The Influence of the Microbiota on the Etiology of Colorectal Cancer

  • Melissa C. Kordahi
  • R. William DePaoloEmail author
Part of the Physiology in Health and Disease book series (PIHD)


The microbiome of the gastrointestinal (GI) tract is estimated to comprise 39 trillion organisms that act in a symbiotic relationship with the surrounding tissue cells to maintain homeostasis. Constituents of the gut microbiota occupy either a planktonic niche within the fecal stream, are adherent to the gut mucosa, or are associated with the mucous layer. Alterations in the gut microbiota at any of these levels, caused by the genetics of an individual or by environmental factors, can disturb this homeostatic relationship and promote disease such as colorectal cancer (CRC). CRC is the third most common form of cancer in both men and women and the second leading cause of cancer-related death in the USA, representing a considerable disease burden. The intimate association between the microbiota and the cells of the colon sets the stage for a number of interactions that may contribute to carcinogenesis. Although only a few specific commensal species may play a direct causal role in CRC, more general shifts in the composition may promote local inflammation through the engagement of innate immune receptors encoded within the colonic tissue. Changes in gene expression within the microbiota may also be important as virulence factors are altered and metabolites are produced that may have detrimental effects on the tissue. In this chapter, we explore the theoretical bodyworks through which certain members of the microbiota are believed to cause CRC, the sensing of microbiota-associated molecular patterns by innate immune receptors known as toll-like-receptors (TLRs) and the various strategies aimed at manipulating the microbiota and targeting the TLRs, in the hope of developing new treatment approaches.


Colon cancer Microbes Microbiota Innate immunity Toll-like receptors 


  1. Abdulamir AS, Hafidh RR, Abu Bakar F (2011) The association of Streptococcus bovis/gallolyticus with colorectal tumors: the nature and the underlying mechanisms of its etiological role. J Exp Clin Cancer Res 30:11PubMedPubMedCentralCrossRefGoogle Scholar
  2. Abed J et al (2016) Fap2 mediates Fusobacterium nucleatum colorectal adenocarcinoma enrichment by binding to tumor-expressed Gal-GalNAc. Cell Host Microbe 20:215–225PubMedPubMedCentralCrossRefGoogle Scholar
  3. Adams S (2009) Toll-like receptor agonists in cancer therapy. Immunotherapy 1:949–964PubMedPubMedCentralCrossRefGoogle Scholar
  4. Ajouz H, Mukherji D, Shamseddine A (2014) Secondary bile acids: an underrecognized cause of colon cancer. World J Surg Oncol 12:164PubMedPubMedCentralCrossRefGoogle Scholar
  5. Akira S, Hemmi H (2003) Recognition of pathogen-associated molecular patterns by TLR family. Immunol Lett 85:85–95PubMedCrossRefGoogle Scholar
  6. Apetoh L et al (2007) Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med 13:1050–1059PubMedCrossRefGoogle Scholar
  7. Apperloo-Renkema HZ, Van der Waaij BD, Van der Waaij D (1990) Determination of colonization resistance of the digestive tract by biotyping of Enterobacteriaceae. Epidemiol Infect 105:355–361PubMedPubMedCentralCrossRefGoogle Scholar
  8. Arthur JC et al (2012) Intestinal inflammation targets cancer-inducing activity of the microbiota. Science 338:120–123PubMedPubMedCentralCrossRefGoogle Scholar
  9. Atarashi K et al (2011) Induction of colonic regulatory T cells by indigenous Clostridium species. Science 331:337–341PubMedCrossRefGoogle Scholar
