国际口腔医学杂志

国际口腔医学杂志 ›› 2023, Vol. 50 ›› Issue (1): 52-60.doi: 10.7518/gjkq.2023011

• 口腔微生物专栏 • 上一篇    下一篇

具核梭杆菌促进结直肠癌发生发展机制的研究进展

罗婉逸1(),韩居熺1,周学东1,2,彭显1,2,郑欣1,2()   

  1. 1.口腔疾病研究国家重点实验室;国家口腔疾病临床医学研究中心;四川大学华西口腔医学院 成都 610041
    2.口腔疾病研究国家重点实验室;国家口腔疾病临床医学研究中心;四川大学华西口腔医院牙体牙髓病科 成都 610041
  • 收稿日期:2022-04-21 修回日期:2022-10-02 出版日期:2023-01-01 发布日期:2023-01-09
  • 通讯作者: 郑欣
  • 作者简介:罗婉逸，学士，Email：1902349799@qq.com
  • 基金资助:
    四川大学华西口腔医院人才队伍建设科研经费(RCDWJ-S2020-11)

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
  • Supported by:
    Research Funding for Talents Developing, West China Hospital of Stomatology, Sichuan University(RCDWJS2020-11)

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摘要：

具核梭杆菌是一种革兰阴性厌氧菌，广泛定植于人体口腔内，是公认的牙周致病菌。该菌不仅在牙周病、口腔癌等口腔疾病中起着重要作用，还与全身各系统多种疾病存在关系，包括心血管疾病、骨关节炎、妊娠不良事件及各系统肿瘤。具核梭杆菌与结直肠癌的关系是当前研究的热点问题。存在肠道炎症的患者，牙周炎或可成为一个促进炎症向癌症转变的风险因素。具核梭杆菌可通过消化道及血液循环两条途径迁移到肠道，进一步通过黏附素-上皮细胞钙黏蛋白和黏附素-糖类肿瘤标记物两条途径与结直肠癌细胞特异性结合。具核梭杆菌对肿瘤内乏氧的高代谢环境具有较强的适应能力，可进一步促进肿瘤的糖酵解，互利共生的关系使得具核梭杆菌在肿瘤中大量富集。与结直肠癌细胞结合后，具核梭杆菌通过调控经典Wnt信号通、核因子κB等信号通路，改变免疫微环境，促进肿瘤的生长和转移，并表现出抗化学治疗的作用，对结直肠癌的发生发展和治疗造成影响。

关键词: 具核梭杆菌, 结直肠癌, 肿瘤免疫微环境

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

中图分类号: 

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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.
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