Table 1 Characteristics of included studies that examine F. nucleatum in colorectal cancer patient
Authors | Year | Country | Details of study | Sample type (n) | Detection method | Main findings |
|---|---|---|---|---|---|---|
Haruki et al. [23] | 2020 | Boston, USA | Analysis of Fn status in tumor tissue and evaluation autophagic activity of tumor cells by analysis SQSTM1, BECN1, and MAP1LC3 expression | Tissue (724) | qPCR | Fn was detected in 14% colorectal cancer cases High and intermediate expression of BECN1 gene in colorectal cancer tissue were inversely associated with the amount of Fn that suggested possible role of autophagy (Ptrend < 0.001) and the expression of SQSTM1 and MAP1LC3 in tumors were not significantly associated with the level of Fn (Ptrend > 0.06) No significant association was observed between the expression of BECN1, MAP1LC3, and SQSTM1 and patient survival (Ptrend > 0.10) |
Okita et al. [24] | 2020 | USA | Assessment whether F. nucleatum status can be a carcinogenic factor and determine molecular characteristics of CRC | Tissue (304) CRC Japan (174) | qPCR | There are a significant association between microsatellite instability-high (MSI-H) and L/E and the amount of F. nucleatum (high and moderate) F. nucleatum infection induce DNA damage in colon tissues |
Chen et al. [25] | 2020 | China | Investigation the relationship between F. nucleatum status and metastasis in CRC patient | Fecal (49) Tissue (83) | qPCR | There was a significant relationship between Fn infection and CRC metastasis so CRC patients with lymph nodes metastasis have high level of F. nucleatum infection F. nucleatum infection can increase KRT7-AS/KRT7 expression which induced cell migration in vivo and in vitro |
Chen et al. [26] | 2020 | China | Assessment F. nucleatum status in CRC patients and investigation its role in tumor metastasis | Tissue (62) | FISH | F. nucleatum was significantly high in metastatic CRC compare to non-metastatic CRC (P = 0.01) F. nucleatum level was higher in metastatic lymph nodes than controls (P = 0.003) |
Abed et al. [27] | 2020 | USA | Evaluation of F. nucleatum in CRC and assessment whether CRC-fusobacteria originate from the oral microbial | Saliva (7) | qPCR Immunofluorescence Hemagglutination Assay | Oral microbial are the source of CRC-fusobacteria Hematogenous fusobacteria were more successful in CRC colonization than gavaged ones in the MC38 and CT26 mouse orthotropic CRC models |
Chen et al. [28] | 2019 | China | Investigation the relationship between F nucleatum and microsatellite instability status, clinicopathological features and its prognostic effect in CRC patient (stages II–III) | FFPE (91) | qPCR | No significant relationship was observed between F. nucleatum status and clinic pathological features (P > 0.05) F nucleatum species (OR: 2.094, 95% CI [1.178–8.122], P = 0.032) and MSI status (OR 2.243, 95% CI 1.136–5.865, P = 0.039) were independent prognostic factors in CRC patient |
Feng et al. [13] | 2019 | China | Analysis of genes and miRNAs involved in the progression of F. nucleatum-induced CRC | Tissues (15) | miRNA microarray Human Transcriptome Array | miR-4717 and miR-4474 were significantly up-regulated in the tumor tissue compared to the normal in response to F. nucleatum infection Bioinformatic analysis revealed that CREB-binding protein (CREBBP) is the primary aberrantly expressed gene in F. nucleatum-induced CRC Real-time RT-PCR analysis showed that miR-4474/4717 was upregulated while CREBBP was downregulated in CRC patients with F. nucleatum infection CREBBP was introduced as a novel target of miR-4474/4717 |
Butt et al. [29] | 2019 | Europe | Assessment whether antibody responses to F. nucleatum are correlated with CRC risk in prediagnostic serum samples of patient | EPIC cohort: serum (485) | Multiplex serology method | No significant association was observed between antibody against F. nucleatum and colorectal cancer risk (OR, 0.81; 95% CI 0.62–1.06) |
