Fusobacterium Nucleatum Is a Risk Factor for Metastatic Colorectal Cancer

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.

Keywords

Fusobacterium nucleatum / colorectal cancer / metastasis

References

[1] BrayF, FerlayJ, SoerjomataramI, 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

[2] BrucknerHW, MotwaniBT. Chemotherapy of advanced cancer of the colon and rectum. Semin Oncol, 1991, 18(5): 443-461

[3] SiegelRL, MillerKD, Goding SauerA, et al.. Colorectal cancer statistics, 2020. CA Cancer J Clin, 2020, 70(3): 145-164

[4] SongJ, ParkS, OhJ, et al.. NUDT7 Loss Promotes Kras(G12D) CRC Development. Cancers (Basel), 2020, 12(3): 576

[5] Palko-LabuzA, MaksymowiczJ, SobieszczanskaB, 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

[6] ZhangK, PengT, YanQ, 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

[7] TuomistoA, NorskovNP, SirnioP, et al.. Serum enterolactone concentrations are low in colon but not in rectal cancer patients. Sci Rep, 2019, 9(1): 11209

[8] FiorentiniC, CarliniF, GerminarioEAP, et al.. Gut Microbiota and Colon Cancer: A Role for Bacterial Protein Toxins?. Int J Mol Sci, 2020, 21(17): 6201

[9] AleksandrovaK, Romero-MosqueraB, HernandezV. Diet, Gut Microbiome and Epigenetics: Emerging Links with Inflammatory Bowel Diseases and Prospects for Management and Prevention. Nutrients, 2017, 9(9): 962

[10] GrechG, ZhanX, YooBC, et al.. EPMA position paper in cancer: current overview and future perspectives. EPMA J, 2015, 6(1): 9

[11] JanneyA, PowrieF, MannEH. Host-microbiota maladaptation in colorectal cancer. Nature, 2020, 585(7826): 509-517

[12] ZhouZ, ChenJ, YaoH, et al.. Fusobacterium and Colorectal Cancer. Front Oncol, 2018, 8: 371

[13] HongBY, IdetaT, LemosBS, et al.. Characterization of Mucosal Dysbiosis of Early Colonic Neoplasia. NPJ Precis Oncol, 2019, 3: 29

[14] HanYW. Fusobacterium nucleatum: a commensal-turned pathogen. Curr Opin Microbiol, 2015, 23: 141-147

[15] ShetUK, OhHK, KimHJ, et al.. Quantitative analysis of periodontal pathogens present in the saliva of geriatric subjects. J Periodontal Implant Sci, 2013, 43(4): 183-190

[16] Allen-VercoeE, JobinC. Fusobacterium and Enterobacteriaceae: important players for CRC?. Immunol Lett, 2014, 162(2): 54-61 Pt A

[17] Hashemi GoradelN, HeidarzadehS, JahangiriS, et al.. Fusobacterium nucleatum and colorectal cancer: A mechanistic overview. J Cell Physiol, 2019, 234(3): 2337-2344

[18] WangS, LiuY, LiJ, et al.. Fusobacterium nucleatum Acts as a Pro-carcinogenic Bacterium in Colorectal Cancer: From Association to Causality. Front Cell Dev Biol, 2021, 9: 710165

[19] SladeDJ. New Roles for Fusobacterium nucleatum in Cancer: Target the Bacteria, Host, or Both?. Trends Cancer, 2021, 7(3): 185-187

[20] KosticAD, GeversD, PedamalluCS, et al.. Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res, 2012, 22(2): 292-298

[21] LiYY, GeQX, CaoJ, et al.. Association of Fusobacterium nucleatum infection with colorectal cancer in Chinese patients. World J Gastroenterol, 2016, 22(11): 3227-3233

[22] CastellarinM, WarrenRL, FreemanJD, et al.. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res, 2012, 22(2): 299-306

[23] RubinsteinMR, WangX, LiuW, 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

