Unexpected guests in the tumor microenvironment: microbiome in cancer

Abstract

Although intestinal microbiome have been established as an important biomarker and regulator of cancer development and therapeutic response, less is known about the role of microbiome at other body sites in cancer. Emerging evidence has revealed that the local microbiota make up an important part of the tumor microenvironment across many types of cancer, especially in cancers arising from mucosal sites, including the lung, skin and gastrointestinal tract. The populations of bacteria that reside specifically within tumors have been found to be tumor-type specific, and mechanistic studies have demonstrated that tumor-associated microbiota may directly regulate cancer initiation, progression and responses to chemo- or immuno-therapies. This review aims to provide a comprehensive review of the important literature on the microbiota in the cancerous tissue, and their function and mechanism of action in cancer development and treatment.

Key words： microbiome; tumor; lung cancer; immune system; tumor-associated microbiota; cancer immunotherapy

References

1 Abreu MT, Peek RM Jr (2014) Gastrointestinal malignancy and the microbiome. Gastroenterology 146:1534–1546.e1533

2 Arthur JC, Perez-Chanona E, Muhlbauer M, Tomkovich S, Uronis JM, Fan TJ, Campbell BJ, Abujamel T, Dogan B, Rogers AB (2012) Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338:120–123

3 Aykut B, Pushalkar S, Chen R, Li Q, Abengozar R, Kim JI, Shadaloey SA, Wu D, Preiss P, Verma N (2019) The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature 574:264–267

4 Balachandran VP, Łuksza M, Zhao JN, Makarov V,Moral JA, Remark R, Herbst B, Askan G,Bhanot U, Senbabaoglu Y (2017) Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551:512–516

5 Banerjee S, Tian T, Wei Z, Shih N, Feldman MD, Peck KN, DeMichele AM, Alwine JC, Robertson ES (2018) Distinct microbial signatures associated with different breast cancer types. Front Microbiol 9:951

6 Baughman RP, Thorpe JE, Staneck J,Rashkin M, Frame PT (1987) Use of the protected specimen brush in patients with endotracheal or tracheostomy tubes. Chest 91:233–236

7 Belkaid Y, Hand TW (2014) Role of the microbiota in immunity and inflammation. Cell 157:121–141

8 Belkaid Y,Naik S (2013) Compartmentalized and systemic control of tissue immunity by commensals. Nat Immunol 14:646–653

9 Bullman S, Pedamallu CS, Sicinska E, Clancy TE, Zhang X, Cai D, Neuberg D, Huang K, Guevara F, Nelson T (2017) Analysis of Fusobacterium persistence and antibiotic response in colorectal cancer. Science 358:1443–1448

10 Cameron SJS, Lewis KE, Huws SA, Hegarty MJ, Lewis PD, Pachebat JA, Mur LAJ (2017) A pilot study using metagenomic sequencing of the sputum microbiome suggests potential bacterial biomarkers for lung cancer. PLoS ONE 12:e0177062

11 Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, Barnes R, Watson P, Allen-Vercoe E, Moore RA (2012) Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res 22:299–306

12 Charlson ES, Bittinger K, Haas AR, Fitzgerald AS, Frank I, Yadav A, Bushman FD, Collman RG (2011) Topographical continuity of bacterial populations in the healthy human respiratory tract. Am J Respir Crit Care Med 184:957–963

13 Chen YE, Tsao H (2013) The skin microbiome: current perspectives and future challenges. J Am Acad Dermatol 69:143–155

14 Costello EK, Lauber CL, Hamady M, Fierer N, Gordon JI, Knight R (2009) Bacterial community variation in human body habitats across space and time. Science (New York NY) 326:1694–1697

15 de Martel C, Ferlay J, Franceschi S, Vignat J,Bray F, Forman D, Plummer M (2012) Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol 13:607–615

16 Dejea CM, Fathi P, Craig JM, Boleij A, Taddese R, Geis AL, Wu X, DeStefano Shields CE, Hechenbleikner EM, Huso DL (2018) Patients with familial adenomatous polyposis harbor colonic biofilms containing tumorigenic bacteria. Science 359:592–597

17 Dickson RP, Erb-Downward JR, Freeman CM, McCloskey L, Beck JM, Huffnagle GB, Curtis JL (2015) Spatial variation in the healthy human lung microbiome and the adapted island model of lung biogeography. Ann Am Thorac Soc 12:821–830

18 Dickson RP, Erb-Downward JR, Huffnagle GB (2013) The role of the bacterial microbiome in lung disease. Expert Rev Respir Med 7:245–257

19 Dickson RP, Martinez FJ, Huffnagle GB (2014) The role of the microbiome in exacerbations of chronic lung diseases. Lancet 384:691–702

