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F. nucleatum is enriched preferentially in KRAS p.G12D-mutant CRC tumor tissues a Exon sequencing and qPCR detection of the mutation status of CRC tissues and F. nucleatum abundance in the indicated group. The relative abundance of F. nucleatum was confirmed using abundance of F. nucleatum /quantity of pgt gene. Significant differences are indicated: one-way ANOVA with Sidak’s multiple comparison test, data are presented as the mean ± SEM. b Correlation of KRAS mutation status and F. nucleatum abundance in CRC tumor tissues. Significant differences are indicated: Chi-square test, two-sided, n = 239. cF. nucleatum (Fn) positive rates under different KRAS mutation types in tumor tissues of CRC (n = 239). d Relative abundance of F. nucleatum in the CRC patients of the indicated groups. Significant differences are indicated: one-way ANOVA with Bonferroni’s multiple comparison test, data are presented as the mean ± SEM. Source data are provided as a Source Data file.
Source publication
Fusobacterium nucleatum (F. nucleatum) promotes intestinal tumor growth and its relative abundance varies greatly among patients with CRC, suggesting the presence of unknown, individual-specific effectors in F. nucleatum-dependent carcinogenesis. Here, we identify that F. nucleatum is enriched preferentially in KRAS p.G12D mutant CRC tumor tissues...
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... Some known bacteria species with pro-tumoral properties are Fusobacterium nucleatum, Helicobacter pylori, Escherichia coli (certain strains), Salmonella Typhimurium (certain strains), and Enterococcus faecalis. [32][33][34] Fusobacterium nucleatum demonstrates a close association with colorectal cancer (CRC), and it promotes cancer by several mechanisms. The bacterial protein Fap2 interacts with the immune checkpoint receptor TIGIT on NK cells and T cells, inhibiting their antitumor activity. ...
Cancer immunotherapy has revolutionized cancer treatment
due to its precise, target-specific approach compared with conventional therapies. However, treating solid tumors remains
challenging as these tumors are inherently immunosuppressive, and their tumor microenvironment (TME) often limits
therapeutic efficacy. Interestingly, certain bacterial species
offer a promising alternative by exhibiting an innate ability
to target and proliferate within tumor environments. Bacterial
structural and functional components can activate innate and
adaptive immune responses, creating tumor-suppressive conditions that reduce tumor mass. Additionally, bacteria can
deliver effector molecules directly into tumor cells, inducing
apoptotic and necrotic cell death. Despite their potential, the
use of bacteria in cancer immunotherapy poses risks due to
possible toxicities and unpredictable in vivo behavior. Advances in genetic engineering have addressed these concerns
by enabling the development of attenuated bacterial strains
with enhanced anticancer properties for safer medical applications. This review highlights the role of bacteria in TME modulation, recent strategies to bioengineer bacterial pathogens as therapeutic tools, and the synergistic effects of combining bacteria with other immunotherapies. It also discusses the challenges and prospects of translating this innovative approach
into clinical practice, offering a comprehensive overview of
bacteria-based cancer immunotherapy’s potential to reshape
the future of cancer treatment.
... To investigate the pro-oncogenic mechanisms of Fn, we chose a commonly used strain, F. nucleatum ATCC 25,586. [44][45][46][47] While a very recent study found that the Fn subspecies, F. nucleatum subsp. animalis (Fna), predominates in the CRC niche. ...
