The Microbiome as a Component of the Tumor Microenvironment

Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1225)


Microbes, which live in the human body, affect a large set of pathophysiological processes. Changes in the composition and proportion of the microbiome are associated with metabolic diseases (Fulbright et al., PLoS Pathog 13:e1006480, 2017; Maruvada et al., Cell Host Microbe 22:589–599, 2017), psychiatric disorders (Macfabe, Glob Adv Health Med 2:52–66, 2013; Kundu et al., Cell 171:1481–1493, 2017), and neoplastic diseases (Plottel and Blaser, Cell Host Microbe 10:324–335, 2011; Schwabe and Jobin, Nat Rev Cancer 13:800–812, 2013; Zitvogel et al., Cell 165:276–287, 2016). However, the number of directly tumorigenic bacteria is extremely low. Microbial dysbiosis is connected to cancers of the urinary tract (Yu, Arch Med Sci 11:385–394, 2015), cervix (Chase, Gynecol Oncol 138:190–200, 2015), skin (Yu et al., J Drugs Dermatol 14:461–465, 2015), airways (Gui et al., Genet Mol Res 14:5642–5651, 2015), colon (Garrett, Science 348:80–86, 2015), lymphomas (Yamamoto and Schiestl, Int J Environ Res Public Health 11:9038–9049, 2014; Yamamoto and Schiestl, Cancer J 20:190–194, 2014), prostate (Yu, Arch Med Sci 11:385–394, 2015), and breast (Flores et al., J Transl Med 10:253, 2012; Fuhrman et al., J Clin Endocrinol Metab 99:4632–4640, 2014; Xuan et al., PLoS One 9:e83744, 2014; Goedert et al., J Natl Cancer Inst 107:djv147, 2015; Chan et al., Sci Rep 6:28061, 2016; Hieken et al., Sci Rep 6:30751, 2016; Urbaniak et al., Appl Environ Microbiol 82:5039–5048, 2016; Goedert et al., Br J Cancer 118:471–479, 2018). Microbial dysbiosis can influence organs in direct contact with the microbiome and organs that are located at distant sites of the body. The altered microbiota can lead to a disruption of the mucosal barrier (Plottel and Blaser, Cell Host Microbe 10:324–335, 2011), promote or inhibit tumorigenesis through the modification of immune responses (Kawai and Akira, Int Immunol 21:317–337, 2009; Dapito et al., Cancer Cell 21:504–516, 2012) and microbiome-derived metabolites, such as estrogens (Flores et al., J Transl Med 10:253, 2012; Fuhrman et al., J Clin Endocrinol Metab 99:4632–4640, 2014), secondary bile acids (Rowland, Role of the gut flora in toxicity and cancer, Academic Press, London, p x, 517 p., 1988; Yoshimoto et al., Nature 499:97–101, 2013; Xie et al., Int J Cancer 139:1764–1775, 2016; Shellman et al., Clin Otolaryngol 42:969–973, 2017; Luu et al., Cell Oncol (Dordr) 41:13–24, 2018; Miko et al., Biochim Biophys Acta Bioenerg 1859:958–974, 2018), short-chain fatty acids (Bindels et al., Br J Cancer 107:1337–1344, 2012), lipopolysaccharides (Dapito et al., Cancer Cell 21:504–516, 2012), and genotoxins (Fulbright et al., PLoS Pathog 13:e1006480, 2017). Thus, altered gut microbiota may change the efficacy of chemotherapy and radiation therapy (McCarron et al., Br J Biomed Sci 69:14–17, 2012; Viaud et al., Science 342:971–976, 2013; Montassier et al., Aliment Pharmacol Ther 42:515–528, 2015; Buchta Rosean et al., Adv Cancer Res 143:255–294, 2019). Taken together, microbial dysbiosis has intricate connections with neoplastic diseases; hereby, we aim to highlight the major contact routes.


