-
Cell Reports Nov 2022Fusobacterium nucleatum (Fn) is a dominant bacterial species in colorectal cancer (CRC) tissue that is associated with cancer progression and poorer patient prognosis....
Fusobacterium nucleatum (Fn) is a dominant bacterial species in colorectal cancer (CRC) tissue that is associated with cancer progression and poorer patient prognosis. Following a small-molecule inhibitor screen of 1,846 bioactive compounds against a Fn CRC isolate, we find that 15% of inhibitors are antineoplastic agents including fluoropyrimidines. Validation of these findings reveals that 5-fluorouracil (5-FU), a first-line CRC chemotherapeutic, is a potent inhibitor of Fn CRC isolates. We also identify members of the intratumoral microbiota, including Escherichia coli, that are resistant to 5-FU. Further, CRC E. coli isolates can modify 5-FU and relieve 5-FU toxicity toward otherwise-sensitive Fn and human CRC epithelial cells. Lastly, we demonstrate that ex vivo patient CRC tumor microbiota undergo community disruption after 5-FU exposure and have the potential to deplete 5-FU levels, reducing local drug efficacy. Together, these observations argue for further investigation into the role of the CRC intratumoral microbiota in patient response to chemotherapy.
Topics: Humans; Fusobacterium nucleatum; Escherichia coli; Fluorouracil; Microbiota; Colorectal Neoplasms
PubMed: 36384132
DOI: 10.1016/j.celrep.2022.111625 -
Current Opinion in Oncology Mar 2023There is growing evidence that suggests a possible role for bacteria in the progression of cancer. Fusobacteria have been detected in different types of cancers,... (Review)
Review
PURPOSE OF REVIEW
There is growing evidence that suggests a possible role for bacteria in the progression of cancer. Fusobacteria have been detected in different types of cancers, including colorectal and oral cancers. Fusobacteria are common opportunistic oral bacteria known to cause various infections. In this review, we focus on the association between Fusobacteria and cancer, specifically oral cancer, and provide insight into the role of Fusobacteria in carcinogenesis and immune evasion.
RECENT FINDINGS
Recently, it has been suggested that Fusobacteria are among the bacteria that contribute to the progression of cancer and might affect disease prognosis and treatment outcome. Moreover, Fusobacteria might alter tumor microenvironment and have an impact on tumor immune response. Thus, understanding the effect of Fusobacteria on cancer cells and tumor microenvironment is crucial to improve treatment outcome.
SUMMERY
Recent evidences suggest that Fusobacteria not only have an impact on tumor progression, but might also affect tumor immune response. Moreover, Fusobacteria presence in the tumor microenvironment might have an impact on treatment outcome and might be used as a prognostic factor.
Topics: Humans; Fusobacterium; Fusobacteria; Immune Evasion; Mouth Neoplasms; Carcinogenesis; Tumor Microenvironment
PubMed: 36633319
DOI: 10.1097/CCO.0000000000000927 -
Journal of Advanced Research Feb 2024Metastasis is an important cause of high mortality and lethality of oral cancer. Fusobacterium nucleatum (Fn) can promote tumour metastasis. Outer membrane vesicles...
INTRODUCTION
Metastasis 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.
OBJECTIVES
We aimed to determine whether and how Fn OMVs mediate oral cancer metastasis.
METHODS
OMVs 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.
RESULTS
Fn 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.
CONCLUSION
Fn OMVs not only induced cancer metastasis but also activated autophagic flux. Blocking autophagic flux weakened Fn OMV-stimulated cancer metastasis.
Topics: Animals; Mice; Fusobacterium nucleatum; Mouth Neoplasms; Autophagy
PubMed: 37059221
DOI: 10.1016/j.jare.2023.04.002 -
International Journal of Molecular... Aug 2023Atherosclerosis (AS) is an inflammatory vascular disease that constitutes a major underlying cause of cardiovascular diseases (CVD) and stroke. Infection is a... (Review)
Review
Atherosclerosis (AS) is an inflammatory vascular disease that constitutes a major underlying cause of cardiovascular diseases (CVD) and stroke. Infection is a contributing risk factor for AS. Epidemiological evidence has implicated individuals afflicted by periodontitis displaying an increased susceptibility to AS and CVD. This review concisely outlines several prevalent periodontal pathogens identified within atherosclerotic plaques, including , , and . We review the existing epidemiological evidence elucidating the association between these pathogens and AS-related diseases, and the diverse mechanisms for which these pathogens may engage in AS, such as endothelial barrier disruption, immune system activation, facilitation of monocyte adhesion and aggregation, and promotion of foam cell formation, all of which contribute to the progression and destabilization of atherosclerotic plaques. Notably, the intricate interplay among bacteria underscores the complex impact of periodontitis on AS. In conclusion, advancing our understanding of the relationship between periodontal pathogens and AS will undoubtedly offer invaluable insights and potential therapeutic avenues for the prevention and management of AS.
