence of F. nucleatum was detected by quantitative real-time PCR (qPCR). Our data show an association between the presence of the bacteria and the progression of carcinogenesis in UC patients. In 39.5% of CAC samples F. nucleatum was detected, compared to only 1.8% in UC cases. The bacteria were detected in 6.3% of samples with initial neoplastic transformation, so-called low-grade dysplasia (LGD), whereas high-grade dysplasia (HGD) resulted in 33.3% of samples positive for F. nucleatum. The fraction of F. nucleatum-positive samples from sCRC cases was 56.3%, which was not significantly different to the CAC group. We conclude that F. nucleatum is associated with the occurrence and progression of colon carcinogenesis, rather than with UC itself.
| S-EPMC10356651 | biostudies-literature
Project description:IntroductionMetastasis is an important cause of high mortality and lethality of oral cancer. Fusobacterium nucleatum (Fn) can promote tumour metastasis. Outer membrane vesicles (OMVs) are secreted by Fn. However, the effects of Fn-derived extracellular vesicles on oral cancer metastasis and the underlying mechanisms are unclear.ObjectivesWe aimed to determine whether and how Fn OMVs mediate oral cancer metastasis.MethodsOMVs were isolated from brain heart infusion (BHI) broth supernatant of Fn by ultracentrifugation. Tumour-bearing mice were treated with Fn OMVs to evaluate the effect of OMVs on cancer metastasis. Transwell assays were performed to determine how Fn OMVs affect cancer cell migration and invasion. The differentially expressed genes in Fn OMV-treated/untreated cancer cells were identified by RNA-seq. Transmission electron microscopy, laser confocal microscopy, and lentiviral transduction were used to detect changes in autophagic flux in cancer cells stimulated with Fn OMVs. Western blotting assay was performed to determine changes in EMT-related marker protein levels in cancer cells. Fn OMVs' effects on migration after blocking autophagic flux by autophagy inhibitors were determined by in vitro and in vivo experiments.ResultsFn OMVs were structurally similar to vesicles. In the in vivo experiment, Fn OMVs promoted lung metastasis in tumour-bearing mice, while chloroquine (CHQ, an autophagy inhibitor) treatment reduced the number of pulmonary metastases resulting from the intratumoral Fn OMV injection. Fn OMVs promoted the migration and invasion of cancer cells in vivo, leading to altered expression levels of EMT-related proteins (E-cadherin downregulation; Vimentin/N-cadherin upregulation). RNA-seq showed that Fn OMVs activate intracellular autophagy pathways. Blocking autophagic flux with CHQ reduced in vitro and in vivo migration of cancer cells induced by Fn OMVs as well as reversed changes in EMT-related protein expression.ConclusionFn OMVs not only induced cancer metastasis but also activated autophagic flux. Blocking autophagic flux weakened Fn OMV-stimulated cancer metastasis.
| S-EPMC10834801 | biostudies-literature