Microbiome Breast cancer Tumor microenvironment Bacterial metabolite Bacterial metabolism Antitumor immunity Tumor metabolism Epithelial-mesenchymal transition Tumorigenesis Metastasis Chemotherapy 



Our work is supported by grants from NKFIH (K123975, PD124110, FK128387, GINOP-2.3.2-15-2016-00006) and the Hungarian Academy of Sciences (NKM-26/2019). EM is supported by a Bolyai Fellowship from the Hungarian Academy of Sciences. We are grateful to Dr. Karen Uray (Department of Medical Chemistry, University of Debrecen) for the revision of the text.


  1. 1.
    Fulbright LE, Ellermann M, Arthur JC (2017) The microbiome and the hallmarks of cancer. PLoS Pathog 13(9):e1006480PubMedPubMedCentralGoogle Scholar
  2. 2.
    Maruvada P et al (2017) The human microbiome and obesity: moving beyond associations. Cell Host Microbe 22(5):589–599PubMedGoogle Scholar
  3. 3.
    Macfabe D (2013) Autism: metabolism, mitochondria, and the microbiome. Glob Adv Health Med 2(6):52–66PubMedPubMedCentralGoogle Scholar
  4. 4.
    Kundu P et al (2017) Our gut microbiome: the evolving inner self. Cell 171(7):1481–1493PubMedGoogle Scholar
  5. 5.
    Plottel CS, Blaser MJ (2011) Microbiome and malignancy. Cell Host Microbe 10(4):324–335PubMedPubMedCentralGoogle Scholar
  6. 6.
    Schwabe RF, Jobin C (2013) The microbiome and cancer. Nat Rev Cancer 13(11):800–812PubMedPubMedCentralGoogle Scholar
  7. 7.
    Zitvogel L et al (2016) Microbiome and anticancer immunosurveillance. Cell 165(2):276–287PubMedGoogle Scholar
  8. 8.
    Yu H et al (2015) Urinary microbiota in patients with prostate cancer and benign prostatic hyperplasia. Arch Med Sci 11(2):385–394PubMedPubMedCentralGoogle Scholar
  9. 9.
    Chase D et al (2015) The vaginal and gastrointestinal microbiomes in gynecologic cancers: a review of applications in etiology, symptoms and treatment. Gynecol Oncol 138(1):190–200PubMedGoogle Scholar
  10. 10.
    Yu Y et al (2015) The role of the cutaneous microbiome in skin cancer: lessons learned from the gut. J Drugs Dermatol 14(5):461–465PubMedGoogle Scholar
  11. 11.
    Gui QF et al (2015) Well-balanced commensal microbiota contributes to anti-cancer response in a lung cancer mouse model. Genet Mol Res 14(2):5642–5651PubMedGoogle Scholar
  12. 12.
    Garrett WS (2015) Cancer and the microbiota. Science 348(6230):80–86PubMedPubMedCentralGoogle Scholar
  13. 13.
    Yamamoto ML, Schiestl RH (2014) Lymphoma caused by intestinal microbiota. Int J Environ Res Public Health 11(9):9038–9049PubMedPubMedCentralGoogle Scholar
  14. 14.
    Yamamoto ML, Schiestl RH (2014) Intestinal microbiome and lymphoma development. Cancer J 20(3):190–194PubMedPubMedCentralGoogle Scholar
  15. 15.
    Flores R et al (2012) Fecal microbial determinants of fecal and systemic estrogens and estrogen metabolites: a cross-sectional study. J Transl Med 10:253PubMedPubMedCentralGoogle Scholar
  16. 16.
    Fuhrman BJ et al (2014) Associations of the fecal microbiome with urinary estrogens and estrogen metabolites in postmenopausal women. J Clin Endocrinol Metab 99(12):4632–4640PubMedPubMedCentralGoogle Scholar
  17. 17.
    Xuan C et al (2014) Microbial dysbiosis is associated with human breast cancer. PLoS One 9(1):e83744PubMedPubMedCentralGoogle Scholar
  18. 18.
    Goedert JJ et al (2015) Investigation of the association between the fecal microbiota and breast cancer in postmenopausal women: a population-based case-control pilot study. J Natl Cancer Inst 107(8):djv147PubMedPubMedCentralGoogle Scholar
