Skip to main content
SpringerLink
Log in

Fusobacterium Nucleatum Is a Risk Factor for Metastatic Colorectal Cancer

  • Published:
Current Medical Science Aims and scope Submit manuscript

Abstract

Objective

Increasing evidence has indicated that there is a correlation between Fusobacterium nucleatum (F. nucleatum) abundance and poor prognosis of colorectal cancer (CRC). Furthermore, tumor metastasis plays a decisive role in the prognosis of CRC patients. Therefore, it was hypothesized that the abundance of F. nucleatum in CRC tissues affects the tumor metastasis.

Methods

In the present study, F. nucleatum DNA obtained from 141 resected CRC samples was quantified by qPCR to determine whether there were differences in F. nucleatum abundance between groups with and without CRC metastasis.

Results

The results revealed that F. nucleatum was more abundant in CRC patients with metastasis, and CRC tissues enriched with F. nucleatum had a higher risk of lymph node metastasis and distant metastasis. The receiver operating characteristic curve indicated that F. nucleatum in CRC tissues could be used as an indicator for CRC metastasis, to some extent. Furthermore, the in vitro experiments (electron microscopy, and migration and invasion trials) revealed that F. nucleatum was a highly invasive bacterial strain, and could significantly enhance the invasion and migration capacity of SW480 and SW620 cells. In addition, a meta-analysis comprehensively indicated a slight correlation between F. nucleatum abundance and advanced CRC stage (RR=1.17, 95% CI: 1.00–1.37, P=0.04, random effect).

Conclusion

There is a correlation between F. nucleatum abundance and CRC metastasis, and F. nucleatum may serve as a metastasis biomarker for CRC patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018,68(6):394–424

    PubMed  Google Scholar 

  2. Bruckner HW, Motwani BT. Chemotherapy of advanced cancer of the colon and rectum. Semin Oncol, 1991,18(5):443–461

    CAS  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin, 2020,70(3):145–164

    Article  PubMed  Google Scholar 

  4. Song J, Park S, Oh J, et al. NUDT7 Loss Promotes Kras(G12D) CRC Development. Cancers (Basel), 2020,12(3):576

    Article  CAS  Google Scholar 

  5. Palko-Labuz A, Maksymowicz J, Sobieszczanska B, et al. Newly Obtained Apple Pectin as an Adjunct to Irinotecan Therapy of Colorectal Cancer Reducing E. coli Adherence and beta-Glucuronidase Activity. Cancers (Basel), 2021,13(12):2952

    Article  CAS  Google Scholar 

  6. Zhang K, Peng T, Yan Q, et al. Jiedu Sangen Decoction Inhibits Migration and Invasion of Colon Cancer SW480 Cells via Suppressing Epithelial Mesenchymal Transition. Evid Based Complement Alternat Med, 2018,2018:1495768

    PubMed  PubMed Central  Google Scholar 

  7. Tuomisto A, Norskov NP, Sirnio P, et al. Serum enterolactone concentrations are low in colon but not in rectal cancer patients. Sci Rep, 2019,9(1):11209

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Fiorentini C, Carlini F, Germinario EAP, et al. Gut Microbiota and Colon Cancer: A Role for Bacterial Protein Toxins? Int J Mol Sci, 2020,21(17):6201

    Article  CAS  PubMed Central  Google Scholar 

  9. Aleksandrova K, Romero-Mosquera B, Hernandez V. Diet, Gut Microbiome and Epigenetics: Emerging Links with Inflammatory Bowel Diseases and Prospects for Management and Prevention. Nutrients, 2017,9(9):962

    Article  PubMed Central  CAS  Google Scholar 

  10. Grech G, Zhan X, Yoo BC, et al. EPMA position paper in cancer: current overview and future perspectives. EPMA J, 2015,6(1):9

