Progress in characterizing the linkage between Fusobacterium nucleatum and gastrointestinal cancer

Abstract

Microbiome research is a rapidly advancing field in human cancers. Fusobacterium nucleatum is an oral bacterium, indigenous to the human oral cavity, that plays a role in periodontal disease. Recent studies have found that F. nucleatum can promote gastrointestinal tumor progression and affect the prognosis of the disease. In addition, F. nucleatum may contribute to the chemo-resistance of gastrointestinal cancers. This review summarizes recent progress in the pathogenesis of F. nucleatum and its impact on gastrointestinal cancer.

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References

  1. 1.

    Arthur JC, Gharaibeh RZ, Muhlbauer M, et al. Microbial genomic analysis reveals the essential role of inflammation in bacteria-induced colorectal cancer. Nat Commun. 2014;5:4724.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Schwabe RF, Jobin C. The microbiome and cancer. Nat Rev Cancer. 2013;13:800–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Abreu MT, Peek RM. Gastrointestinal malignancy and the microbiome. Gastroenterology. 2014;146:1534–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Al-Haddad S, El-Zimaity H, Hafezi-Bakhtiari S, et al. Infection and esophageal cancer. Ann N Y Acad Sci. 2014;1325:187–96.

    Article  PubMed  Google Scholar 

  5. 5.

    Louis P, Hold GL, Flint HJ. The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol. 2014;12:661–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Ley RE, Turnbaugh PJ, Klein S, et al. Human gut microbes associated with obesity. Nature. 2006;444:1022–3.

    Article  CAS  Google Scholar 

  7. 7.

    Ohkusa T, Okayasu I, Ogihara T, et al. Induction of experimental ulcerative colitis by Fusobacterium varium isolated from colonic mucosa of patients with ulcerative colitis. Gut. 2003;52:79–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 8.

    Hotamisligil GS. Inflammation and metabolic disorders. Nature. 2006;444:860–7.

    Article  CAS  Google Scholar 

  9. 9.

    Yoneda M, Naka S, Nakano K, et al. Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease. BMC Gastroenterol. 2012;12:16.

    Article  PubMed  PubMed Central  Google Scholar 

  10. 10.

    Garrett WS. Cancer and the microbiota. Science. 2015;348:80–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Becattini S, Taur Y, Pamer EG. Antibiotic-induced changes in the intestinal microbiota and disease. Trends Mol Med. 2016;22:458–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Pamer EG. Resurrecting the intestinal microbiota to combat antibiotic-resistant pathogens. Science. 2016;352:535–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Ianiro G, Tilg H, Gasbarrini A. Antibiotics as deep modulators of gut microbiota: between good and evil. Gut. 2016;65:1906–15.

    Article  CAS  PubMed  Google Scholar 

  14. 14.

    Bashir A, Miskeen AY, Hazari YM, et al. Fusobacterium nucleatum, inflammation, and immunity: the fire within human gut. Tumour Biol. 2016;37:2805–10.

    Article  CAS  PubMed  Google Scholar 

  15. 15.

    Han YW. Fusobacterium nucleatum: a commensal-turned pathogen. Curr Opin Microbiol. 2015;23:141–7.

    Article  CAS  PubMed  Google Scholar 

  16. 16.

    Citron DM. Update on the taxonomy and clinical aspects of the genus fusobacterium. Clin Infect Dis. 2002;35:S22–7.

    Article  PubMed  Google Scholar 

  17. 17.

    Signat B, Roques C, Poulet P, et al. Fusobacterium nucleatum in periodontal health and disease. Curr Issues Mol Biol. 2011;13:25–36.

    CAS  PubMed  Google Scholar 

  18. 18.

    Dzink JL, Sheenan MT, Socransky SS. Proposal of three subspecies of Fusobacterium nucleatum Knorr 1922: Fusobacterium nucleatum subsp. nucleatum subsp. nov., comb. nov.; Fusobacterium nucleatum subsp. polymorphum subsp. nov., nom. rev., comb. nov.; and Fusobacterium nucleatum subsp. vincentii subsp. nov., nom. rev., comb. nov. Int J Syst Bacteriol. 1990;40:74–8.

    Article  CAS  PubMed  Google Scholar 

  19. 19.

    Castellarin M, Warren RL, Freeman JD, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res. 2012;22:299–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Kaplan CW, Lux R, Haake SK, et al. The Fusobacterium nucleatum outer membrane protein RadD is an arginine-inhibitable adhesin required for inter-species adherence and the structured architecture of multispecies biofilm. Mol Microbiol. 2009;71:35–47.