  19. 19.
    Chan AA et al (2016) Characterization of the microbiome of nipple aspirate fluid of breast cancer survivors. Sci Rep 6:28061PubMedPubMedCentralGoogle Scholar
  20. 20.
    Hieken TJ et al (2016) The microbiome of aseptically collected human breast tissue in benign and malignant disease. Sci Rep 6:30751PubMedPubMedCentralGoogle Scholar
  21. 21.
    Urbaniak C et al (2016) The microbiota of breast tissue and its association with breast cancer. Appl Environ Microbiol 82(16):5039–5048PubMedPubMedCentralGoogle Scholar
  22. 22.
    Goedert JJ et al (2018) Postmenopausal breast cancer and oestrogen associations with the IgA-coated and IgA-noncoated faecal microbiota. Br J Cancer 118(4):471–479PubMedPubMedCentralGoogle Scholar
  23. 23.
    Kawai T, Akira S (2009) The roles of TLRs, RLRs and NLRs in pathogen recognition. Int Immunol 21(4):317–337PubMedPubMedCentralGoogle Scholar
  24. 24.
    Dapito DH et al (2012) Promotion of hepatocellular carcinoma by the intestinal microbiota and TLR4. Cancer Cell 21(4):504–516PubMedPubMedCentralGoogle Scholar
  25. 25.
    Rowland IR (1988) Role of the gut flora in toxicity and cancer. Academic Press, London, p x, 517 pGoogle Scholar
  26. 26.
    Yoshimoto S et al (2013) Obesity-induced gut microbial metabolite promotes liver cancer through senescence secretome. Nature 499(7456):97–101PubMedGoogle Scholar
  27. 27.
    Xie G et al (2016) Dysregulated hepatic bile acids collaboratively promote liver carcinogenesis. Int J Cancer 139(8):1764–1775PubMedPubMedCentralGoogle Scholar
  28. 28.
    Shellman Z et al (2017) Bile acids: a potential role in the pathogenesis of pharyngeal malignancy. Clin Otolaryngol 42(5):969–973PubMedGoogle Scholar
  29. 29.
    Luu TH et al (2018) Lithocholic bile acid inhibits lipogenesis and induces apoptosis in breast cancer cells. Cell Oncol (Dordr) 41(1):13–24Google Scholar
  30. 30.
    Miko E et al (2018) Lithocholic acid, a bacterial metabolite reduces breast cancer cell proliferation and aggressiveness. Biochim Biophys Acta Bioenerg 1859(9):958–974PubMedGoogle Scholar
  31. 31.
    Bindels LB et al (2012) Gut microbiota-derived propionate reduces cancer cell proliferation in the liver. Br J Cancer 107(8):1337–1344PubMedPubMedCentralGoogle Scholar
  32. 32.
    McCarron AJ et al (2012) Antibacterial effects on acinetobacter species of commonly employed antineoplastic agents used in the treatment of haematological malignancies: an in vitro laboratory evaluation. Br J Biomed Sci 69(1):14–17PubMedGoogle Scholar
  33. 33.
    Viaud S et al (2013) The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science 342(6161):971–976PubMedPubMedCentralGoogle Scholar
  34. 34.
    Montassier E et al (2015) Chemotherapy-driven dysbiosis in the intestinal microbiome. Aliment Pharmacol Ther 42(5):515–528PubMedGoogle Scholar
  35. 35.
    Buchta Rosean C et al (2019) Impact of the microbiome on cancer progression and response to anti-cancer therapies. Adv Cancer Res 143:255–294PubMedGoogle Scholar
  36. 36.
    Garcia-Castillo V et al (2016) Microbiota dysbiosis: a new piece in the understanding of the carcinogenesis puzzle. J Med Microbiol 65(12):1347–1362PubMedGoogle Scholar
  37. 37.
    Arslan N (2014) Obesity, fatty liver disease and intestinal microbiota. World J Gastroenterol 20(44):16452–16463PubMedPubMedCentralGoogle Scholar
  38. 38.
