The role of microbiota in tumorigenesis, progression and treatment of bladder cancer

Abstract

For decades, the urinary system was regarded as a sterile environment due to the absence of any bacterial growth in clinical standard urine cultures from healthy individuals. However, a diverse array of microbes colonizes the urinary system in small quantities, exhibiting a variable compositional signature influenced by differences in sex, age, and pathological state. Increasing pieces of evidence suggest microbiota exists in tumor tissue and plays a crucial role in tumor microenvironment based on research in multiple cancer models. Current studies about microbiota and bladder cancer have preliminarily characterized the bladder cancer-related microbiota, but how the microbiota influences the biological behavior of bladder cancer remains unclarified. This review summarizes the characteristics of microbiota in bladder cancer, aims to propose possible mechanisms that microbiota acts in tumorigenesis and progression of bladder cancer based on advances in gut microbiota, and discusses the potential clinical application of microbiota in bladder cancer.

Keywords

Microbiota / bladder cancer / mechanism / tumor microenvironment / microbial metabolites

References

[1] Sung H,Siegel RL.Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin2021;71:209-49

[2] Jubber I,Bukavina L.Epidemiology of bladder cancer in 2023: a systematic review of risk factors.Eur Urol2023;84:176-90

[3] Gaffney CD,D’Souza N,Matulewicz RS.Bladder cancer carcinogens: opportunities for risk reduction.Eur Urol Focus2023;9:575-8 PMCID:PMC10524287

[4] Hilt EE,Pearce MM.Urine is not sterile: use of enhanced urine culture techniques to detect resident bacterial flora in the adult female bladder.J Clin Microbiol2014;52:871-6 PMCID:PMC3957746

[5] Wolfe AJ.“Sterile urine” and the presence of bacteria.Eur Urol2015;68:173-4 PMCID:PMC4659483

[6] Aragón IM,Queipo-Ortuño MI.The urinary tract microbiome in health and disease.Eur Urol Focus2018;4:128-38

[7] Poore GD,Zhu Q.Microbiome analyses of blood and tissues suggest cancer diagnostic approach.Nature2020;579:567-74 PMCID:PMC7500457

[8] Rebersek M.Gut microbiome and its role in colorectal cancer.BMC Cancer2021;21:1325 PMCID:PMC8666072

[9] Stewart OA,Chen Y.The role of gastric microbiota in gastric cancer.Gut Microbes2020;11:1220-30 PMCID:PMC7524314

[10] Al-Ansari MM,Dahabiyeh LA.Metabolomics-microbiome crosstalk in the breast cancer microenvironment.Metabolites2021;11:758 PMCID:PMC8619468

[11] Helmink BA,Hermann A,Wargo JA.The microbiome, cancer, and cancer therapy.Nat Med2019;25:377-88

[12] Wong-Rolle A,Zhao C.Unexpected guests in the tumor microenvironment: microbiome in cancer.Protein Cell2021;12:426-35 PMCID:PMC8106554

[13] Jones-Freeman B,Marcelino VR,Forster SC.The microbiome and host mucosal interactions in urinary tract diseases.Mucosal Immunol2021;14:779-92

[14] Chipollini J,Nwanosike H.Characterization of urinary microbiome in patients with bladder cancer: Results from a single-institution, feasibility study.Urol Oncol2020;38:615-21

[15] Xu W,Lee P.Mini-review: perspective of the microbiome in the pathogenesis of urothelial carcinoma.Am J Clin Exp Urol2014;2:57-61 PMCID:PMC4219294

[16] Bučević Popović V, Šitum M, Chow CT, Chan LS, Roje B, Terzić J. The urinary microbiome associated with bladder cancer.Sci Rep2018;8:12157 PMCID:PMC6092344

[17] Wu P,Zhao J.Profiling the urinary microbiota in male patients with bladder cancer in China.Front Cell Infect Microbiol2018;8:167 PMCID:PMC5990618

[18] Pederzoli F,Amato V.Sex-specific alterations in the urinary and tissue microbiome in therapy-naïve urothelial bladder cancer patients.Eur Urol Oncol2020;3:784-8