The intracellular bacterium Fusobacterium nucleatum (Fn) mediates tumorigenesis and progression in colorectal cancer (CRC). However, the origin of intratumoral Fn and the role of Fn-infected immunocytes in the tumor microenvironment remain unclear. Here, we observed that Fn-infected neutrophils/macrophages (PMNs/MΦs), especially PMNs, accumulate in tumor tissues and fecal Fn abundance correlates positively with an abundance of blood PD-L1⁺ PMNs in CRC patients. Moreover, Fn accumulates in tumor tissues of tumor-bearing mice via intragingival infection and intravenous injection. Mechanistically, Fn can survive inside PMNs by reducing intracellular ROS levels and producing H2S. Specifically, the lysozyme inhibitor Fn1792 as a novel virulence factor of Fn suppressed apoptosis of phagocytes by inducing CX3CR1 expression. Furthermore, Fn-driven CX3CR1⁺PD-L1⁺ phagocytes transfer intracellular Fn to tumor cells, which recruit PMNs/MΦs through the CXCL2/8-CXCR2 and CCL5/CCR5 axes. Consequently, CX3CR1⁺PD-L1⁺ PMNs infiltration promotes CRC metastasis and weakens the efficacy of immunotherapy. Treatment with the doxycycline eradicated intracellular Fn, thereby reducing the CX3CR1⁺PD-L1⁺ PMNs populations and slowing Fn-promoted tumor growth and metastasis in mice. These results suggest phagocytes as Fn-presenting cells use mutualistic strategies to home to tumor tissues and induce immunosuppression, and treatment with ROS-enhanced antibiotics can inhibit Fn-positive tumor progression.
... Fusobacterium nucleatus promoted colorectal neoplasia in Villin-Cre/Kras G12D+/− mice, while P. distasonis could antagonize it and reduce the number and size of tumors. 125 Smoke exposure is one of the main inducer of CRC. Significant differences of gut bacteria abundance were monitored in the smoking mice, including the enrichment of Eggerthella lenta and loss of P. distasonis. ...
... P. distasonis inhibited the invasion of F. nucleatum, prevented it from binding to DHX15, reduced the expression of Ki67 in colonic organoids, inhibited intestinal epithelial over proliferation, and alleviated the progression of CRC with KRAS p.G12D mutation. 125 P. distasonis stimulates mature immune cells to secrete antibodies, mobilize the systemic immune system and killer system, and eliminate these aging lesions, mutated tissues (such as tumor cells), and exotic pathogenic microorganisms. Initially, some scholars found that Bacteroides enhanced its antitumor effect and reduced gastrointestinal toxicity in melanoma patients who received CTLA-4 blocking therapy. ...
Increasing evidences indicate that the gut microbiota is involved in the development and therapy of gastrointestinal and hepatic disease. Imbalance of gut microbiota occurs in the early stages of diseases, and maintaining the balance of the gut microbiota provides a new strategy for the treatment of diseases. It has been reported that Parabacteroides distasonis is associated with multiple diseases. As the next‐generation probiotics, several studies have demonstrated its positive regulation on the gastrointestinal and hepatic disease, including inflammatory bowel disease, colorectal cancer, hepatic fibrosis, and fatty liver. The function of P. distasonis and its metabolites mainly affect host immune system, intestinal barrier function, and metabolic networks. Manipulation of P. distasonis with natural components lead to the protective effect on enterohepatic disease. In this review, the metabolic pathways regulated by P. distasonis are summarized to illustrate its active metabolites and their impact on host metabolism, the role and action mechanism in gastrointestinal and hepatic disease are discussed. More importantly, the natural components can be used to manipulate P. distasonis as treatment strategies, and the challenges and perspectives of P. distasonis in clinical applications are discussed.
... Fusobacterium nucleatum (Fn), a gram-negative anaerobe, has been reported as a potential pathogen in colorectal cancer (CRC) [1,2]. Evidence suggests that enrichment of Fn affects CRC's development, progression, and poor prognosis [3,4]. ...
Fusobacterium nucleatum (Fn) has been extensively studied for its connection to colorectal cancer (CRC) and its potential role in chemotherapy resistance. Studies indicate that Fn is commonly found in CRC tissues and is associated with unfavorable prognosis and treatment failure. It has been shown that Fn promotes chemoresistance by affecting autophagy, a cellular process that helps cells survive under stressful conditions. Additionally, Fn targets specific signaling pathways that activate particular microRNAs and modulate the response to chemotherapy. Understanding the current molecular mechanisms and investigating the importance of Fn-inducing chemoresistance could provide valuable insights for developing novel therapies. This review surveys the role of Fn in tumor proliferation, metastasis, and chemoresistance in CRC, focusing on its effects on the tumor microenvironment, gene expression, and resistance to conventional chemotherapy drugs. It also discusses the therapeutic implications of targeting Fn in CRC treatment and highlights the need for further research.