    Lynch SV, Pedersen O (2016) The human intestinal microbiome in health and disease. N Engl J Med 375(24):2369–2379PubMedGoogle Scholar
  39. 39.
    Khan AA, Shrivastava A, Khurshid M (2012) Normal to cancer microbiome transformation and its implication in cancer diagnosis. Biochim Biophys Acta 1826(2):331–337PubMedGoogle Scholar
  40. 40.
    Walsh CJ et al (2014) Beneficial modulation of the gut microbiota. FEBS Lett 588(22):4120–4130PubMedGoogle Scholar
  41. 41.
    Petersen C, Round JL (2014) Defining dysbiosis and its influence on host immunity and disease. Cell Microbiol 16(7):1024–1033PubMedPubMedCentralGoogle Scholar
  42. 42.
    Kovacs T et al (2019) Cadaverine, a metabolite of the microbiome, reduces breast cancer aggressiveness through trace amino acid receptors. Sci Rep 9(1):1300PubMedPubMedCentralGoogle Scholar
  43. 43.
    Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144(5):646–674PubMedPubMedCentralGoogle Scholar
  44. 44.
    Balkwill FR, Capasso M, Hagemann T (2012) The tumor microenvironment at a glance. J Cell Sci 125(23):5591–5596PubMedGoogle Scholar
  45. 45.
    Fernandez MF et al (2018) Breast cancer and its relationship with the microbiota. Int J Environ Res Public Health 15(8):E1747PubMedGoogle Scholar
  46. 46.
    Hackam DJ, Good M, Sodhi CP (2013) Mechanisms of gut barrier failure in the pathogenesis of necrotizing enterocolitis: toll-like receptors throw the switch. Semin Pediatr Surg 22(2):76–82PubMedPubMedCentralGoogle Scholar
  47. 47.
    Brahmer JR et al (2012) Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med 366(26):2455–2465PubMedPubMedCentralGoogle Scholar
  48. 48.
    Yang JC et al (2007) Ipilimumab (anti-CTLA4 antibody) causes regression of metastatic renal cell cancer associated with enteritis and hypophysitis. J Immunother 30(8):825–830PubMedPubMedCentralGoogle Scholar
  49. 49.
    Topalian SL et al (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366(26):2443–2454PubMedPubMedCentralGoogle Scholar
  50. 50.
    Vetizou M et al (2015) Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science 350(6264):1079–1084PubMedPubMedCentralGoogle Scholar
  51. 51.
    Sivan A et al (2015) Commensal Bifidobacterium promotes antitumor immunity and facilitates anti-PD-L1 efficacy. Science 350(6264):1084–1089PubMedPubMedCentralGoogle Scholar
  52. 52.
    Gopalakrishnan V et al (2018) Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science 359(6371):97–103PubMedGoogle Scholar
  53. 53.
    Matson V et al (2018) The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359(6371):104–108PubMedPubMedCentralGoogle Scholar
  54. 54.
    Routy B et al (2018) Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science 359(6371):91–97PubMedGoogle Scholar
  55. 55.
    Ridlon JM, Kang DJ, Hylemon PB (2006) Bile salt biotransformations by human intestinal bacteria. J Lipid Res 47(2):241–259PubMedGoogle Scholar
  56. 56.
    Louis P, Hold GL, Flint HJ (2014) The gut microbiota, bacterial metabolites and colorectal cancer. Nat Rev Microbiol 12(10):661–672PubMedGoogle Scholar
  57. 57.
    Miko E et al (2019) Microbiome-microbial metabolome-cancer cell interactions in breast cancer-familiar, but unexplored. Cell 8(4):E293Google Scholar
  58. 58.
    Gandhi N, Das GM (2019) Metabolic reprogramming in breast cancer and its therapeutic implications. Cell 8(2):E89Google Scholar
  59. 59.