  10. Bardhan K, Liu K (2013) Epigenetics and colorectal cancer pathogenesis. Cancers 5:676–713PubMedPubMedCentralCrossRefGoogle Scholar
  11. Barrasa JI, Olmo N, Lizarbe MA, Turnay J (2013) Bile acids in the colon, from healthy to cytotoxic molecules. Toxicol Vitro Int J Publ Assoc BIBRA 27:964–977CrossRefGoogle Scholar
  12. Belkaid Y, Hand T (2014) Role of the microbiota in immunity and inflammation. Cell 157:121–141PubMedPubMedCentralCrossRefGoogle Scholar
  13. Berg JW, Howell MA, Silverman SJ (1973) Dietary hypotheses and diet-related research in the etiology of colon cancer. Health Serv Rep 88:915–924PubMedPubMedCentralCrossRefGoogle Scholar
  14. Bhardwaj N, Gnjatic S, Sawhney NB (2010) TLR AGONISTS: are they good adjuvants? Cancer J Sudbury Mass 16:382–391CrossRefGoogle Scholar
  15. Boleij A, Schaeps RMJ, Tjalsma H (2009) Association between Streptococcus bovis and colon cancer. J Clin Microbiol 47:516PubMedPubMedCentralCrossRefGoogle Scholar
  16. Burmølle M, Ren D, Bjarnsholt T, Sørensen SJ (2014) Interactions in multispecies biofilms: do they actually matter? Trends Microbiol 22:84–91PubMedCrossRefGoogle Scholar
  17. Carey EJ, Lindor KD (2012) Chemoprevention of colorectal cancer with ursodeoxycholic acid: cons. Clin Res Hepatol Gastroenterol 36(Suppl 1):S61–S64PubMedCrossRefGoogle Scholar
  18. Cario E (2013) The human TLR4 variant D299G mediates inflammation-associated cancer progression in the intestinal epithelium. Oncoimmunology 2:e24890PubMedPubMedCentralCrossRefGoogle Scholar
  19. Chen W, Liu F, Ling Z, Tong X, Xiang C (2012) Human intestinal lumen and mucosa-associated microbiota in patients with colorectal cancer. PLoS One 7:e39743PubMedPubMedCentralCrossRefGoogle Scholar
  20. Coley WB (1991) The treatment of malignant tumors by repeated inoculations of erysipelas. With a report of ten original cases. 1893. Clin Orthop 262:3–11Google Scholar
  21. Couturier-Maillard A et al (2013) NOD2-mediated dysbiosis predisposes mice to transmissible colitis and colorectal cancer. J Clin Invest 123:700–711PubMedPubMedCentralGoogle Scholar
  22. Cuevas-Ramos G et al (2010) Escherichia coli induces DNA damage in vivo and triggers genomic instability in mammalian cells. Proc Natl Acad Sci USA 107:11537–11542PubMedPubMedCentralCrossRefGoogle Scholar
  23. Darfeuille-Michaud A et al (2004) High prevalence of adherent-invasive Escherichia coli associated with ileal mucosa in Crohn’s disease. Gastroenterology 127:412–421PubMedCrossRefGoogle Scholar
  24. Dejea CM et al (2014) Microbiota organization is a distinct feature of proximal colorectal cancers. Proc Natl Acad Sci USA 111:18321–18326PubMedPubMedCentralCrossRefGoogle Scholar
  25. Depaolo RW et al (2008) Toll-like receptor 6 drives differentiation of tolerogenic dendritic cells and contributes to LcrV-mediated plague pathogenesis. Cell Host Microbe 4:350–361PubMedPubMedCentralCrossRefGoogle Scholar
  26. Devkota S et al (2012) Dietary-fat-induced taurocholic acid promotes pathobiont expansion and colitis in Il10-/- mice. Nature 487:104–108PubMedPubMedCentralCrossRefGoogle Scholar
  27. Dovedi SJ et al (2016) Intravenous administration of the selective toll-like receptor 7 agonist DSR-29133 leads to anti-tumor efficacy in murine solid tumor models which can be potentiated by combination with fractionated radiotherapy. Oncotarget 7:17035–17046PubMedPubMedCentralCrossRefGoogle Scholar
  28. Fitzgerald KA et al (2001) Mal (MyD88-adapter-like) is required for toll-like receptor-4 signal transduction. Nature 413:78–83PubMedCrossRefGoogle Scholar