    Article  CAS  PubMed  Google Scholar 

  21. 21.

    Bachrach G, Ianculovici C, Naor R, et al. Fluorescence based measurements of Fusobacterium nucleatum coaggregation and of fusobacterial attachment to mammalian cells. FEMS Microbiol Lett. 2005;248:235–40.

    Article  CAS  PubMed  Google Scholar 

  22. 22.

    Fardini Y, Wang X, Temoin S, et al. Fusobacterium nucleatum adhesin FadA binds vascular endothelial cadherin and alters endothelial integrity. Mol Microbiol. 2011;82:1468–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Han YW, Ikegami A, Rajanna C, et al. Identification and characterization of a novel adhesin unique to oral fusobacteria. J Bacteriol. 2005;187:5330–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67:177–93.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Dienstmann R, Vermeulen L, Guinney J, et al. Consensus molecular subtypes and the evolution of precision medicine in colorectal cancer. Nat Rev Cancer. 2017;17:79–92.

    Article  CAS  PubMed  Google Scholar 

  26. 26.

    Burgess DJ. Gene expression: colorectal cancer classifications. Nat Rev Cancer. 2013;13:380–1.

    Article  CAS  PubMed  Google Scholar 

  27. 27.

    Flemer B, Warren RD, Barrett MP, et al. The oral microbiota in colorectal cancer is distinctive and predictive. Gut. 2018;67:1454–63.

    Article  CAS  PubMed  Google Scholar 

  28. 28.

    Kostic AD, Gevers D, Pedamallu CS, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res. 2012;22:292–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Mima K, Nishihara R, Qian ZR, et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut. 2016;65:1973–80.

    Article  CAS  PubMed  Google Scholar 

  30. 30.

    Mima K, Cao Y, Chan AT, et al. Fusobacterium nucleatum in colorectal carcinoma tissue according to tumor location. Clin Transl Gastroenterol. 2016;7:e200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Flanagan L, Schmid J, Ebert M, et al. Fusobacterium nucleatum associates with stages of colorectal neoplasia development, colorectal cancer and disease outcome. Eur J Clin Microbiol Infect Dis. 2014;33:1381–90.

    Article  CAS  PubMed  Google Scholar 

  32. 32.

    Yamaoka Y, Suehiro Y, Hashimoto S, et al. Fusobacterium nucleatum as a prognostic marker of colorectal cancer in a Japanese population. J Gastroenterol. 2018;53:517–24.

    Article  CAS  PubMed  Google Scholar 

  33. 33.

    Eklof V, Lofgren-Burstrom A, Zingmark C, et al. Cancer-associated fecal microbial markers in colorectal cancer detection. Int J Cancer. 2017;141:2528–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Wong SH, Kwong TNY, Chow TC, et al. Quantitation of faecal Fusobacterium improves faecal immunochemical test in detecting advanced colorectal neoplasia. Gut. 2017;66:1441–8.

    Article  CAS  PubMed  Google Scholar 

  35. 35.

    Liang Q, Chiu J, Chen Y, et al. Fecal bacteria act as novel biomarkers for noninvasive diagnosis of colorectal cancer. Clin Cancer Res. 2017;23:2061–70.

    Article  CAS  PubMed  Google Scholar 

  36. 36.

    Ito M, Kanno S, Nosho K, et al. Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway. Int J Cancer. 2015;137:1258–68.

    Article  CAS  PubMed  Google Scholar 

  37. 37.

    Nosho K, Sukawa Y, Adachi Y, et al. Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer. World J Gastroenterol. 2016;22:557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. 38.

    Park HE, Kim JH, Cho NY, et al. Intratumoral Fusobacterium nucleatum abundance correlates with macrophage infiltration and CDKN2A methylation in microsatellite-unstable colorectal carcinoma. Virchows Arch. 2017;471:329–36.

    Article  CAS  PubMed  Google Scholar 

  39. 39.

    Tahara T, Yamamoto E, Suzuki H, et al. Fusobacterium in colonic flora and molecular features of colorectal carcinoma. Can Res. 2014;74:1311–8.

    Article  CAS  Google Scholar 

  40. 40.

    Lee DW, Han SW, Kang JK, et al. Association Between Fusobacterium nucleatum, pathway mutation, and patient prognosis in colorectal cancer. Ann Surg Oncol. 2018;25(11):3389–95.

    Article  PubMed  Google Scholar 

  41. 41.

