Int J Stomatol ›› 2023, Vol. 50 ›› Issue (1): 52-60.doi: 10.7518/gjkq.2023011

• Oral Microbiology • Previous Articles     Next Articles

Research progress on the mechanism of Fusobacterium nucleatum promoting the initiation and development of colorectal cancer

Luo Wanyi1(),Han Juxi1,Zhou Xuedong1,2,Peng Xian1,2,Zheng Xin1,2()   

  1. 1.State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & West China School of Stomatology, Sichuan University, Chengdu 610041, China
    2.State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Di-seases & Dept. of Cariology and Endodontics, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
  • Received:2022-04-21 Revised:2022-10-02 Online:2023-01-01 Published:2023-01-09
  • Contact: Xin Zheng E-mail:1902349799@qq.com;xinzheng@scu.edu.cn
  • Supported by:
    Research Funding for Talents Developing, West China Hospital of Stomatology, Sichuan University(RCDWJS2020-11)

Abstract:

Fusobacterium nucleatum (F. nucleatum) is a Gram-negative anaerobic bacterium that widely colonizes the human oral cavity and is recognized as a periodontal pathogen. F. nucleatum plays an important role in oral diseases, such as periodontal disease and oral cancer, and is biologically associated with a variety of systematic diseases, including cardiovascular disease, alveolar bone loss, adverse pregnancy outcomes, and cancers of various systems. The correlation between F.nucleatum and colorectal cancer (CRC) is well documented. We conclude that periodontitis may be a risk factor for inflammatory transition to cancer in patients with intestinal inflammation. F. nucleatum migrates to the intestine through the digestive tract and blood circulation and binds specifically to CRC cells via the adhesin FadA/E-cadherin and adhesin Fap2/disaccharide tumor marker in gal-GalNac pathways. F.nucleatum can adapt to the highly metabolic, oxygen-lacking environment of tumors and further promote the glycolysis of tumors, which leads to the high abundance of F.nucleatum in CRC. By binding to CRC cells, F.nucleatum regulates canonical Wnt/β-catenin pathway and nuclear factor kappa-B signaling pathways, thus promoting the initiation, metastasis, and chemoresistance of cancer cells and affecting the tumor immune microenvironment.

Key words: Fusobacterium nucleatum, colorectal cancer, tumor immune microenvironment

CLC Number: 