Guven et al. [30] | 2019 | Turkey | Examination the quantities of three CRC related bacteria such as F. nucleatum, etc. in CRC patients | Saliva (71) | qPCR | F. nucleatum amount was higher in Saliva samples of CRC patient compared to controls (P = 0.001) No significant results was observed in ROC curve analyses for F. nucleatum |
Tunsjø et al. [31] | 2019 | Norway | Investigation the levels of Fusobacterium nucleatum in order to evaluate microbiome-based biomarkers for non-invasive detection of CRC | Stool and mucosa (72) | qPCR | Levels of F. nucleatum in stool samples were significantly higher in the cancer group compared with the the polyp group(P = 0.0028) and control group (P = 0.0073) |
Kunzmann et al. [32] | 2019 | Czech Republic | Evaluation of F. nucleatum as a prognostic biomarker and assessing its association with post-diagnosis survival | Tissues (190) | qRT-PCR | F. nucleatum level was significantly high in the tumor tissue compared to the normal mucosa (P = 0.002) High levels of Fn was associated with poorer overall survival (HR 1.68, 95% CI 1.02–2.77, P = 0.04) |
Zhang et al. [33] | 2019 | China | Assessment whether high expression of BIRC3 induced by F. nucleatum can be responsible for chemoresistance to 5-Fu in CRC patient | FFPE (94) | qPCR | F. nucleatum infection can upregulate BIRC3 expression by the TLR4/NF-κB pathway in CRC cells and decrease the chemosensitivity of cancer cells to 5-Fu in vitro and in vivo There was a significant correlation between high level of F. nucleatum and chemoresistance in high stage CRC patients treated by 5-Fu-based adjuvant chemotherapy |
Lee et al. [34] | 2018 | Korea | Investigation the association between F. nucleatum status, patient prognosis and pathway mutation in CRC patient (stages II–III) | FFPE and Tissue (246) | qPCR | F. nucleatum amount was higher in CRC subjects compared to controls (P < 0.001) High levels of Fn was associated with poorer overall survival in metastatic CRC (P = 0.042) Mutation rate of AMER1 (P = 0.030), ATM (P = 0.008), and TGF-b pathway (P = 0.020) were associated with high amount of F. nucleatum |
Yamaoka et al. [35] | 2018 | Japan | Measuring absolute copy numbers of F. nucleatum | Tissue (100) | droplet digital PCR | F. nucleatum was detected in 75.0% CRC tissues and significantly higher in CRC tissue than normal (P = 0.0031) Fn copy number (median) was 1.6 copies/ng DNA in CRC and 0.4 copies/ng DNA in normal group (P = 0.0046) |
Hamada et al. [36] | 2018 | USA | Assessment the association of F. nucleatum in colorectal cancer tissue with immune response might differ by tumor MSI status | NHS and HPFS Cohorts: Tissue (1041) | qPCR | Negative association was observed between F. nucleatum level and tumor-infiltrating lymphocytes (TIL) in MSI-high tumors (OR: 0.45; 95% CI [0.22–0.92]) but positive association was observed between the presence of F. nucleatum and TIL in non-MSI-high tumors(OR: 1.91; 95% CI [1.12–3.25]) |
Chen et al. [37] | 2018 | China | Evaluation the association between the presence of F. nucleatum with CD4+ T-cell density and thymocyte selection-associated high-mobility group box (TOX) protein expression | Tissue (138) | IHC, FISH, Immuno-fluorescence | CD4+ T-cell density and TOX expression were higher in F. nucleatum-negative tissues compared F. nucleatum-positive tissues (P = 0.002, P < 0.001, respectively) Negative correlation was observed between F. nucleatum level and TOX expression (P < 0.001) and CD4+ T-cell density (P < 0.001) F. nucleatum may inhibit antitumor immune response by reduction in TOX expression and CD4+ T-cell density in the colorectal cancer |
Liu et al. [38] | 2018 | USA | Examination inflammatory diet intakes in relation to incidence of colorectal cancer subtypes in response to F. nucleatum infection in tumor tissue | NHS and HPFS Cohorts: (951) | qPCR | Increased risk of F. nucleatum-positive colorectal tumors was associated with higher dietary inflammatory pattern (EDIP) score (Ptrend = 0.03) There was a significant associated between proximal F. nucleatum-positive colorectal tumors and High EDIP scores (Pheterogeneity = 0.003) |