20 DiDonato JA, Mercurio F, Karin M (2012) NF-kappaB and the link between inflammation and cancer. Immunol Rev 246:379–400

21 Dzutsev A, Badger JH, Perez-Chanona E, Roy S, Salcedo R, Smith CK, Trinchieri G (2017) Microbes and cancer. Annu Rev Immunol 35:199–228

22 Elinav E, Nowarski R, Thaiss CA, Hu B, Jin C, Flavell RA (2013) Inflammation-induced cancer: crosstalk between tumours, immune cells and microorganisms. Nat Rev Cancer 13:759–771

23 Erb-Downward JR, Thompson DL, Han MK, Freeman CM, McCloskey L, Schmidt LA, Young VB, Toews GB, Curtis JL, Sundaram B (2011) Analysis of the lung microbiome in the “healthy” smoker and in COPD. PLoS ONE 6:e16384

24 Garrett WS (2015) Cancer and the microbiota. Science 348:80–86

25 Garrett WS (2019) The gut microbiota and colon cancer. Science 364:1133–1135

26 Geller LT, Barzily-Rokni M, Danino T, Jonas OH, Shental N, Nejman D, Gavert N, Zwang Y, Cooper ZA, Shee K (2017) Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357:1156–1160

27 Gomes S, Cavadas B, Ferreira JC, Marques PI, Monteiro C, Sucena M, Sousa C,Vaz Rodrigues L, Teixeira G, Pinto P (2019) Profiling of lung microbiota discloses differences in adenocarcinoma and squamous cell carcinoma. Sci Rep 9:12838

28 Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, Prieto PA, Vicente D, Hoffman K, Wei SC (2018) Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359:97–103

29 Greathouse KL, Stone JK, Harris CC (2020) Cancer-type-specific bacteria: freeloaders or partners? Cancer Cell 38:158–160

30 Greathouse KL, White JR, Vargas AJ, Bliskovsky VV,Beck JA, von Muhlinen N, Polley EC, Bowman ED, Khan MA, Robles AI (2018) Interaction between the microbiome and TP53 in human lung cancer. Genome Biol 19:123

31 Guerra L, Guidi R, Frisan T (2011) Do bacterial genotoxins contribute to chronic inflammation, genomic instability and tumor progression? FEBS J 278:4577–4588

32 Gur C, Ibrahim Y, Isaacson B, Yamin R, Abed J, Gamliel M, Enk J,Bar-On Y, Stanietsky-Kaynan N, Coppenhagen-Glazer S (2015) Binding of the Fap2 protein of Fusobacterium nucleatum to human inhibitory receptor TIGIT protects tumors from immune cell attack. Immunity 42:344–355

33 Gustafson AM, Soldi R, Anderlind C, Scholand MB, Qian J, Zhang X, Cooper K, Walker D, McWilliams A, Liu G (2010) Airway PI3K pathway activation is an early and reversible event in lung cancer development. Sci Transl Med 2:26ra25

34 Hieken TJ, Chen J, Hoskin TL, Walther-Antonio M, Johnson S, Ramaker S, Xiao J, Radisky DC, Knutson KL, Kalari KR (2016) The microbiome of aseptically collected human breast tissue in benign and malignant disease. Sci Rep 6:30751

35 Hilty M, Burke C, Pedro H, Cardenas P, Bush A, Bossley C, Davies J, Ervine A, Poulter L, Pachter L (2010) Disordered microbial communities in asthmatic airways. PLoS ONE 5:e8578

36 Hoste E, Arwert EN, Lal R, South AP, Salas-Alanis JC, Murrell DF, Donati G, Watt FM (2015) Innate sensing of microbial products promotes wound-induced skin cancer. Nat Commun 6:5932

37 Huffnagle GB, Dickson RP, Lukacs NW (2017) The respiratory tract microbiome and lung inflammation: a two-way street. Mucosal Immunol 10:299–306

38 Human Microbiome Project Consortium (2012) Structure, function and diversity of the healthy human microbiome. Nature 486:207–214

39 Iida N, Dzutsev A, Stewart CA, Smith L, Bouladoux N, Weingarten RA, Molina DA, Salcedo R, Back T, Cramer S (2013) Commensal bacteria control cancer response to therapy by modulating the tumor microenvironment. Science 342:967–970

40 Jin C, Lagoudas GK, Zhao C, Bullman S, Bhutkar A, Hu B, Ameh S, Sandel D, Liang XS, Mazzilli S (2019) Commensal microbiota promote lung cancer development via gammadelta T cells. Cell 176(998–1013):e1016

41 Kadosh E, Snir-Alkalay I, Venkatachalam A,May S, Lasry A, Elyada E,Zinger A,Shaham M, Vaalani G,Mernberger M (2020) The gut microbiome switches mutant p53 from tumour-suppressive to oncogenic. Nature 586:133–138