  • R 780.2

TrendMD: 
1 Gao L, Kang MS, Zhang MJ, et al. Polymicrobial periodontal disease triggers a wide radius of effect and unique virome[J]. Npj Biofilms Microbiomes, 2020, 6: 10.
2 Tefiku U, Popovska M, Cana A, et al. Determination of the role of Fusobacterium nucleatum in the pathogenesis in and out the mouth[J]. Pril (Makedon Akad Nauk Umet Odd Med Nauki), 2020, 41(1): 87-99.
3 Chukkapalli SS, Ambadapadi S, Varkoly K, et al. Impaired innate immune signaling due to combined Toll-like receptor 2 and 4 deficiency affects both pe-riodontitis and atherosclerosis in response to polybacterial infection[J]. Pathog Dis, 2018, 76(8): fty-076.
4 Ebbers M, Lübcke PM, Volzke J, et al. Interplay between P. gingivalis, F. nucleatum and A. actinomycetemcomitans in murine alveolar bone loss, arthritis onset and progression[J]. Sci Rep, 2018, 8: 15129.
5 Vander Haar EL, So J, Gyamfi-Bannerman C, et al. Fusobacterium nucleatum and adverse pregnancy outcomes: epidemiological and mechanistic evidence[J]. Anaerobe, 2018, 50: 55-59.
6 Parhi L, Alon-Maimon T, Sol A, et al. Breast cancer colonization by Fusobacterium nucleatum accelera-tes tumor growth and metastatic progression[J]. Nat Commun, 2020, 11: 3259.
7 Alkharaan H, Lu LY, Gabarrini G, et al. Circulating and salivary antibodies to Fusobacterium nucleatum are associated with cystic pancreatic neoplasm malignancy[J]. Front Immunol, 2020, 11: 2003.
8 Nejman D, Livyatan I, Fuks G, et al. The human tumor microbiome is composed of tumor type-speci-fic intracellular bacteria[J]. Science, 2020, 368(6494): 973-980.
9 Kalaora S, Nagler A, Nejman D, et al. Identification of bacteria-derived HLA-bound peptides in melanoma[J]. Nature, 2021, 592(7852): 138-143.
10 Nwizu N, Wactawski-Wende J, Genco RJ. Periodontal disease and cancer: epidemiologic studies and possible mechanisms[J]. Periodontol 2000, 2020, 83(1): 213-233.
11 Michaud DS, Liu Y, Meyer M, et al. Periodontal di-sease, tooth loss, and cancer risk in male health professionals: a prospective cohort study[J]. Lancet Oncol, 2008, 9(6): 550-558.
12 Hiraki A, Matsuo K, Suzuki T, et al. Teeth loss and risk of cancer at 14 common sites in Japanese[J]. Cancer Epidemiol Biomarkers Prev, 2008, 17(5): 1222-1227.
13 Ren HG, Luu HN, Cai H, et al. Oral health and risk of colorectal cancer: results from three cohort stu-dies and a meta-analysis[J]. Ann Oncol, 2016, 27(7): 1329-1336.
14 Nwizu NN, Marshall JR, Moysich K, et al. Perio-dontal disease and incident cancer risk among postmenopausal women: results from the women’s hea-lth initiative observational cohort[J]. Cancer Epidemiol Biomarkers Prev, 2017, 26(8): 1255-1265.
15 Michaud DS, Kelsey KT, Papathanasiou E, et al. Periodontal disease and risk of all cancers among male never smokers: an updated analysis of the Health Professionals Follow-up Study[J]. Ann Oncol, 2016, 27(5): 941-947.
16 Komiya Y, Shimomura Y, Higurashi T, et al. Patients with colorectal cancer have identical strains of Fusobacterium nucleatum in their colorectal cancer and oral cavity[J]. Gut, 2019, 68(7): 1335-1337.
17 Kitamoto S, Nagao-Kitamoto H, Jiao Y, et al. The intermucosal connection between the mouth and gut in commensal pathobiont-driven colitis[J]. Cell, 2020, 182(2): 447-462.e14.
18 Shah SC, Itzkowitz SH. Colorectal cancer in inflammatory bowel disease: mechanisms and management[J]. Gastroenterology, 2022, 162(3): 715-730.