Topics: Humans; Plaque, Atherosclerotic; Atherosclerosis; Fusobacterium nucleatum; Cardiovascular Diseases; Porphyromonas gingivalis
PubMed: 37629042
DOI: 10.3390/ijms241612861 -
Advanced Materials (Deerfield Beach,... Nov 2023Clinical evidence indicates that tumor-colonizing bacteria can be closely related to the tumor development and therapeutic responses. Selectively eliminating bacteria...
Clinical evidence indicates that tumor-colonizing bacteria can be closely related to the tumor development and therapeutic responses. Selectively eliminating bacteria within tumors may be an attractive approach to enhance cancer treatment without additional side effects. Herein, it is found that, owing to the high affinity between the membrane protein Fap-2 on Fusobacterium nucleatum and d-galactose-β (1-3)-N-acetyl-d-galactosamine (Gal-GalNAc) overexpressed on colorectal tumor cells, F. nucleatum can colonize in colorectal tumors, as evidenced by both clinical samples and animal tumor models. Notably, F. nucleatum colonized in colorectal tumors can lead to an immunosuppressive tumor microenvironment, greatly reducing their responses to immune checkpoint blockade (ICB) therapy. Inspired by this finding, an F. nucleatum-mimetic nanomedicine is designed by fusing F. nucleatum cytoplasmic membrane (FM) with Colistin-loaded liposomes to achieve selective killing of tumor-colonizing F. nucleatum without affecting gut microbes. As a result, the therapeutic responses of F. nucleatum-colonized tumors to ICB therapies can be successfully restored, as demonstrated in an F. nucleatum-infected subcutaneous CT-26 tumor model, chemically induced spontaneous colorectal cancer models, and MC-38 tumor model. In summary, this work presents an F. nucleatum-mimicking nanomedicine that can selectively eliminate tumor-colonized bacteria, which is promising for enhancing the responses of cancer immunotherapy against F. nucleatum-colonized colorectal cancer.
Topics: Animals; Fusobacterium nucleatum; Nanomedicine; Colorectal Neoplasms; Anti-Bacterial Agents; Immunotherapy; Tumor Microenvironment
PubMed: 37722134
DOI: 10.1002/adma.202306281 -
Advanced Drug Delivery Reviews Jun 2024The microbiome has emerged as a significant biomarker and modulator in cancer development and treatment response. Recent research highlights the notable role of... (Review)
Review
The microbiome has emerged as a significant biomarker and modulator in cancer development and treatment response. Recent research highlights the notable role of Fusobacterium nucleatum (F. nucleatum) in various tumor types, including breast, colorectal, esophageal, gastric, pancreatic, and lung cancers. Accumulating evidence suggests that the local microbial community forms an integral component of the tumor microenvironment, with bacterial communities within tumors displaying specificity to tumor types. Mechanistic investigations indicate that tumor-associated microbiota can directly influence tumor initiation, progression, and responses to chemotherapy or immunotherapy. This article presents a comprehensive review of microbial communities especially F. nucleatum in tumor tissue, exploring their roles and underlying mechanisms in tumor development, treatment, and prevention. When the tumor-associated F. nucleatum is killed, the host immune response is activated to recognize tumor cells. Bacteria epitopes restricted by the host antigens, can be identified for future anti-bacteria/tumor vaccine development.
Topics: Humans; Fusobacterium nucleatum; Neoplasms; Drug Delivery Systems; Carcinogenesis; Tumor Microenvironment; Animals
PubMed: 38643839
DOI: 10.1016/j.addr.2024.115319 -
Annals of Oncology : Official Journal... Oct 2020
Topics: Colorectal Neoplasms; Fusobacterium nucleatum; Humans; Neoplasm Recurrence, Local; Rectal Neoplasms; Rectum
PubMed: 32629022
DOI: 10.1016/j.annonc.2020.06.019 -
Nature Microbiology Aug 2021Fusobacterium nucleatum, long known as a constituent of the oral microflora, has recently garnered renewed attention for its association with several different human...