Guo et al. [39] | 2018 | China | Measuring the relative the quantities of F. nucleatum and several probiotics in of CRC Evaluation the diagnostic performance of these microbial ratios and investigation the bactericidal activity of F. nucleatum against probiotics | Stool Cohort I. CRC (215), BCD (178), NGC (100), 156 HCs Cohort II. CRC (152), 102 HCs | qPCR 16S rDNA sequencing | The sensitivity of 84.6% and specificity of 92.3% for in detecting CRC was calculated in the microbial ratio of F. nucleatum to Bifidobacterium F. nucleatum negatively correlated with Fusobacterium nucleatum in CRC patient F. nucleatum may have role in dysbiosis via the secreted antagonistic against Bifidobacterium and Faecalibacterium prausnitzii |
Proença et al. [40] | 2018 | Brazil | Examination the effect of F. nucleatum on the microenvironment of colonic neoplasms and the expression of inflammatory mediators and miRNAs | Tissue sample CRC (43) CRA (27) | qPCR | F. nucleatum was detected in 51.8% CRA and in 72.1% CRC tissues F. nucleatum level was correlated with the expression of miR-22 (r = 0.38, P = 0.0331), IL8 (r = 0.54, P = 0.0013), IL1B (r = 0.46, P = 0.0066), IL6 (r = 0.47, P = 0.0059), and IL8 (r = 0.54, P = 0.0013) Positive correlations were observed between F. nucleatum level and miR-22 (r = 0.38, P = 0.0331), cytokines; IL8 (r = 0.54, P = 0.0013), IL1B (r = 0.46, P = 0.0066), IL6 (r = 0.47, P = 0.0059), and IL8 (r = 0.54, P = 0.0013) in the CRC group Negative correlation were observed between F. nucleatum level and TLR4 (r = − 0.62, P = 0.0235) in the CRA group The abundance of F. nucleatum was associated with KRAS mutation (P = 0.0432) in CRC samples |
Chen et al. [41] | 2017 | China | Assessment the association between β-catenin nuclear accumulation and F. nucleatum infection in CRC patient and examination whether F. nucleatum infection can activate β-catenin signaling via the TLR4/P-PAK1/P-β-catenin S675 cascade in CRC patient | Tissue 98 | FISH | No significant association was observed between F. nucleatum status and clinicopathologic features in CRC tissue (P > 0.05) F. nucleatum infection was higher in proximal CRCs than in distal CRCs (P = 0.045) The frequency of TLR4, PAK1 and nuclear β-catenin proteins were higher in Fn-positive than Fn-negative CRCs (P < 0.05) F. nucleatum significantly can increase TLR4/P-PAK1/P-β-catenin S675/C-myc/CyclinD1 proteins expression suggesting that F. nucleatum infection can active β-catenin in TLR4/PAK1 cascade and help to the carcinogenesis of CRCs |
Yan et al. [42] | 2017 | China | Analysis the levels of Fn and its prognostic significance in human CRC (stage III/IV) and normal tissues | Tissues (280) | qPCR | Fn level is significantly higher in CRC tissues than in adjacent normal tissues (P < 0.001) High level of Fn was significantly correlated with lymph node metastasis status (P = 0.008), tumor invasion (P = 0.015), and distant metastasis (P = 0.020). Fn level was significantly correlated with the expression of E-cadherin (r =  − 0.301, P < 0.001), N-cadherin N-cadherin (r = 0.377, P < 0.001), and Nanog (r = 0.362, P < 0.001) Patients with low level of Fn had a significantly better cancer-specific survival (CSS) and disease-free survival (DFS) than those with high Fn level (CSS, P < 0.001; DFS, P < 0.001) |
Suehiro et al. [43] | 2017 | Japan | Developing a method for F. nucleatum detection in stool sample of CRC patient and investigation the association between F. nucleatum status in stool with the progression of colorectal cancer | Feces: CIS (19) CRC (158) | ddPCR | F. nucleatum level was higher in stool sample of CRC patient (P < 0.0001) and advanced adenoma/CIS group (P = 0.0060) than controls Droplet digital PCR has high sensitivity for detection of F. nucleatum in the stool sample of CRC patient |