    Rubinstein MR, Wang X, Liu W, et al. Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/beta-catenin signaling via its FadA adhesin. Cell Host Microbe. 2013;14:195–206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Abed J, Emgard JE, Zamir G, et al. Fap2 Mediates Fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc. Cell Host Microbe. 2016;20:215–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Yang Y, Weng W, Peng J, et al. Fusobacterium nucleatum increases proliferation of colorectal cancer cells and tumor development in mice by activating toll-like receptor 4 signaling to nuclear factor-kappaB, and up-regulating expression of MicroRNA-21. Gastroenterology. 2017;152:851–66.

    Article  CAS  PubMed  Google Scholar 

  44. 44.

    Chen YY, Peng Y, Yu JH, et al. Invasive Fusobacterium nucleatum activates beta-catenin signaling in colorectal cancer via a TLR4/P-PAK1 cascade. Oncotarget. 2017;8:31802–14.

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Yu YN, Yu TC, Zhao HZ, et al. Berberine may rescue Fusobacterium nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment. Oncotarget. 2015;6:32013–26.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Kumar A, Thotakura PL, Tiwary BK, et al. Target identification in Fusobacterium nucleatum by subtractive genomics approach and enrichment analysis of host-pathogen protein-protein interactions. BMC Microbiol. 2016;16:84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Tang B, Wang K, Jia YP, et al. Fusobacterium nucleatum-induced impairment of autophagic flux enhances the expression of proinflammatory cytokines via ROS in Caco-2 cells. PLoS One. 2016;11:e0165701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. 48.

    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. Immunity. 2015;42:344–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Saito T, Nishikawa H, Wada H, et al. Two FOXP3(+)CD4(+) T cell subpopulations distinctly control the prognosis of colorectal cancers. Nat Med. 2016;22:679–84.

    Article  CAS  PubMed  Google Scholar 

  50. 50.

    Mima K, Sukawa Y, Nishihara R, et al. Fusobacterium nucleatum and T Cells in colorectal carcinoma. JAMA Oncol. 2015;1:653–61.

    Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Kostic AD, Chun E, Robertson L, et al. Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe. 2013;14:207–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Ye X, Wang R, Bhattacharya R, et al. Fusobacterium Nucleatum subspecies Animalis influences proinflammatory cytokine expression and monocyte activation in human colorectal tumors. Cancer Prev Res (Phila). 2017;10:398–409.

    Article  CAS  PubMed  Google Scholar 

  53. 53.

    Peters BA, Wu J, Pei Z, et al. Oral microbiome composition reflects prospective risk for esophageal cancers. Cancer Res. 2017;77:6777–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Yamamura K, Baba Y, Nakagawa S, et al. Human microbiome Fusobacterium Nucleatum in esophageal cancer tissue is associated with prognosis. Clin Cancer Res. 2016;22:5574–81.

    Article  CAS  PubMed  Google Scholar 

  55. 55.

    Fan X, Alekseyenko AV, Wu J, et al. Human oral microbiome and prospective risk for pancreatic cancer: a population-based nested case–control study. Gut. 2018;67:120–7.

    Article  CAS  PubMed  Google Scholar 

  56. 56.

    Mitsuhashi K, Nosho K, Sukawa Y, et al. Association of Fusobacterium species in pancreatic cancer tissues with molecular features and prognosis. Oncotarget. 2015;6:7209–20.

    PubMed  PubMed Central  Google Scholar 

  57. 57.

    Yamamura K, Baba Y, Miyake K, et al. Fusobacterium nucleatum in gastroenterological cancer: evaluation of measurement methods using quantitative polymerase chain reaction and a literature review. Oncol Lett. 2017;14:6373–8.

    PubMed  PubMed Central  Google Scholar 

  58. 58.

    Bullman S, Pedamallu CS, Sicinska E, et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science. 2017;358:1443–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Jemal A, Bray F, Center MM, et al. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.

    Article  PubMed  PubMed Central  Google Scholar 

  60. 60.

    Castano-Rodriguez N, Goh KL, Fock KM, et al. Dysbiosis of the microbiome in gastric carcinogenesis. Sci Rep. 2017;7:15957.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. 61.

    Hsieh YY, Tung SY, Pan HY, et al. Increased abundance of clostridium and fusobacterium in gastric microbiota of patients with gastric cancer in Taiwan. Sci Rep. 2018;8:158.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. 62.

    Wei ZL, Cao SG, Liu SL, et al. Could gut microbiota serve as prognostic biomarker associated with colorectal cancer patients’ survival? A pilot study on relevant mechanism. Oncotarget. 2016;7:46158–72.