[19] Mansour B,Makra N.Bladder cancer-related microbiota: examining differences in urine and tissue samples.Sci Rep2020;10:11042 PMCID:PMC7338485

[20] Sepich-Poore GD,Straussman R,Wargo JA.The microbiome and human cancer.Science2021;371:eabc4552 PMCID:PMC8767999

[21] Liu F,Lu X.Dysbiosis signatures of the microbial profile in tissue from bladder cancer.Cancer Med2019;8:6904-14 PMCID:PMC6854010

[22] Parra-Grande M,Martínez-Priego L.Profiling the bladder microbiota in patients with bladder cancer.Front Microbiol2021;12:718776 PMCID:PMC8859159

[23] Ainsworth C.Microbiome: A bag of surprises.Nature2017;551:S40-1

[24] Johnson JS,Hong BY.Evaluation of 16S rRNA gene sequencing for species and strain-level microbiome analysis.Nat Commun2019;10:5029 PMCID:PMC6834636

[25] Bayne CE,Herbst KW.Role of urinary tract infection in bladder cancer: a systematic review and meta-analysis.World J Urol2018;36:1181-90

[26] Schwabe RF.The microbiome and cancer.Nat Rev Cancer2013;13:800-12 PMCID:PMC3986062

[27] Belkaid Y.Role of the microbiota in immunity and inflammation.Cell2014;157:121-41 PMCID:PMC4056765

[28] Winkler J,Metcalf KJ.Concepts of extracellular matrix remodelling in tumour progression and metastasis.Nat Commun2020;11:5120 PMCID:PMC7547708

[29] Huang J,Wan D.Extracellular matrix and its therapeutic potential for cancer treatment.Signal Transduct Target Ther2021;6:153 PMCID:PMC8062524

[30] Parsons CL,Jones S,Callahan H.Bladder surface glycosaminoglycans: an epithelial permeability barrier.J Urol1990;143:139-42

[31] Alfano M,Nebuloni M,Montorsi F.The interplay of extracellular matrix and microbiome in urothelial bladder cancer.Nat Rev Urol2016;13:77-90 PMCID:PMC7097604

[32] Schwartz DJ,Hultgren SJ.Population dynamics and niche distribution of uropathogenic Escherichia coli during acute and chronic urinary tract infection.Infect Immun2011;79:4250-9 PMCID:PMC3187256

[33] Crusz SM.Inflammation and cancer: advances and new agents.Nat Rev Clin Oncol2015;12:584-96

[34] Lenis AT,Chamie K.Bladder cancer: a review.JAMA2020;324:1980-91

[35] LaRue H,Bergeron A.Toll-like receptors in urothelial cells - targets for cancer immunotherapy.Nat Rev Urol2013;10:537-45

[36] Elinav E,Thaiss CA,Jin C.Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms.Nat Rev Cancer2013;13:759-71

[37] Cao D,Pang Y.Retinoic acid-related orphan receptor c regulates proliferation, glycolysis, and chemoresistance via the PD-L1/ITGB6/STAT3 signaling axis in bladder cancer.Cancer Res2019;79:2604-18

[38] He H,Zhang B.USP24-GSDMB complex promotes bladder cancer proliferation via activation of the STAT3 pathway.Int J Biol Sci2021;17:2417-29 PMCID:PMC8315027

[39] Jiang N,Wang M.BUB1 drives the occurrence and development of bladder cancer by mediating the STAT3 signaling pathway.J Exp Clin Cancer Res2021;40:378 PMCID:PMC8638147

[40] Flores-Mireles AL,Caparon M.Urinary tract infections: epidemiology, mechanisms of infection and treatment options.Nat Rev Microbiol2015;13:269-84 PMCID:PMC4457377

[41] McLellan LK.Urinary Tract Infection: Pathogenesis and outlook.Trends Mol Med2016;22:946-57 PMCID:PMC5159206

[42] Santos LL,Gouveia MJ.Urogenital schistosomiasis-history, pathogenesis, and bladder cancer.J Clin Med2021;10:205 PMCID:PMC7826813

[43] Wu S,Zhang M,Sears CL.Bacteroides fragilis toxin stimulates intestinal epithelial cell shedding and gamma-secretase-dependent E-cadherin cleavage.J Cell Sci2007;120:1944-52 PMCID:PMC3056613