    Article  PubMed  PubMed Central  Google Scholar 

  11. Janney A, Powrie F, Mann EH. Host-microbiota maladaptation in colorectal cancer. Nature, 2020,585(7826):509–517

    Article  CAS  PubMed  Google Scholar 

  12. Zhou Z, Chen J, Yao H, et al. Fusobacterium and Colorectal Cancer. Front Oncol, 2018,8:371

    Article  PubMed  PubMed Central  Google Scholar 

  13. Hong BY, Ideta T, Lemos BS, et al. Characterization of Mucosal Dysbiosis of Early Colonic Neoplasia. NPJ Precis Oncol, 2019,3:29

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  14. Han YW. Fusobacterium nucleatum: a commensal-turned pathogen. Curr Opin Microbiol, 2015,23:141–147

    Article  CAS  PubMed  Google Scholar 

  15. Shet UK, Oh HK, Kim HJ, et al. Quantitative analysis of periodontal pathogens present in the saliva of geriatric subjects. J Periodontal Implant Sci, 2013,43(4):183–190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Allen-Vercoe E, Jobin C. Fusobacterium and Enterobacteriaceae: important players for CRC? Immunol Lett, 2014,162(2 Pt A):54–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hashemi Goradel N, Heidarzadeh S, Jahangiri S, et al. Fusobacterium nucleatum and colorectal cancer: A mechanistic overview. J Cell Physiol, 2019,234(3):2337–2344

    Article  CAS  PubMed  Google Scholar 

  18. Wang S, Liu Y, Li J, et al. Fusobacterium nucleatum Acts as a Pro-carcinogenic Bacterium in Colorectal Cancer: From Association to Causality. Front Cell Dev Biol, 2021,9:710165

    Article  PubMed  PubMed Central  Google Scholar 

  19. Slade DJ. New Roles for Fusobacterium nucleatum in Cancer: Target the Bacteria, Host, or Both? Trends Cancer, 2021,7(3):185–187

    Article  CAS  PubMed  Google Scholar 

  20. Kostic AD, Gevers D, Pedamallu CS, et al. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res, 2012,22(2):292–298

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Li YY, Ge QX, Cao J, et al. Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients. World J Gastroenterol, 2016,22(11):3227–3233

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Castellarin M, Warren RL, Freeman JD, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res, 2012,22(2):299–306

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. 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(2):195–206

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Efrat L Amitay, Simone Werner, Marius Vital, et al. Fusobacterium and colorectal cancer: causal factor or passenger? Results from a large colorectal cancer screening study. Carcinogenesis, 2017,38(8):781–788

    Article  Google Scholar 

  25. Feng Q, Liang S, Jia H, et al. Gut microbiome development along the colorectal adenoma-carcinoma sequence. Nat Commun, 2015,6:6528

    Article  CAS  PubMed  Google Scholar 

  26. Yu J, Feng Q, Wong SH, et al. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer. Gut, 2017,66(1):70–78

    Article  CAS  PubMed  Google Scholar 

  27. Wei Z, Cao S, Liu S, et al. Could gut microbiota serve as prognostic biomarker associated with colorectal cancer patients’ survival? A pilot study on relevant mechanism. Oncotarget, 2016,7(29):46158–46172

    Article  PubMed  PubMed Central  Google Scholar 

  28. 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(4):851–866 e824

    Article  CAS  PubMed  Google Scholar 

  29. Chen Y, Chen Y, Zhang J, et al. Fusobacterium nucleatum Promotes Metastasis in Colorectal Cancer by Activating Autophagy Signaling via the Upregulation of CARD3 Expression. Theranostics, 2020,10(1):323–339

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Zhang S, Yang Y, Weng W, et al. Fusobacterium nucleatum promotes chemoresistance to 5-fluorouracil by upregulation of BIRC3 expression in colorectal cancer. J Exp Clin Cancer Res, 2019,38(1):14

    Article  PubMed  PubMed Central  Google Scholar 

  31. Haruki K, Kosumi K, Hamada T, et al. Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer. J Pathol, 2020,250 (4):397–408

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mima K, Nishihara R, Qian ZR, et al. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut, 2016,65(12):1973–1980

    Article  CAS  PubMed  Google Scholar 

  33. 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(2):557–566

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. 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(6):1258–1268