... nucleatum) is a Gram-negative anaerobic bacterium that primarily inhabits the human oral cavity but is also abundant in colorectal cancer tissues. Recent studies have shown that it is involved in the progression of colorectal cancer, including promoting tumor cell proliferation, aiding immune evasion, causing recurrence, and potentially affecting chemotherapy resistance (Zhu et al., 2024). Despite its commensal characteristics in certain niches, F. nucleatum has garnered recognition as a versatile pathogen with implications in diverse infectious and systemic diseases (Umaña et al., 2019). ...
... Byrd et al. [22] also found higher abundance of Alisterella, Casatella, and Fusobacteriaceae in tumor tissues with high microsatellite instability. Fn is also preferentially enriched in CRC tumor tissues with KRAS p.G12D mutations, and it promotes tumor progression of KRAS p.G12D mutant CRC by binding to DEAH-box helicase 15 [23]. ...
Colorectal cancer (CRC) is one of the most prevalent and lethal malignant tumors globally, posing significant health risks and societal burdens. Recently, advancements in next-generation sequencing technology have identified CRC intratumoral microbiota, thereby opening up novel avenues for further research. This review synthesizes the current advancements in CRC intratumoral microbiota and their impact on CRC progression and discusses the disparities in the relative abundance and community composition of CRC intratumoral microbiota across various colorectal tumors based on their anatomical location and molecular subtypes, as well as the tumor stages, and spatial tumor distribution. Intratumoral microbiota predominantly influence CRC development by modulating colonic epithelial cells, tumor cells, and the tumor microenvironment. Mechanistically, they can cause DNA damage, apoptosis and epithelial-mesenchymal transition. The effects of different intratumoral microbiota on CRC have been shown to be two-fold. In the future, to address the limitations of existing studies, it is important to develop comprehensive experimental protocols and suitable in vitro models for elucidating more mechanisms of intratumoral microbiota on CRC, which will facilitate the clinical application of microbe-related therapeutic strategies in CRC and potentially other tumors.
... It is understandable that microorganisms can infiltrate tumors in tissues or organs that are in direct contact with the external environment, such as the gastrointestinal tract, lungs, oral cavity, nasopharynx, and genitourinary organs, due to compromised mucosal barriers caused by tumorigenesis. Among these, Fusobacterium nucleatum not only characterized the gut microbial feature of colorectal cancer (CRC) patients [73], but also exhibited enrichment in CRC tumor tissues, particularly in those with certain molecular subtypes such as Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation and microsatellite instability-high [74,75] Providing specificity and spatial localization of intratumor microbiota 1. Restricted by the specificity of antibodies targeting microbial antigens; ...
... Remarkably, intratumoral F. nucleatum can promote tumor growth through modulating multiple pathways. Zhu et al. revealed that in CRC tumor tissues, F. nucleatum upregulated the oncoprotein DHX15 by activating the ERK-STAT3 pathway [74]. Similarly, F. nucleatum infection activated the mitogen-activated protein kinase (MAPK) pathway, leading to increased expression of Matrix metalloproteinase 7 protein and enhanced CRC cell migration capacity [107]. ...