Ye et al. [44] | 2017 | Texas | Identification the specific Fusobacterium spp. and ssp. in clinical CRC specimens and assessment the behavior of colorectal cancer cells and monocytes in response to F. nucleatum infection in coculture systems | Tissue (25) | qPCR Cytokine panel assay, ELISA | F. nucleatum ssp. Animalis induced CCL20 expression in monocytes and colorectal cancer cells in In in vitro co-culture experiment F. nucleatum ssp. Animalis infection can induce inflammatory response and promote colorectal cancer |
Yu et al. [45] | 2017 | China | Investigation the contribution of gut microbiota to chemoresistance in CRC patients | Cohort 1: Tissue (31) Cohort 2: FFPE (92) Cohort 3: FFPE (173) | qPCR | F. nucleatum amount was high in CRC patients with recurrence post chemotherapy and may promote chemoresistance by the Autophagy Pathway F. nucleatum -induced chemoresistance is regulated by MiR-18a* and miR-4802 |
Mehta et al. [46] | 2017 | USA | Assessment the associations of prudent and Western diets with colorectal cancer risk in response to F. nucleatum infection in tumor tissue | NHS and HPFS Cohorts: (137,217) | qPCR | The association between prudent diet and colorectal cancer risk significantly differed in F. nucleatum infection (Pheterogeneity = 0.01) Significant inverse correlation was observed between Prudent diet score and F. nucleatum-positive cancer risk (Ptrend = 0.003), but not with F. nucleatum-negative cancer risk (Ptrend = 0.47) |
Amitay et al. [47] | 2017 | Germany | Examination the presence and relative abundance of F. nucleatum in fecal samples | Stool (500) | 16S rRNA gene analysis | F. nucleatum level in feces was associated with the colorectal cancer (P < 0.0001) |
Mima et al. [48] | 2016 | USA | Measuring the amount of F. nucleatum DNA in colorectal tumor tissue and analysis the relationship of a bowel subsite variable with F. nucleatum level | FFPE (1102) | qPCR | F. nucleatum DNA was detected in 13% of colorectal carcinoma tissue F. nucleatum status gradually increases from rectum(2.5%) to cecum(11%) in CRC with a significant trend along all subsites (P < 0.0001) |
Nosho et al. [49] | 2016 | Japan | Analysis of Fn status in DNA samples from formalin-fixed paraffin embedded (FFPE) tissues in CRC patient (stages I–IV) | Tissues (511) | qPCR | Fn positivity in the Japanese patient was 8.6% which was lower than that in United States cohort studies (13%) Similar to the United States studies, Fn positivity in Japanese colorectal cancers was significantly associated with microsatellite instability (MSI)-high status. Regarding the immune response in colorectal cancer, high levels of infiltrating T-cell subsets (i.e., CD3+, CD8+, CD45RO+, and FOXP3+ cells) have been associated with better patient prognosis |
Li et al. [50] | 2016 | China | Investigation the Fn abundance in tissues and its association with CRC | Tissues (101) | q-PCR FISH | Fn was over-represented in 87.1% of CRC tissues and Fn level is significantly higher in CRC tissues than in adjacent normal tissues (P < 0.001) F. nucleatum level was significantly higher in the lymph node metastases group than in the non-metastases group (P < 0.005) |
Mima et al. [51] | 2016 | USA | Analysis of the association between F. nucleatum level and worse clinical outcome | FFPE (1069) | qPCR | F. nucleatum was detected in 13% CRC tissues F. nucleatum level is associated with shorter survival in CRC patient (Ptrend = 0.020) The level of F. nucleatum was associated with MSI-high (multivariable OR: 5.22; 95% CI 2.86 to 9.55) |
Wang et al. [52] | 2016 | China | Measuring anti-Fn antibodies levels in CRC patients and evaluation of diagnostic value of serum anti-Fn antibodies in CRC patients | Stool (10) Serum (258) | PCR indirect whole-cell ELISA | Fn-infection can induce high level of anti-Fn antibodies in the serum of CRC patients Anti-Fn-IgA and -IgG were significantly higher in CRC patient than benign colon and control group (P < 0.001) Combination of anti-Fn-IgA with carcino-embryonic antigen (CEA) had diagnostic value CRC patient (Sen: 53.10%, Spe: 96.41%; AUC = 0.848) |