19 Rajamäki K, Taira A, Katainen R, et al. Genetic and epigenetic characteristics of inflammatory bowel disease-associated colorectal cancer[J]. Gastroente-rology, 2021, 161(2): 592-607.
20 Nadeem MS, Kumar V, Al-Abbasi FA, et al. Risk of colorectal cancer in inflammatory bowel diseases[J]. Semin Cancer Biol, 2020(64): 51-60.
21 Koliarakis I, Messaritakis I, Nikolouzakis TK, et al. Oral bacteria and intestinal dysbiosis in colorectal cancer[J]. Int J Mol Sci, 2019, 20(17): 4146.
22 Nakajima M, Arimatsu K, Kato T, et al. Oral admi-nistration of P. gingivalis induces dysbiosis of gut microbiota and impaired barrier function leading to dissemination of enterobacteria to the liver[J]. PLoS One, 2015, 10(7): e0134234.
23 Parahitiyawa NB, Jin LJ, Leung WK, et al. Micro-biology of odontogenic bacteremia: beyond endocarditis[J]. Clin Microbiol Rev, 2009, 22(1): 46-64.
24 Mima K, Cao Y, Chan AT, et al. Fusobacterium nucleatum in colorectal carcinoma tissue according to tumor location[J]. Clin Transl Gastroenterol, 2016, 7(11): e200.
25 Ito M, Kanno S, Nosho K, et al. Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway[J]. Int J Cancer, 2015, 137(6): 1258-1268.
26 Phipps AI, Chan AT, Ogino S. Anatomic subsite of primary colorectal cancer and subsequent risk and distribution of second cancers[J]. Cancer, 2013, 119(17): 3140-3147.
27 Kostic AD, Chun E, Robertson L, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment[J]. Cell Host Microbe, 2013, 14(2): 207-215.
28 Anu V, Madan Kumar PD, Shivakumar M. Salivary flow rate, pH and buffering capacity in patients undergoing fixed orthodontic treatment-a prospective study[J]. Indian J Dent Res, 2019, 30(4): 527.
29 Guven DC, Dizdar O, Alp A, et al. Analysis of Fusobacterium nucleatum and Streptococcus gallolyticus in saliva of colorectal cancer patients[J]. Biomar-kers Med, 2019, 13(9): 725-735.
30 Engevik AC, Kaji I, Goldenring JR. The physiology of the gastric parietal cell[J]. Physiol Rev, 2020, 100(2): 573-602.
31 Seedorf H, Griffin NW, Ridaura VK, et al. Bacteria from diverse habitats colonize and compete in the mouse gut[J]. Cell, 2014, 159(2): 253-266.
32 Li BL, Ge Y, Cheng L, et al. Oral bacteria colonize and compete with gut microbiota in gnotobiotic mice[J]. Int J Oral Sci, 2019, 11: 10.
33 Peters BA, Wu J, Hayes RB, et al. The oral fungal mycobiome: characteristics and relation to periodontitis in a pilot study[J]. BMC Microbiol, 2017, 17(1): 157.
34 Saus E, Iraola-Guzmán S, Willis JR, et al. Micro-biome and colorectal cancer: roles in carcinogenesis and clinical potential[J]. Mol Aspects Med, 2019, 69: 93-106.
35 Abed J, Emgård JEM, Zamir G, et al. Fap2 mediates Fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed gal-GalNAc[J]. Cell Host Microbe, 2016, 20(2): 215-225.
36 Sharma N, Bhatia S, Sodhi AS, et al. Oral micro-biome and health[J]. AIMS Microbiol, 2018, 4(1): 42-66.
37 Walker MY, Pratap S, Southerland JH, et al. Role of oral and gut microbiome in nitric oxide-mediated colon motility[J]. Nitric Oxide, 2018, 73: 81-88.
38 Hajishengallis G. Periodontitis: from microbial immune subversion to systemic inflammation[J]. Nat Rev Immunol, 2015, 15(1): 30-44.
39 Fardini Y, Wang XW, Témoin S, et al. Fusobacte-rium nucleatum adhesin FadA binds vascular endothelial cadherin and alters endothelial integrity[J]. Mol Microbiol, 2011, 82(6): 1468-1480.