    Article  CAS  PubMed  Google Scholar 

  35. 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(4):517–524

    Article  CAS  PubMed  Google Scholar 

  36. 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(3):329–336

    Article  CAS  PubMed  Google Scholar 

  37. Kunzmann AT, Proenca MA, Jordao HW, et al. Fusobacterium nucleatum tumor DNA levels are associated with survival in colorectal cancer patients. Eur J Clin Microbiol Infect Dis, 2019,38(10):1891–1899

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Eklöf V, Löfgren-Burström A, Zingmark C, et al. Cancer-associated fecal microbial markers in colorectal cancer detection. Int J Cancer, 2017,141(12):2528–2536

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. 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(8):2061–2070

    Article  CAS  PubMed  Google Scholar 

  40. 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(1):86–91

    Article  CAS  PubMed  Google Scholar 

  41. Tunsjø HS, Gundersen G, Rangnes F, et al. Detection of Fusobacterium nucleatum in stool and colonic tissues from Norwegian colorectal cancer patients. Eur J Clin Microbiol Infect Dis, 2019,38(7):1367–1376

    Article  PubMed  Google Scholar 

  42. Wong SH, Kwong TNY, Chow TC, et al. Quantitation of faecal Fusobacterium improves faecal immunochemical test in detecting advanced colorectal neoplasia. Gut, 2017,66(8):1441–1448

    Article  CAS  PubMed  Google Scholar 

  43. Xie YH, Gao QY, Cai GX, et al. Fecal Clostridium symbiosum for Noninvasive Detection of Early and Advanced Colorectal Cancer: Test and Validation Studies. EBioMedicine, 2017,25:32–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen S, Su T, Zhang Y, et al. Fusobacterium nucleatum promotes colorectal cancer metastasis by modulating KRT7-AS/KRT7. Gut Microbes, 2020,11(3):511–525

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. 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, 2017,10:5031–5046

    Article  PubMed  PubMed Central  Google Scholar 

  46. Bullman S, Pedamallu CS, Sicinska E, et al. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science, 2017,358(6369):1443–1448

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Xu C, Fan L, Lin Y, et al. Fusobacterium nucleatum promotes colorectal cancer metastasis through miR-1322/CCL20 axis and M2 polarization. Gut Microbes, 2021,13:1980347

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Cheng K, Yan X, Zhu Y, et al. Fusobacterium nucleatum Promotes the Development of Colorectal Cancer by Activating a Cytochrome P450/Epoxyoctadecenoic Acid Axis via TLR4/Keap1/NRF2 Signaling. Cancer Res, 2021,81(17):4485–4498

    Article  Google Scholar 

  49. 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(7):921–927

    Article  PubMed  PubMed Central  Google Scholar 

  50. 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, 2018,16(10):1622–1631.e3

    Article  PubMed  PubMed Central  Google Scholar 

  51. 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):3389–3395

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Both authors contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Laboratory, Qilu Hospital of Shandong University, Jinan, 250012, China

    Wen-dan Chen, Xin Zhang, Ya-ping Zhang, Cong-bo Yue, Hong-wei Pan, Hui Liu & Yi Zhang

  2. Department of General Surgery, Qilu Hospital of Shandong University, Jinan, 250012, China

    Yan-lei Wang

  3. Department of Clinical Laboratory, Shandong Provincial Third Hospital, Jinan, 250031, China

    Yan-li Zhang

Authors
  1. Wen-dan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xin Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ya-ping Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cong-bo Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan-lei Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong-wei Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yan-li Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hui Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yi Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yi Zhang.

Additional information

Conflict of Interest Statement

All authors declare that they have no conflicts of interest.

This work was supported by grants from the National Natural Science Foundation of China (No. 81972005 and No. 82172339), the Natural Science Foundation of Shandong Province (No. ZR2020MH238 and No. ZR2020MH257), and the Shandong Medical and Health Technology Development Project (No. 2018WSB20002).

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Wd., Zhang, X., Zhang, Yp. et al. Fusobacterium Nucleatum Is a Risk Factor for Metastatic Colorectal Cancer. CURR MED SCI 42, 538–547 (2022). https://doi.org/10.1007/s11596-022-2597-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11596-022-2597-1

Key words

Search

Navigation