Fukugaiti et al. [53] | 2015 | Brazil | Evaluation the presence of oral and intestinal microorganisms in the fecal microbiota of CRC patients and controls | Stool (17) | qRT-PCR | They were detected significantly more F. nucleatum in the Cancer Group than in the healthy Group (P = 0.01) |
Mima et al. [54] | 2015 | USA | Assessment the hypothesis that F. nucleatum status in colorectal carcinoma is associated with lower amount of T-cells in tumor | NHS and HPFS Cohorts: FFPE (598) | qPCR Tissue microarray IHC | F. nucleatum was detected in 13% of colorectal carcinoma tissue Negative association was observed between F. nucleatum status and CD3+ T-cell density in colorectal carcinoma tissue OR, 0.47; 95% CI [0.26 to 0.87]; Ptrend = 0.006) No significant association was observed between F. nucleatum and density of CD8+, CD45RO+ , or FOXP3+ T-cells (Ptrend > 0.013) |
Ito et al [55] | 2015 | Japan | Investigation F. nucleatum status in premalignant colorectal lesions and its association with CIMP, MSI and microRNA-31 status | FFPE (511) | qPCR | F. nucleatum was detected in CIMP-high premalignant lesions than in CIMP-low/zero lesions (P = 0.0023) F. nucleatum positivity was higher in CRCs (56%) than in premalignant lesions of any histological type (P < 0.0001) |
Tahara et al. [56] | 2014 | Japan | Analysis of F. nucleatum (Fn) status and molecular features of tissue samples of colorectal cancer patient, colonic mucosae and control groups | Tissues (149) | q-PCR | Fn was detected in CRC tissues (74%) and the amount of Fusobacterial in normal tissue was 250-fold lower (mean) compared to CRC tissues Fn species in CRC group were associated with microsatellite instability (P = 0.018), CpG island methylator phenotype positivity (P = 0.001) and some genes: TP53 wild type (P = 0.015), hMLH1 methylation (P = 0.0028) CHD7/8 mutation positivity (P = 0.002) |
Flanagan et al. [57] | 2014 | Germany Czech Republic (CZ) | Evaluation of the potential of F. nucleatum as a biomarker for CRC by measuring survival outcomes and assessing its association with the adenoma to cancer progression | Tissue Czech cohort (49) German cohort (45) Irish cohort (28) adenoma (52) Stool CRC (7) adenoma (24) | qPCR | F. nucleatum amount was higher in cancerous than matched normal tissue (P < 0.0001) No significant association was observed in the F. nucleatum level between disease versus normal tissue (P = 0.06) in colorectal adenoma (CRA) Low Fn levels was associated with longer overall survival time CRC patients (P = 0.008) No significant association was observed in the F. nucleatum level between disease versus normal stool samples (CRC P = 0.33, CRA P = 0.15) |
McCoy et al. [58] | 2013 | USA | Assess the abundance of Fusobacterium in the normal rectal mucosa of subjects with and without adenomas and Confirmatory Study in CRC | Tissue Adenoma (48) CRC (10) | qPCR, FISH pyrosequencing | F. nucleatum level is higher in adenoma subjects compared to controls (P = 0.01) No significant correlation was observed between adenoma size and F. nucleatum species (P = 0.57) Positive correlations were found between F. nucleatum species and IL-10 (r = 0.443 P = 0.01) |
Kostic AD et al. [18] | 2013 | USA | Assessment of F. nucleatum status in patients with colorectal adenomas and adenocarcinomas Investigation Fn infection on cancer progression and inflammation in mouse models | Stool (56) and tissue (31) | qPCR FISH analysis | F. nucleatum was significantly high in adenomas compared to the normal adenomas (P < 0.004) Fusobacterium spp was high in CRC patients (P < 1 × 10–5) and in the stool samples with adenomas as compared to control groups (P < 5 × 10–3) F. nucleatum expands tumor-infiltrating myeloid cells in the selective manner, which can promote intestinal tumor progression and increases tumor multiplicity |
Castellarin et al. [59] | 2012 | Canada | Evaluation of the association inflammatory microorganisms with other gastrointestinal (GI) cancers | Tissue (99) | qPCR RNA-seq | F. nucleatum amount was higher in tumor versus normal control (P = 2.5 * 10–6) Positive correlations were observed between F. nucleatum species and lymph node metastasis (P = 0.0035) |