40 Jang JY, Baek KJ, Choi Y, et al. Relatively low invasive capacity of Porphyromonas gingivalis strains into human gingival fibroblasts in vitro [J]. Arch Oral Biol, 2017, 83: 265-271.
41 Xue Y, Xiao H, Guo SH, et al. Indoleamine 2,3-dioxygenase expression regulates the survival and proliferation of Fusobacterium nucleatum in THP-1-derived macrophages[J]. Cell Death Dis, 2018,9(3): 355.
42 Chen WG, Liu FL, Ling ZX, et al. Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer[J]. PLoS One, 2012, 7(6): e39743.
43 Rubinstein MR, Wang XW, Liu W, et al. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin[J]. Cell Host Microbe, 2013, 14(2): 195-206.
44 Gallimidi AB, Fischman S, Revach B, et al. Perio-dontal pathogens Porphyromonas gingivalis and Fusobacterium nucleatum promote tumor progression in an oral-specific chemical carcinogenesis model[J]. Oncotarget, 2015, 6(26): 22613-22623.
45 Kostic AD, Gevers D, Pedamallu CS, et al. Geno-mic analysis identifies association of Fusobacterium with colorectal carcinoma[J]. Genome Res, 2012, 22(2): 292-298.
46 Yachida S, Mizutani S, Shiroma H, et al. Metagenomic and metabolomic analyses reveal distinct stage-specific phenotypes of the gut microbiota in colorectal cancer[J]. Nat Med, 2019, 25(6): 968-976.
47 Kasper SH, Morell-Perez C, Wyche TP, et al. Colorectal cancer-associated anaerobic bacteria proliferate in tumor spheroids and alter the microenvironment[J]. Sci Rep, 2020, 10: 5321.
48 Hong J, Guo FF, Lu SY, et al. F. nucleatum targets lncRNA ENO1-IT1 to promote glycolysis and oncogenesis in colorectal cancer[J]. Gut, 2021, 70(11): 2123-2137.
49 Zheng X, Liu R, Zhou CC, et al. ANGPTL4-media-ted promotion of glycolysis facilitates the colonization of Fusobacterium nucleatum in colorectal cancer[J]. Cancer Res, 2021, 81(24): 6157-6170.
50 Rubinstein MR, Baik JE, Lagana SM, et al. Fusobacterium nucleatum promotes colorectal cancer by inducing Wnt/β-catenin modulator Annexin A1[J]. EMBO Rep, 2019, 20(4): e47638.
51 Morikawa R, Nemoto Y, Yonemoto Y, et al. Intraepithelial lymphocytes suppress intestinal tumor growth by cell-to-cell contact via CD103/E-cadherin signal[J]. Cell Mol Gastroenterol Hepatol, 2021, 11(5): 1483-1503.
52 Ouyang HY, Luong P, Frödin M, et al. p190A RhoGAP induces CDH1 expression and cooperates with E-cadherin to activate LATS kinases and suppress tumor cell growth[J]. Oncogene, 2020, 39(33): 5570-5587.
53 Shi CZ, Yang YZ, Xia Y, et al. Novel evidence for an oncogenic role of microRNA-21 in colitis-asso-ciated colorectal cancer[J]. Gut, 2016, 65(9): 1470-1481.
54 Yang YZ, Weng WH, Peng JJ, et al. Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activa-ting toll-like receptor 4 signaling to nuclear factor-κB, and up-regulating expression of MicroRNA-21[J]. Gastroenterology, 2017, 152(4): 851-866.e24.
55 Mima K, Nishihara R, Qian ZR, et al. Fusobacte-rium nucleatumin colorectal carcinoma tissue and patient prognosis[J]. Gut, 2016, 65(12): 1973-1980.
56 Yu T, Guo FF, Yu YN, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy[J]. Cell, 2017, 170(3): 548-563.e16.
57 Zhang S, Yang YZ, Weng WH, et al. Fusobacterium nucleatum promotes chemoresistance to 5-fluorouracil by upregulation of BIRC3 expression in colorectal cancer[J]. J Exp Clin Cancer Res, 2019, 38: 14.