[24] EfratL A, SimoneW, MariusV, et al.. Fusobacterium and colorectal cancer: causal factor or passenger? Results from a large colorectal cancer screening study. Carcinogenesis, 2017, 38(8): 781-788

[25] FengQ, LiangS, JiaH, et al.. Gut microbiome development along the colorectal adenoma-carcinoma sequence. Nat Commun, 2015, 6: 6528

[26] YuJ, FengQ, WongSH, et al.. Metagenomic analysis of faecal microbiome as a tool towards targeted non-invasive biomarkers for colorectal cancer. Gut, 2017, 66(1): 70-78

[27] WeiZ, CaoS, LiuS, 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

[28] YangY, WengW, PengJ, 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

[29] ChenY, ChenY, ZhangJ, 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

[30] ZhangS, YangY, WengW, 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

[31] HarukiK, KosumiK, HamadaT, et al.. Association of autophagy status with amount of Fusobacterium nucleatum in colorectal cancer. J Pathol, 2020, 250(4): 397-408

[32] MimaK, NishiharaR, QianZR, et al.. Fusobacterium nucleatum in colorectal carcinoma tissue and patient prognosis. Gut, 2016, 65(12): 1973-1980

[33] NoshoK, SukawaY, AdachiY, et al.. Association of Fusobacterium nucleatum with immunity and molecular alterations in colorectal cancer. World J Gastroenterol, 2016, 22(2): 557-566

[34] ItoM, KannoS, NoshoK, et al.. Association of Fusobacterium nucleatum with clinical and molecular features in colorectal serrated pathway. Int J Cancer, 2015, 137(6): 1258-1268

[35] YamaokaY, SuehiroY, HashimotoS, et al.. Fusobacterium nucleatum as a prognostic marker of colorectal cancer in a Japanese population. J Gastroenterol, 2018, 53(4): 517-524

[36] ParkHE, KimJH, ChoNY, 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

[37] KunzmannAT, ProencaMA, JordaoHW, 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

[38] EklöfV, Löfgren-BurströmA, ZingmarkC, et al.. Cancer-associated fecal microbial markers in colorectal cancer detection. Int J Cancer, 2017, 141(12): 2528-2536

[39] LiangQ, ChiuJ, ChenY, et al.. Fecal Bacteria Act as Novel Biomarkers for Noninvasive Diagnosis of Colorectal Cancer. Clin Cancer Res, 2017, 23(8): 2061-2070

[40] SuehiroY, SakaiK, NishiokaM, 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

[41] TunsjøHS, GundersenG, RangnesF, 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

[42] WongSH, KwongTNY, ChowTC, et al.. Quantitation of faecal Fusobacterium improves faecal immunochemical test in detecting advanced colorectal neoplasia. Gut, 2017, 66(8): 1441-1448

[43] XieYH, GaoQY, CaiGX, et al.. Fecal Clostridium symbiosum for Noninvasive Detection of Early and Advanced Colorectal Cancer: Test and Validation Studies. EBioMedicine, 2017, 25: 32-40

[44] ChenS, SuT, ZhangY, et al.. Fusobacterium nucleatum promotes colorectal cancer metastasis by modulating KRT7-AS/KRT7. Gut Microbes, 2020, 11(3): 511-525

[45] YanX, LiuL, LiH, 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

[46] BullmanS, PedamalluCS, SicinskaE, et al.. Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science, 2017, 358(6369): 1443-1448

[47] XuC, FanL, LinY, et al.. Fusobacterium nucleatum promotes colorectal cancer metastasis through miR-1322/CCL20 axis and M2 polarization. Gut Microbes, 2021, 13: 1980347

[48] ChengK, YanX, ZhuY, 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

[49] MehtaRS, NishiharaR, CaoY, 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

[50] LiuL, TabungFK, ZhangX, 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

[51] LeeDW, HanSW, KangJK, et al.. Association Between Fusobacterium nucleatum, Pathway Mutation, and Patient Prognosis in Colorectal Cancer. Ann Surg Oncol, 2018, 25(11): 3389-3395