Fusobacterium nucleatum, long known as a constituent of the oral microflora, has recently garnered renewed attention for its association with several different human cancers. The growing interest in this emerging cancer-associated bacterium contrasts with a paucity of knowledge about its basic gene expression features and physiological responses. As fusobacteria lack all established small RNA-associated proteins, post-transcriptional networks in these bacteria are also unknown. In the present study, using differential RNA-sequencing, we generate high-resolution global RNA maps for five clinically relevant fusobacterial strains-F. nucleatum subspecies nucleatum, animalis, polymorphum and vincentii, as well as F. periodonticum-for early, mid-exponential growth and early stationary phase. These data are made available in an online browser, and we use these to uncover fundamental aspects of fusobacterial gene expression architecture and a suite of non-coding RNAs. Developing a vector for functional analysis of fusobacterial genes, we discover a conserved fusobacterial oxygen-induced small RNA, FoxI, which serves as a post-transcriptional repressor of the major outer membrane porin FomA. Our findings provide a crucial step towards delineating the regulatory networks enabling F. nucleatum adaptation to different environments, which may elucidate how these bacteria colonize different compartments of the human body.
Topics: Bacterial Proteins; Fusobacterium Infections; Fusobacterium nucleatum; Humans; Neoplasms; Porins; RNA, Bacterial
PubMed: 34239075
DOI: 10.1038/s41564-021-00927-7 -
The Veterinary Clinics of North... Nov 2022Liver abscesses are a bacterial infection, which occurs because of entry, via portal vein, of pyogenic bacteria into the hepatic parenchyma. Liver abscesses are a... (Review)
Review
Liver abscesses are a bacterial infection, which occurs because of entry, via portal vein, of pyogenic bacteria into the hepatic parenchyma. Liver abscesses are a polymicrobial infection; however, Fusobacterium necrophorum, a ruminal bacterium, is the primary etiologic agent. Ruminal acidosis disrupts the protective barrier function of the ruminal epithelium and facilitates entry and colonization of F. necrophorum in the ruminal wall and subsequent entry into the portal circulation. Virulence factors of F. necrophorum contribute to the evasion of host defense mechanisms and cause tissue damage to set up an infection in the liver. The potential role of the hindgut in pathogenesis remains to be investigated.
Topics: Animals; Cattle; Cattle Diseases; Fusobacterium Infections; Fusobacterium necrophorum; Liver Abscess; Rumen; Virulence Factors
PubMed: 36243456
DOI: 10.1016/j.cvfa.2022.08.001 -
NPJ Biofilms and Microbiomes Jul 2023Periodontitis is the most important cause of tooth loss in adults and is closely related to various systemic diseases. Its etiologic factor is plaque biofilm, and the...
Periodontitis is the most important cause of tooth loss in adults and is closely related to various systemic diseases. Its etiologic factor is plaque biofilm, and the primary treatment modality is plaque control. Studies have confirmed that Fusobacterium nucleatum can cause periodontitis through its virulence factors and copolymerizing effects with other periodontal pathogens, such as the red complex. Inhibiting F. nucleatum is an essential target for preventing periodontitis. The time-consuming and costly traditional periodontal treatment, periodontal scaling, and root planing are a significant burden on individual and public health. Antibiotic use may lead to oral microbial resistance and microbiome imbalance, while probiotics regulate microbial balance. Akkermansia muciniphila is a critical probiotic isolated from the human intestine. It can protect the integrity of the epithelial barrier, regulate and maintain flora homeostasis, improve metabolism, and colonize the oral cavity. Its abundance is inversely correlated with various diseases. We hypothesized that A. muciniphila could inhibit the effects of F. nucleatum and alleviate periodontitis. Bacterial co-culture experiments showed that A. muciniphila could inhibit the expression of the virulence gene of F. nucleatum. After treating gingival epithelial cells (GECs) with F. nucleatum and A. muciniphila, transcriptome sequencing and ELISA experiments on medium supernatant showed that A. muciniphila inhibited the inflammatory effect of F. nucleatum on GECs by inhibiting TLR/MyD88/NF-κB pathway modulation and secretion of inflammatory factors. Finally, animal experiments demonstrated that A. muciniphila could inhibit F. nucleatum-induced periodontitis in BALB/c mice.
Topics: Adult; Animals; Mice; Humans; Fusobacterium nucleatum; Periodontitis; Akkermansia; Gingiva
PubMed: 37460552
DOI: 10.1038/s41522-023-00417-0