    PubMed  PubMed Central  Google Scholar 

  63. 63.

    Yan X, Liu L, Li H, et al. Clinical significance of Fusobacterium nucleatum, epithelial-mesenchymal transition, and cancer stem cell markers in stage III/IV colorectal cancer patients. Onco Targets Ther. 2017;10:5031–46.

    Article  PubMed  PubMed Central  Google Scholar 

  64. 64.

    Yu T, Guo F, Yu Y, et al. Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell. 2017;170(548–563):e516.

    Google Scholar 

  65. 65.

    Mehta RS, Nishihara R, Cao Y, et al. Association of dietary patterns with risk of colorectal cancer subtypes classified by Fusobacterium nucleatum in tumor tissue. JAMA Oncol. 2017;3:921–7.

    Article  PubMed  PubMed Central  Google Scholar 

  66. 66.

    Pollock J, Glendinning L, Wisedchanwet T, et al. The madness of microbiome: attempting to find consensus “best practice” for 16S microbiome studies. Appl Environ Microbiol. 2018;84(7). pii: e02627–17. https://doi.org/10.1128/AEM.02627-17.

  67. 67.

    Liu L, Tabung FK, Zhang X, et al. Diets that promote colon inflammation associate with risk of colorectal carcinomas that contain Fusobacterium nucleatum. Clin Gastroenterol Hepatol. 2018. https://doi.org/10.1016/j.cgh.2018.04.030.

    Article  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Chen T, Li Q, Zhang X, et al. TOX expression decreases with progression of colorectal cancers and is associated with CD4 T-cell density and Fusobacterium nucleatum infection. Hum Pathol. 2018;79:93–101.

    Article  CAS  PubMed  Google Scholar 

  69. 69.

    Li YY, Ge QX, Cao J, et al. Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients. World J Gastroenterol. 2016;22:3227–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Wang HF, Li LF, Guo SH, et al. Evaluation of antibody level against Fusobacterium nucleatum in the serological diagnosis of colorectal cancer. Sci Rep. 2016;6:33440.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Wu N, Yang X, Zhang R, et al. Dysbiosis signature of fecal microbiota in colorectal cancer patients. Microb Ecol. 2013;66:462–70.

    Article  CAS  PubMed  Google Scholar 

  72. 72.

    Suehiro Y, Sakai K, Nishioka M, et al. Highly sensitive stool DNA testing of Fusobacterium nucleatum as a marker for detection of colorectal tumours in a Japanese population. Ann Clin Biochem. 2017;54:86–91.

    Article  CAS  PubMed  Google Scholar 

  73. 73.

    Mira-Pascual L, Cabrera-Rubio R, Ocon S, et al. Microbial mucosal colonic shifts associated with the development of colorectal cancer reveal the presence of different bacterial and archaeal biomarkers. J Gastroenterol. 2015;50:167–79.

    Article  CAS  PubMed  Google Scholar 

  74. 74.

    Amitay EL, Werner S, Vital M, et al. Fusobacterium and colorectal cancer: causal factor or passenger? Results from a large colorectal cancer screening study. Carcinogenesis. 2017;38:781–8.

    Article  PubMed  Google Scholar 

  75. 75.

    Guo SH, Wang HF, Nian ZG, et al. Immunization with alkyl hydroperoxide reductase subunit C reduces Fusobacterium nucleatum load in the intestinal tract. Sci Rep. 2017;7:10566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 76.

    Zanzoni A, Spinelli L, Braham S, et al. Perturbed human sub-networks by Fusobacterium nucleatum candidate virulence proteins. Microbiome. 2017;5:89.

    Article  PubMed  PubMed Central  Google Scholar 

  77. 77.

    Dix A, Vlaic S, Guthke R, et al. Use of systems biology to decipher host-pathogen interaction networks and predict biomarkers. Clin Microbiol Infect. 2016;22:600–6.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported in part by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, Grant numbers 17H04273, 17K19702 and 17KK0195 (to Y.B.).

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Correspondence to Hideo Baba.

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Liu, Y., Baba, Y., Ishimoto, T. et al. Progress in characterizing the linkage between Fusobacterium nucleatum and gastrointestinal cancer. J Gastroenterol 54, 33–41 (2019). https://doi.org/10.1007/s00535-018-1512-9

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Keywords

  • Fusobacterium nucleatum
  • Microbiome
  • Gastrointestinal cancer
  • Colon cancer
  • Esophageal cancer