The intricate interplay between the host and its microbiota has garnered increasing attention in the past decade. Specifically, the emerging recognition of microorganisms within diverse cancer tissues, previously presumed sterile, has ignited a resurgence of enthusiasm and research endeavors. Four potential migratory routes have been identified as the sources of intratumoral microbial “dark matter,” including direct invasion of mucosal barriers, spreading from normal adjacent tissue, hematogenous spread, and lymphatic drainage, which contribute to the highly heterogeneous features of intratumor microbiota. Importantly, multitudes of studies delineated the roles of intratumor microbiota in cancer initiation and progression, elucidating underlying mechanisms such as genetic alterations, epigenetic modifications, immune dysfunctions, activating oncogenic pathways, and inducing metastasis. With the deepening understanding of intratumoral microbial composition, novel microbiota-based strategies for early cancer diagnosis and prognostic stratification continue to emerge. Furthermore, intratumor microbiota exerts significant influence on the efficacy of cancer therapeutics, particularly immunotherapy, making it an enticing target for intervention in cancer treatment. In this review, we present a comprehensive discussion of the current understanding pertaining to the developmental history, heterogeneous profiles, underlying originations, and carcinogenic mechanisms of intratumor microbiota, and uncover its potential predictive and intervention values, as well as several inevitable challenges as a target for personalized cancer management strategies.
... In our study, we showed an increase in Fusobacterium in UC patients compared to CD patients and we identified Fusobacterium as a biomarker for high MDI and extensive colitis, the most severe form of UC. Indeed, the literature confirms that Fusobacterium characterises active-phase pancolitis [66] and predisposes one to colorectal cancer (CRC) [67][68][69][70]. Furthermore, as with Enterobacteriaceae, we found that Fusobacterium was negatively correlated with Parabacteroides, which, in addition to its protective role in the intestinal mucosa (as mentioned above), also has anti-inflammatory effects in colitis, atherosclerosis, type 2 diabetes mellitus, food allergy and obesity [71]. ...
... Furthermore, as with Enterobacteriaceae, we found that Fusobacterium was negatively correlated with Parabacteroides, which, in addition to its protective role in the intestinal mucosa (as mentioned above), also has anti-inflammatory effects in colitis, atherosclerosis, type 2 diabetes mellitus, food allergy and obesity [71]. Moreover, Parabacteroides has been recognised as the most important probiotic in protecting against CRC and metabolic disorders [70]. Therefore, further knowledge on Parabacteroides as a potential future probiotic in IBD therapy is needed. ...
Recent evidence indicates that the gut microbiota (GM) has a significant impact on the inflammatory bowel disease (IBD) progression. Our aim was to investigate the GM profiles, the Microbial Dysbiosis Index (MDI) and the intestinal microbiota-associated markers in relation to IBD clinical characteristics and disease state. We performed 16S rRNA metataxonomy on both stools and ileal biopsies, metabolic dysbiosis tests on urine and intestinal permeability and mucosal immunity activation tests on the stools of 35 IBD paediatric patients. On the GM profile, we assigned the MDI to each patient. In the statistical analyses, the MDI was correlated with clinical parameters and intestinal microbial-associated markers. In IBD patients with high MDI, Gemellaceae and Enterobacteriaceae were increased in stools, and Fusobacterium, Haemophilus and Veillonella were increased in ileal biopsies. Ruminococcaceae and WAL_1855D were enriched in active disease condition; the last one was also positively correlated to MDI. Furthermore, the MDI results correlated with PUCAI and Matts scores in ulcerative colitis patients (UC). Finally, in our patients, we detected metabolic dysbiosis, intestinal permeability and mucosal immunity activation. In conclusion, the MDI showed a strong association with both severity and activity of IBD and a positive correlation with clinical scores, especially in UC. Thus, this evidence could be a useful tool for the diagnosis and prognosis of IBD.
... Our previous study also revealed a significant disparity in the microbial composition between tumor and paratumor tissues, particularly with regards to the higher abundance of Fusobacterium periodonticum (F.p) in tumor tissue compared to adjacent tumor tissue as determined by 16 S rDNA sequencing [15]. Microorganisms are involved in the development of many diseases, such as Fusarium induced inflammatory disorders [16], and the Fusobacterium nucleatum regulated the occurrence and development of cancers [17,18]. Although the F.p was been founded high infiltrated in the EC tissues, the role of F.P in EC was still unknown. ...
Background
The cancer microbiota was considered the main risk factor for cancer progression. We had proved that Fusobacterium periodonticum (F.p) was higher abundance in Esophageal cancer(EC)tissues. Bioinformation analysis found that BCT was a key virulence protein of F.p. However, little is known about the role and mechanism of BCT in EC. This study aimed to recognize the key virulence protein of F.p and explore the mechanism of BCT in promoting EC.