[44] Chung L,Geis AL.Bacteroides fragilis toxin coordinates a pro-carcinogenic inflammatory cascade via targeting of colonic epithelial cells.Cell Host Microbe2018;23:203-14.e5 PMCID:PMC5954996

[45] Wang X,Huycke MM.Commensal-infected macrophages induce dedifferentiation and reprogramming of epithelial cells during colorectal carcinogenesis.Oncotarget2017;8:102176-90 PMCID:PMC5731944

[46] Huang H,Zhang X,Ji Z.LncRNA CARLo-7 facilitates proliferation, migration, invasion, and EMT of bladder cancer cells by regulating Wnt/β-catenin and JAK2/STAT3 signaling pathways.Transl Androl Urol2020;9:2251-61 PMCID:PMC7658127

[47] Jiang LJ,Huang ZY.PHB promotes bladder cancer cell epithelial-mesenchymal transition via the Wnt/β-catenin signaling pathway.Pathol Res Pract2023;247:154536

[48] Kotolloshi R,Grimm MO.Wnt/β-catenin signalling and its cofactor BCL9L have an oncogenic effect in bladder cancer cells.Int J Mol Sci2022;23:5319 PMCID:PMC9141496

[49] Korac-Prlic J,Vilović K.Targeting Stat3 signaling impairs the progression of bladder cancer in a mouse model.Cancer Lett2020;490:89-99

[50] Oresta B,Lazzeri M.The microbiome of catheter collected urine in males with bladder cancer according to disease stage.J Urol2021;205:86-93

[51] Nejman D,Fuks G.The human tumor microbiome is composed of tumor type-specific intracellular bacteria.Science2020;368:973-80 PMCID:PMC7757858

[52] Galeano Niño JL,LaCourse KD.Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer.Nature2022;611:810-7 PMCID:PMC9684076

[53] Li Q,Liu WX.Carnobacterium maltaromaticum boosts intestinal vitamin D production to suppress colorectal cancer in female mice.Cancer Cell2023;41:1450-65.e8

[54] Zhang Y,Zhou H.Urinary Eubacterium sp. CAG:581 promotes non-muscle invasive bladder cancer (NMIBC) development through the ECM1/MMP9 pathway.Cancers2023;15:809 PMCID:PMC9913387

[55] Hezaveh K,Klötgen A.Tryptophan-derived microbial metabolites activate the aryl hydrocarbon receptor in tumor-associated macrophages to suppress anti-tumor immunity.Immunity2022;55:324-40.e8 PMCID:PMC8888129

[56] Bender MJ,Phelps CM.Dietary tryptophan metabolite released by intratumoral Lactobacillus reuteri facilitates immune checkpoint inhibitor treatment.Cell2023;186:1846-62.e26 PMCID:PMC10148916

[57] Jia W,Jia W.Bile acid-microbiota crosstalk in gastrointestinal inflammation and carcinogenesis.Nat Rev Gastroenterol Hepatol2018;15:111-28 PMCID:PMC5899973

[58] Collins SL,Bisanz JE,Patterson AD.Bile acids and the gut microbiota: metabolic interactions and impacts on disease.Nat Rev Microbiol2023;21:236-47

[59] Kalaora S,Nejman D.Identification of bacteria-derived HLA-bound peptides in melanoma.Nature2021;592:138-43 PMCID:PMC9717498

[60] Samuelsson P,Wullt B,Svanborg C.Toll-like receptor 4 expression and cytokine responses in the human urinary tract mucosa.Infect Immun2004;72:3179-86 PMCID:PMC415697

[61] Ching C,Spencer JD.Innate immunity and urinary tract infection.Pediatr Nephrol2020;35:1183-92 PMCID:PMC6908784

[62] Johnson DE,Grandis JR.Targeting the IL-6/JAK/STAT3 signalling axis in cancer.Nat Rev Clin Oncol2018;15:234-48 PMCID:PMC5858971

[63] Gatta LB,Bugatti M.Hyper-activation of STAT3 sustains progression of non-papillary basal-type bladder cancer via FOSL1 regulome.Cancers2019;11:1219 PMCID:PMC6770563