58 Hu XY, Meng Y, Xu L, et al. Cul4 E3 ubiquitin ligase regulates ovarian cancer drug resistance by targeting the antiapoptotic protein BIRC3[J]. Cell Death Dis, 2019, 10(2): 104.
59 Rouhrazi H, Turgan N, Oktem G. Zoledronic acid overcomes chemoresistance by sensitizing cancer stem cells to apoptosis[J]. Biotech Histochem, 2018, 93(2): 77-88.
60 Huangfu SC, Zhang WB, Zhang HR, et al. Clinicopathological and prognostic significance of Fusobacterium nucleatum infection in colorectal cancer: a meta-analysis[J]. J Cancer, 2021, 12(6): 1583-1591.
61 Li YY, Ge QX, Cao J, et al. Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients[J]. World J Gastroenterol, 2016, 22(11): 3227-3233.
62 Chen SJ, Su TT, Zhang Y, et al. Fusobacterium nucleatum promotes colorectal cancer metastasis by modulating KRT7-AS/KRT7[J]. Gut Microbes, 2020, 11(3): 511-525.
63 Huang B, Song JH, Cheng Y, et al. Long non-coding antisense RNA KRT7-AS is activated in gastric cancers and supports cancer cell progression by increa-sing KRT7 expression[J]. Oncogene, 2016, 35(37): 4927-4936.
64 Wang W, Wang J, Yang C, et al. MicroRNA-216a targets WT1 expression and regulates KRT7 transcription to mediate the progression of pancreatic cancer-a transcriptome analysis[J]. IUBMB Life, 2021, 73(6): 866-882.
65 Zhang ZY, Tu KJ, Liu FY, et al. FoxM1 promotes the migration of ovarian cancer cell through KRT5 and KRT7[J]. Gene, 2020, 757: 144947.
66 Harbaum L, Pollheimer MJ, Kornprat P, et al. Keratin 7 expression in colorectal cancer-freak of nature or significant finding[J]. Histopathology, 2011, 59(2): 225-234.
67 An Q, Liu T, Wang MY, et al. KRT7 promotes epithelial-mesenchymal transition in ovarian cancer via the TGF‑β/Smad2/3 signaling pathway[J]. Oncol Rep, 2021, 45(2): 481-492.
68 Chen YY, Chen Y, Zhang JX, et al. Fusobacterium nucleatum promotes metastasis in colorectal cancer by activating autophagy signaling via the upregulation of CARD3 expression[J]. Theranostics, 2020, 10(1): 323-339.
69 Tkach M, Théry C. Communication by extracellular vesicles: where we are and where we need to go[J]. Cell, 2016, 164(6): 1226-1232.
70 Guo SH, Chen J, Chen FF, et al. Exosomes derived from Fusobacterium nucleatum-infected colorectal cancer cells facilitate tumour metastasis by selectively carrying miR-1246/92b-3p/27a-3p and CXCL16[J]. Gut, 2020: gutjnl-2020-321187.
71 Bullman S, Pedamallu CS, Sicinska E, et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer[J]. Science, 2017, 358(6369): 1443-1448.
72 Bruger AM, Vanhaver C, Bruderek K, et al. Protocol to assess the suppression of T-cell proliferation by human MDSC[J]. Methods Enzymol, 2020, 632: 155-192.
73 de Cicco P, Ercolano G, Ianaro A. The new era of cancer immunotherapy: targeting myeloid-derived suppressor cells to overcome immune evasion[J]. Front Immunol, 2020, 11: 1680.
74 Gur C, Ibrahim Y, Isaacson B, et al. Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack[J]. Immunity, 2015, 42(2): 344-355.
75 Chen T, Li Q, Wu J, et al. Fusobacterium nucleatum promotes M2 polarization of macrophages in the microenvironment of colorectal tumours via a TLR4-dependent mechanism[J]. Cancer Immunol Immunother, 2018, 67(10): 1635-1646.
76 Yunna C, Mengru H, Lei W, et al. Macrophage M1/M2 polarization[J]. Eur J Pharmacol, 2020, 877: 173090.
77 Locati M, Curtale G, Diversity Mantovani A., me-chanisms, and significance of macrophage plasticity [J]. Annu Rev Pathol, 2020, 15: 123-147.