Methods
We constructed a eukaryotic expression vector and purified the recombinant protein BCT. CCK8 used to analyzed the activity of EC after treated by different concentration of BCT. UPLC-MS/MS and ELISA used to detect the metabonomics and metabolites. The ability of migration and invasion was completed by transwell assay. RT-QPCR, WB used to analyze the expression of relevant genes.
Results
Our data showed that BCT was higher expression in EC tumor tissues (p < 0.05) and BCT in 20 µg/mL promoted the survival, invasion and migration of EC cells (EC109) (p < 0.05). Meanwhile, UPLC-MS/MS results suggested that BCT resulted in an augmentation of hypotaurine metabolism, arachidonic acid metabolism, glycolysis/gluconeogenesis, tryptophan metabolism, citrate cycle activity in EC109. The metabolic changes resulted in decreasing in glucose and pyruvate levels but increase in lactate dehydrogenase (LDH) activity and lactic acid (LA) as well as the expression of glucose transporter 1, Hexokinase 2, LDH which regulated the glycolysis were all changed (p < 0.05). The BCT treatment upregulated the expression of TLR4, Akt, HIF-1α (p < 0.05) which regulated the production of LA. Furthermore, LA stimulation promoted the expression of GPR81, Wnt, and β-catenin (p < 0.05), thereby inducing EMT and metastasis in EC109 cells.
Conclusion
Altogether, these findings identified that impact of BCT in regulation of glycolysis in EC109 and its involves the TLR4/Akt/HIF-1α pathway. Meanwhile, glycolysis increasing the release of LA and promote the EMT of EC109 by GPR81/Wnt/β-catenin signaling pathway. In summary, our findings underscore the potential of targeting BCT as an innovative strategy to mitigate the development of EC.
... Finally, many studies have pointed out the role of the gut microbiome as a prognostic and predictive biomarker in colorectal cancer [68,69]. In colorectal cancer, Fusobacterium nucleatum has been related to genetic and epigenetic lesions, such as microsatellite instability, the CpG island methylator phenotype, and genome mutations in colorectal cancer tissues [70]. Indeed, F. nucleatum could promote proliferation and metabolism, remodel the immune microenvironment, and facilitate metastasis and chemoresistance in the tumorigenesis and development of CRC [68]. ...
Kirsten rat sarcoma virus oncogene homolog (KRAS) is the most frequently mutated oncogene in human cancer. In colorectal cancer (CRC), KRAS mutations are present in more than 50% of cases, and the KRAS glycine-to-cysteine mutation at codon 12 (KRAS G12C) occurs in up to 4% of patients. This mutation is associated with short responses to standard chemotherapy and worse overall survival compared to non-G12C mutations. In recent years, several KRAS G12C inhibitors have demonstrated clinical activity, although all patients eventually progressed. The identification of negative feedback through the EGFR receptor has led to the development of KRAS inhibitors plus an anti-EGFR combination, thus boosting antitumor activity. Currently, several KRAS G12C inhibitors are under development, and results from phase I and phase II clinical trials are promising. Moreover, the phase III CodeBreaK 300 trial demonstrates the superiority of sotorasib-panitumumab over trifluridine/tipiracil, establishing a new standard of care for patients with colorectal cancer harboring KRAS G12C mutations. Other combinations such as adagrasib-cetuximab, divarasib-cetuximab, or FOLFIRI-panitumumab-sotorasib have also shown a meaningful response rate and are currently under evaluation. Nonetheless, most of these patients will eventually relapse. In this setting, liquid biopsy emerges as a critical tool to characterize the mechanisms of resistance, consisting mainly of acquired genomic alterations in the MAPK and PI3K pathways and tyrosine kinase receptor alterations, but gene fusions, histological changes, or conformational changes in the kinase have also been described. In this paper, we review the development of KRAS G12C inhibitors in colorectal cancer as well as the main mechanisms of resistance.