[64] Alfaro C,Rodríguez-Ruiz ME.Interleukin-8 in cancer pathogenesis, treatment and follow-up.Cancer Treat Rev2017;60:24-31

[65] Fluckiger A,Sassi M.Cross-reactivity between tumor MHC class I-restricted antigens and an enterococcal bacteriophage.Science2020;369:936-42

[66] Jin C,Zhao C.Commensal microbiota promote lung cancer development via γδ T cells.Cell2019;176:998-1013.e16 PMCID:PMC6691977

[67] Xue C,Zheng Q.Tryptophan metabolism in health and disease.Cell Metab2023;35:1304-26

[68] Han JX,Wang JL.Microbiota-derived tryptophan catabolites mediate the chemopreventive effects of statins on colorectal cancer.Nat Microbiol2023;8:919-33

[69] Zhang W,Shi D.MicroRNA-153 decreases tryptophan catabolism and inhibits angiogenesis in bladder cancer by targeting indoleamine 2,3-dioxygenase 1.Front Oncol2019;9:619 PMCID:PMC6636202

[70] Lee SH,Tham SM.Tryptophan-kynurenine ratio as a biomarker of bladder cancer.BJU Int2021;127:445-53

[71] Wang R,Zhang X.Urinary metabolomics for discovering metabolic biomarkers of bladder cancer by UPLC-MS.BMC Cancer2022;22:214 PMCID:PMC8883652

[72] Lai CR,Chang HH.Enhancement of farnesoid x receptor inhibits migration, adhesion and angiogenesis through proteasome degradation and VEGF reduction in bladder cancers.Int J Mol Sci2022;23:5259 PMCID:PMC9103877

[73] Lai CR,Tsai WC.Farnesoid X receptor overexpression decreases the migration, invasion and angiogenesis of human bladder cancers via AMPK activation and cholesterol biosynthesis inhibition.Cancers2022;14:4398 PMCID:PMC9497084

[74] Wang H,Zhao G.The microbial metabolite trimethylamine N-oxide promotes antitumor immunity in triple-negative breast cancer.Cell Metab2022;34:581-94.e8

[75] Mirji G,Bhat SA.The microbiome-derived metabolite TMAO drives immune activation and boosts responses to immune checkpoint blockade in pancreatic cancer.Sci Immunol2022;7:eabn0704 PMCID:PMC9925043

[76] Luu M,Baldrich A.Microbial short-chain fatty acids modulate CD8⁺ T cell responses and improve adoptive immunotherapy for cancer.Nat Commun2021;12:4077 PMCID:PMC8249424

[77] Szarvas T,Ergün S.Matrix metalloproteinases and their clinical relevance in urinary bladder cancer.Nat Rev Urol2011;8:241-54

[78] Minoli M,Hanhart D.Bladder cancer organoids as a functional system to model different disease stages and therapy response.Nat Commun2023;14:2214 PMCID:PMC10113240

[79] Goubet AG,Derosa L,Zitvogel L.From mucosal infection to successful cancer immunotherapy.Nat Rev Urol2023;20:682-700

[80] Geller LT,Danino T.Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine.Science2017;357:1156-60 PMCID:PMC5727343

[81] Compérat E,Cathomas R.Current best practice for bladder cancer: a narrative review of diagnostics and treatments.Lancet2022;400:1712-21

[82] Teoh JY,Black PC,Shariat SF.Recurrence mechanisms of non-muscle-invasive bladder cancer - a clinical perspective.Nat Rev Urol2022;19:280-94

[83] Aso Y.Prophylactic effect of a Lactobacillus casei preparation on the recurrence of superficial bladder cancer.Urol Int1992;49:125-9

[84] Aso Y,Kotake T.Preventive effect of a Lactobacillus casei preparation on the recurrence of superficial bladder cancer in a double-blind trial.Eur Urol1995;27:104-9

[85] Herr H.Reduced recurrence of low-grade papillary bladder tumors associated with asymptomatic bacteriuria.Urology2019;124:179-82

[86] Zeng J,Chen C.Alterations in urobiome in patients with bladder cancer and implications for clinical outcome: a single-institution study.Front Cell Infect Microbiol2020;10:555508 PMCID:PMC7769872