42 Kostic AD, Chun E, Robertson L, Glickman JN, Gallini CA, Michaud M, Clancy TE, Chung DC, Lochhead P, Hold GL (2013) Fusobacterium nucleatum potentiates intestinal tumorigenesis and modulates the tumor-immune microenvironment. Cell Host Microbe 14:207–215

43 Kostic AD, Gevers D, Pedamallu CS, Michaud M,Duke F, Earl AM, Ojesina AI, Jung J, Bass AJ, Tabernero J (2012) Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 22:292–298

44 Le Noci V, Guglielmetti S, Arioli S, Camisaschi C, Bianchi F, Sommariva M, Storti C, Triulzi T, Castelli C, Balsari A (2018) Modulation of pulmonary microbiota by antibiotic or probiotic aerosol therapy: a strategy to promote immunosurveillance against lung metastases. Cell Rep 24:3528–3538

45 Lee SH, Sung JY, Yong D, Chun J, Kim SY, Song JH, Chung KS, Kim EY, Jung JY, Kang YA (2016) Characterization of microbiome in bronchoalveolar lavage fluid of patients with lung cancer comparing with benign mass like lesions. Lung Cancer 102:89–95

46 Ley RE, Peterson DA, Gordon JI (2006) Ecological and evolutionary forces shaping microbial diversity in the human intestine. Cell 124:837–848

47 Liu HX, Tao LL, Zhang J, Zhu YG, Zheng Y, Liu D,Zhou M, Ke H, Shi MM, Qu JM (2018) Difference of lower airway microbiome in bilateral protected specimen brush between lung cancer patients with unilateral lobar masses and control subjects. Int J Cancer 142:769–778

48 Lloyd CM, Marsland BJ (2017) Lung homeostasis: influence of age, microbes, and the immune system. Immunity 46:549–561

49 Matson V, Fessler J, Bao R, Chongsuwat T, Zha Y, Alegre M-L, Luke JJ, Gajewski TF (2018) The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359:104–108

50 Mrázek J,Mekadim C, Kučerová P, Švejstil R, Salmonová H, Vlasáková J, Tarasová R, Čížková J,Červinková M(2019) Melanoma-related changes in skin microbiome. Folia Microbiol (Praha) 64:435–442

51 Nakatsuji T, Chen TH, Butcher AM, Trzoss LL, Nam SJ, Shirakawa KT, Zhou W, Oh J, Otto M, Fenical W (2018) A commensal strain of Staphylococcus epidermidis protects against skin neoplasia. Sci Adv 4:eaao4502

52 Nejman D, Livyatan I,Fuks G,Gavert N,Zwang Y, Geller LT, Rotter-Maskowitz A, Weiser R, Mallel G,Gigi E (2020) The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368:973–980

53 Norenhag J, Du J, Olovsson M, Verstraelen H, Engstrand L, Brusselaers N (2020) The vaginal microbiota, human papillomavirus and cervical dysplasia: a systematic review and network meta-analysis. BJOG 127:171–180

54 Nougayrede JP, Homburg S, Taieb F, Boury M,Brzuszkiewicz E, Gottschalk G, Buchrieser C, Hacker J, Dobrindt U, Oswald E (2006) Escherichia coli induces DNA double-strand breaks in eukaryotic cells. Science 313:848–851

55 O’Dwyer DN, Dickson RP, Moore BB (2016) The lung microbiome, immunity, and the pathogenesis of chronic lung disease. J Immunol 196:4839–4847

56 Pilette C, Ouadrhiri Y, Godding V, Vaerman JP, Sibille Y (2001) Lung mucosal immunity: immunoglobulin—a revisited. Eur Respir J 18:571–588

57 Pushalkar S, Hundeyin M, Daley D, Zambirinis CP, Kurz E, Mishra A, Mohan N, Aykut B, Usyk M, Torres LE (2018) The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov 8:403–416

58 Putze J, Hennequin C, Nougayrede JP, Zhang W, Homburg S, Karch H, Bringer MA, Fayolle C, Carniel E, Rabsch W (2009) Genetic structure and distribution of the colibactin genomic island among members of the family Enterobacteriaceae. Infect Immun 77:4696–4703

59 Ramirez-Labrada AG, Isla D, Artal A, Arias M, Rezusta A, Pardo J,Galvez EM (2020) The influence of lung microbiota on lung carcinogenesis, immunity, and immunotherapy. Trends Cancer 6:86–97

60 Riquelme E, Zhang Y, Zhang L, Montiel M, Zoltan M, Dong W, Quesada P, Sahin I, Chandra V,San Lucas A (2019) Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell 178:795–806.e712