78 Braune J, Weyer U, Hobusch C, et al. IL-6 regulates M2 polarization and local proliferation of adipose tissue macrophages in obesity[J]. J Immunol, 2017, 198(7): 2927-2934.
[1] Yang Mingyan,Zhang Fan,Zhao Lei. Research progress on oral flora changes affecting the course of radiotherapy and chemotherapy-related oral mucositis [J]. Int J Stomatol, 2023, 50(1): 43-51.
[2] Guo Simin,Chen Ting. Research progress on the gene family with sequence similarity 83 member H related to autosomal dominant hypocalcified amelogenesis imperfecta and its mutation [J]. Int J Stomatol, 2022, 49(5): 600-606.
[3] Li Shanshan,Yang Fang. Research progress on the relationship between Streptococcus mutans and Candida albicans in caries [J]. Int J Stomatol, 2022, 49(4): 392-396.
[4] Zha Yunchen,Zhang Jiajia,Kong Weidong.. Research progress on the etiology of primary failure of eruption [J]. Int J Stomatol, 2022, 49(4): 386-391.
[5] Zhou Shuangshuang, Zheng Xin, Zhou Xuedong, Xu Xin. Relationship of alkali production by plaque biofilm and dental caries [J]. Inter J Stomatol, 2016, 43(5): 573-577.
[6] Sun Fei1, Zhang Jiangang2, Xiao Shuiqing2. Structural function and pathogenic mechanism of cytolethal distending toxin and outer membrane proteins [J]. Inter J Stomatol, 2016, 43(5): 565-568.
[7] Xu Xinyue1, Li Xuejian1, Ren Gaotong1, Jiao Kai2,3, Niu Lina3,4. Function of immunocyte-derived catecholamine in physiological metabolism and inflammatory diseases [J]. Inter J Stomatol, 2016, 43(5): 599-604.
[8] Huang Hui, Zhang Qiong, Zou Jing. Research progress on oral microbiota of early childhood caries [J]. Inter J Stomatol, 2016, 43(3): 295-297.
[9] Xu Peng, Chen Chuanjun. The progress of relationship between primary trigeminal neuralgia and herpes simplex virus infection [J]. Inter J Stomatol, 2016, 43(2): 220-222.
[10] Zheng Sainan, Jiang Li, Li Wei. Research progress on oral bacterial adhesion mechanism [J]. Inter J Stomatol, 2016, 43(2): 223-227.
[11] Yu Pei, Xue Jing, Li Wei.. Research strategies of microbial metabolomics and its application in human microbes [J]. Inter J Stomatol, 2015, 42(6): 703-709.
[12] Ou Meizhen, Ling Junqi. Multiple effect of polyamines on biofilm [J]. Inter J Stomatol, 2015, 42(3): 361-363.
[13] Zhang Ruirui, Sun Keqin. Pathogenicity, detection, and elimination of Enterococcus faecalis in post-treatment endodontic disease [J]. Inter J Stomatol, 2015, 42(3): 357-360.
[14] Zhou Zheng, Zhao Changming, Jiao Kai, Wang Meiqing. Regulatory role of sympathetic nervous system–adrenergic receptor on bone remodeling [J]. Inter J Stomatol, 2015, 42(3): 348-351.
[15] Cheng Yuan, Yin Yanli, Zhao Lei. Research progress on Filifactor alocis [J]. Inter J Stomatol, 2014, 41(5): 593-597.
Viewed
Full text


Abstract

Cited

  Shared   
  Discussed   
[1] . [J]. Foreign Med Sci: Stomatol, 1999, 26(06): .
[2] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[3] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[4] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[5] . [J]. Foreign Med Sci: Stomatol, 1999, 26(05): .
[6] . [J]. Foreign Med Sci: Stomatol, 1999, 26(04): .
[7] . [J]. Foreign Med Sci: Stomatol, 2005, 32(06): 458 -460 .
[8] . [J]. Foreign Med Sci: Stomatol, 2005, 32(06): 452 -454 .
[9] . [J]. Inter J Stomatol, 2008, 35(S1): .
[10] . [J]. Inter J Stomatol, 2008, 35(S1): .