[87] James C,Desai S.Impact of intravesical Bacillus Calmette-Guérin and chemotherapy on the bladder microbiome in patients with non-muscle invasive bladder cancer.Front Cell Infect Microbiol2023;13:1125809 PMCID:PMC10114608

[88] Integrative HMP (iHMP) Research Network ConsortiumThe integrative human microbiome project.Nature2019;569:641-8 PMCID:PMC6784865

[89] Pettenati C.Mechanisms of BCG immunotherapy and its outlook for bladder cancer.Nat Rev Urol2018;15:615-25

[90] Knorr J,Adler A.PD12-01 bladder tumor microbiome may augment response to BCG in non-muscle invasive bladder cancer.J Urol2022;207:e195

[91] Knorr J,Agudelo J.PD42-04 tumor microbiome associated with BCG response in non-muscle invasive bladder cancer.J Urol2021;206:e725-6

[92] Hussein AA,Durrani M.Investigating the association between the urinary microbiome and bladder cancer: an exploratory study.Urol Oncol2021;39:370.e9-19

[93] Han J,Li Y.Mechanisms of BCG in the treatment of bladder cancer-current understanding and the prospect.Biomed Pharmacother2020;129:110393

[94] Morad G,Sharma P.Hallmarks of response, resistance, and toxicity to immune checkpoint blockade.Cell2021;184:5309-37 PMCID:PMC8767569

[95] Rhea LP,Kim D.Role of immunotherapy in bladder cancer.Cancer Treat Res Commun2021;26:100296

[96] Siefker-Radtke A.Immunotherapy in metastatic urothelial carcinoma: focus on immune checkpoint inhibition.Nat Rev Urol2018;15:112-24

[97] Cathomas R,Bruins HM.The 2021 updated european association of urology guidelines on metastatic urothelial carcinoma.Eur Urol2022;81:95-103

[98] Vétizou M,Daillère R.Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota.Science2015;350:1079-84 PMCID:PMC4721659

[99] Mager LF,Pett N.Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy.Science2020;369:1481-9

[100] Pederzoli F,Raggi D.Is there a detrimental effect of antibiotic therapy in patients with muscle-invasive bladder cancer treated with neoadjuvant pembrolizumab?.Eur Urol2021;80:319-22

[101] Gopalakrishnan V,Nezi L.Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients.Science2018;359:97-103 PMCID:PMC5827966

[102] Matson V,Bao R.The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients.Science2018;359:104-8 PMCID:PMC6707353

[103] Chen C,Huang P.Urogenital microbiota:potentially important determinant of PD-L1 expression in male patients with non-muscle invasive bladder cancer.BMC Microbiol2022;22:7 PMCID:PMC8725255

[104] Shen X.Efficacy of PD-1 or PD-L1 inhibitors and PD-L1 expression status in cancer: meta-analysis.BMJ2018;362:k3529 PMCID:PMC6129950

[105] Brausi M,Sylvester R.Side effects of Bacillus Calmette-Guérin (BCG) in the treatment of intermediate- and high-risk Ta, T1 papillary carcinoma of the bladder: results of the EORTC genito-urinary cancers group randomised phase 3 study comparing one-third dose with full dose and 1 year with 3 years of maintenance BCG.Eur Urol2014;65:69-76

[106] Domingos-Pereira S,La Rosa S.Intravesical Ty21a vaccine promotes dendritic cells and T cell-mediated tumor regression in the MB49 bladder cancer model.Cancer Immunol Res2019;7:621-9

[107] Hinshaw DC.The tumor microenvironment innately modulates cancer progression.Cancer Res2019;79:4557-66 PMCID:PMC6744958

[108] Hou J,Sun B.Targeting cancer-promoting inflammation - have anti-inflammatory therapies come of age?.Nat Rev Clin Oncol2021;18:261-79 PMCID:PMC8978805

[109] Fu A,Dong T.Tumor-resident intracellular microbiota promotes metastatic colonization in breast cancer.Cell2022;185:1356-72.e26

[110] Pushalkar S,Daley D.The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression.Cancer Discov2018;8:403-16 PMCID:PMC6225783