61 Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillere R,Fluckiger A,Messaoudene M, Rauber C, Roberti MP (2018) Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359:91–97

62 Rubinstein MR, Wang X, Liu W, Hao Y, Cai G, Han YW (2013) Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 14:195–206

63 Sears CL (2009) Enterotoxigenic Bacteroides fragilis: a rogue among symbiotes. Clin Microbiol Rev 22:349–369 (Table of Contents)

64 Shalapour S, Karin M (2020) Cruel to be kind: epithelial, microbial, and immune cell interactions in gastrointestinal cancers. Annu Rev Immunol 38:649–671

65 Shang S, Hua F, Hu Z-W (2017) The regulation of β-catenin activity and function in cancer: therapeutic opportunities. OncoTarget 8:33972–33989

66 Shannon B, Yi TJ, Perusini S, Gajer P, Ma B, Humphrys MS, Thomas-Pavanel J, Chieza L, Janakiram P, Saunders M (2017) Association of HPV infection and clearance with cervicovaginal immunology and the vaginal microbiota. Mucosal Immunol 10:1310–1319

67 Shi Y, Zheng W, Yang K, Harris KG, Ni K, Xue L, Lin W, Chang EB, Weichselbaum RR, Fu YX (2020) Intratumoral accumulation of gut microbiota facilitates CD47-based immunotherapy via STING signaling. J Exp Med 217(5):e20192282

68 Siegel RL, Miller KD, Jemal A (2018) Cancer statistics, 2018. CA Cancer J Clin 68:7–30

69 Siegel RL, Miller KD, Jemal A (2019) Cancer statistics, 2019. CA Cancer J Clin 69:7–34

70 Sivan A, Corrales L, Hubert N, Williams JB, Aquino-Michaels K, Earley ZM, Benyamin FW, Lei YM, Jabri B, Alegre ML (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350:1084–1089

71 Sommariva M, Le Noci V, Bianchi F, Camelliti S, Balsari A, Tagliabue E, Sfondrini L(2020) The lung microbiota: role in maintaining pulmonary immune homeostasis and its implications in cancer development and therapy. Cell Mol Life Sci 77:2739–2749

72 Thorpe JE, Baughman RP, Frame PT, Wesseler TA, Staneck JL (1987) Bronchoalveolar lavage for diagnosing acute bacterial pneumonia. J Infect Dis 155:855–861

73 Tsay JJ, Wu BG, Badri MH, Clemente JC, Shen N ,Meyn P, Li Y, Yie TA, Lhakhang T,Olsen E (2018) Airway microbiota is associated with upregulation of the PI3K pathway in lung cancer. Am J Respir Crit Care Med 198:1188–1198

74 Urbaniak C, Gloor GB, Brackstone M, Scott L, Tangney M,Reid G (2016) The microbiota of breast tissue and its association with breast cancer. Appl Environ Microbiol 82:5039–5048

75 Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, Rusakiewicz S, Routy B, Roberti MP, Duong CPM (2015) Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350:1079–1084

76 Viaud S, Saccheri F, Mignot G, Yamazaki T,Daillere R, Hannani D, Enot DP, Pfirschke C, Engblom C, Pittet MJ (2013) The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342:971–976

77 Vitiello GA, Cohen DJ, Miller G (2019) Harnessing the microbiome for pancreatic cancer immunotherapy. Trends Cancer 5:670–676

78 Wilson MR, Jiang Y, Villalta PW, Stornetta A, Boudreau PD, Carrá A, Brennan CA, Chun E,Ngo L, Samson LD (2019) The human gut bacterial genotoxin colibactin alkylates DNA. Science 363: eaar7785

79 Yamamura K, Baba Y, Nakagawa S,Mima K, Miyake K, Nakamura K, Sawayama H, Kinoshita K, Ishimoto T, Iwatsuki M (2016) Human microbiome Fusobacterium nucleatum in esophageal cancer tissue is associated with prognosis. Clin Cancer Res 22:5574–5581

80 Yan X, Yang M, Liu J, Gao R, Hu J, Li J, Zhang L, Shi Y,Guo H,Cheng J (2015) Discovery and validation of potential bacterial biomarkers for lung cancer. Am J Cancer Res 5:3111–3122

81 Yu G, Gail MH, Consonni D, Carugno M, Humphrys M, Pesatori AC, Caporaso NE, Goedert JJ, Ravel J, Landi MT (2016) Characterizing human lung tissue microbiota and its relationship to epidemiological and clinical features. Genome Biol 17:163

82 Yu T, Guo F, Yu Y, Sun T, Ma D, Han J, Qian Y, Kryczek I, Sun D, Nagarsheth N (2017) Fusobacterium nucleatum promotes chemoresistance to colorectal cancer by modulating autophagy. Cell 170:548–563.e516