    Sansone P et al (2017) Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proc Natl Acad Sci U S A 114(43):E9066–E9075PubMedPubMedCentralGoogle Scholar
  60. 60.
    Ivan J et al (2017) The short-chain fatty acid propionate inhibits adipogenic differentiation of human chorion-derived mesenchymal stem cells through the free fatty acid receptor 2. Stem Cells Dev 26(23):1724–1733PubMedPubMedCentralGoogle Scholar
  61. 61.
    Fruge AD et al (2018) Fecal Akkermansia muciniphila is associated with body composition and microbiota diversity in overweight and obese women with breast Cancer participating in a presurgical weight loss trial. J Acad Nutr Diet.
  62. 62.
    Swales KE et al (2006) The farnesoid X receptor is expressed in breast cancer and regulates apoptosis and aromatase expression. Cancer Res 66(20):10120–10126PubMedGoogle Scholar
  63. 63.
    Salaspuro M (1997) Microbial metabolism of ethanol and acetaldehyde and clinical consequences. Addict Biol 2(1):35–46PubMedGoogle Scholar
  64. 64.
    Vida A et al (2018) Deletion of poly(ADPribose) polymerase-1 changes the composition of the microbiome in the gut. Mol Med Rep 18(5):4335–4341PubMedPubMedCentralGoogle Scholar
  65. 65.
    Morgan XC et al (2012) Dysfunction of the intestinal microbiome in inflammatory bowel disease and treatment. Genome Biol 13(9):R79PubMedPubMedCentralGoogle Scholar
  66. 66.
    Giles GI, Jacob C (2002) Reactive sulfur species: an emerging concept in oxidative stress. Biol Chem 383(3–4):375–388PubMedGoogle Scholar
  67. 67.
    Khoruts A et al (2010) Changes in the composition of the human fecal microbiome after bacteriotherapy for recurrent Clostridium difficile-associated diarrhea. J Clin Gastroenterol 44(5):354–360PubMedGoogle Scholar
  68. 68.
    Roh YS, Seki E (2013) Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis. J Gastroenterol Hepatol 28(Suppl 1):38–42PubMedPubMedCentralGoogle Scholar
  69. 69.
    Zambirinis CP et al (2014) Pancreatic cancer, inflammation, and microbiome. Cancer J 20(3):195–202PubMedPubMedCentralGoogle Scholar
  70. 70.
    Houghton AM (2013) Mechanistic links between COPD and lung cancer. Nat Rev Cancer 13(4):233–245PubMedGoogle Scholar
  71. 71.
    Schmidt BL et al (2014) Changes in abundance of oral microbiota associated with oral cancer. PLoS One 9(6):e98741PubMedPubMedCentralGoogle Scholar
  72. 72.
    Zackular JP et al (2013) The gut microbiome modulates colon tumorigenesis. MBio 4(6):e00692–e00613PubMedPubMedCentralGoogle Scholar
  73. 73.
    Arthur JC, Jobin C (2011) The struggle within: microbial influences on colorectal cancer. Inflamm Bowel Dis 17(1):396–409PubMedPubMedCentralGoogle Scholar
  74. 74.
    Banerjee S et al (2015) Distinct microbiological signatures associated with triple negative breast cancer. Sci Rep 5:15162PubMedPubMedCentralGoogle Scholar
  75. 75.
    Luu TH et al (2017) Intestinal proportion of Blautia sp. is associated with clinical stage and histoprognostic grade in patients with early-stage breast cancer. Nutr Cancer 69(2):267–275PubMedGoogle Scholar

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© Springer Nature Switzerland AG 2020

Authors and Affiliations

  1. 1.Department of Medical Chemistry, Faculty of MedicineUniversity of DebrecenDebrecenHungary
  2. 2.MTA-DE Lendület Laboratory of Cellular MetabolismDebrecenHungary
  3. 3.Research Center for Molecular Medicine, Faculty of MedicineUniversity of DebrecenDebrecenHungary

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