  29. Fukata M et al (2009) Innate immune signaling by toll-like receptor-4 (TLR4) shapes the inflammatory microenvironment in colitis-associated tumors. Inflamm Bowel Dis 15:997–1006PubMedPubMedCentralCrossRefGoogle Scholar
  30. Fukata M et al (2011) Constitutive activation of epithelial TLR4 augments inflammatory responses to mucosal injury and drives colitis-associated tumorigenesis. Inflamm Bowel Dis 17:1464–1473PubMedCrossRefGoogle Scholar
  31. Fung KYC, Cosgrove L, Lockett T, Head R, Topping DL (2012) A review of the potential mechanisms for the lowering of colorectal oncogenesis by butyrate. Br J Nutr 108:820–831PubMedCrossRefGoogle Scholar
  32. Fűri I et al (2013) Epithelial toll-like receptor 9 signaling in colorectal inflammation and cancer: clinico-pathogenic aspects. World J Gastroenterol 19:4119–4126PubMedPubMedCentralCrossRefGoogle Scholar
  33. Furusawa Y et al (2013) Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature 504:446–450PubMedCrossRefGoogle Scholar
  34. Gay NJ, Gangloff M (2007) Structure and function of Toll receptors and their ligands. Annu Rev Biochem 76:141–165PubMedCrossRefGoogle Scholar
  35. Geng J, Fan H, Tang X, Zhai H, Zhang Z (2013) Diversified pattern of the human colorectal cancer microbiome. Gut Pathog 5:2PubMedPubMedCentralCrossRefGoogle Scholar
  36. Gerner EW, Meyskens FL (2004) Polyamines and cancer: old molecules, new understanding. Nat Rev Cancer 4:781–792PubMedCrossRefGoogle Scholar
  37. Gianotti L et al (2010) A randomized double-blind trial on perioperative administration of probiotics in colorectal cancer patients. World J Gastroenterol 16:167–175PubMedPubMedCentralCrossRefGoogle Scholar
  38. Grivennikov SI, Greten FR, Karin M (2010) Immunity, inflammation, and cancer. Cell 140:883–899PubMedPubMedCentralCrossRefGoogle Scholar
  39. Grivennikov SI et al (2012) Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth. Nature 491:254–258PubMedPubMedCentralCrossRefGoogle Scholar
  40. Gupta RB et al (2007) Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology 133:1099–1105; quiz 1340–1341PubMedPubMedCentralCrossRefGoogle Scholar
  41. Heckelsmiller K et al (2002a) Combined dendritic cell- and CpG oligonucleotide-based immune therapy cures large murine tumors that resist chemotherapy. Eur J Immunol 32:3235–3245PubMedCrossRefGoogle Scholar
  42. Heckelsmiller K et al (2002b) Peritumoral CpG DNA elicits a coordinated response of CD8 T cells and innate effectors to cure established tumors in a murine colon carcinoma model. J Immunol 1950 169:3892–3899CrossRefGoogle Scholar
  43. Hedayat M, Takeda K, Rezaei N (2012) Prophylactic and therapeutic implications of toll-like receptor ligands. Med Res Rev 32:294–325PubMedCrossRefGoogle Scholar
  44. Hoen B et al (1994) Tumors of the colon increase the risk of developing Streptococcus bovis endocarditis: case-control study. Clin Infect Dis Off Publ Infect Dis Soc Am 19:361–362CrossRefGoogle Scholar
  45. Ishikawa H et al (2005) Randomized trial of dietary fiber and Lactobacillus casei administration for prevention of colorectal tumors. Int J Cancer 116:762–767PubMedCrossRefGoogle Scholar
  46. Jiang Q, Wei H, Tian Z (2008) Poly I:C enhances cycloheximide-induced apoptosis of tumor cells through TLR3 pathway. BMC Cancer 8:12PubMedPubMedCentralCrossRefGoogle Scholar
  47. Jin Y et al (2016) Hemolytic E. coli promotes colonic tumorigenesis in females. Cancer Res 76:2891–2900PubMedCrossRefGoogle Scholar
  48. Johnson CH et al (2015) Metabolism links bacterial biofilms and colon carcinogenesis. Cell Metab 21:891–897PubMedPubMedCentralCrossRefGoogle Scholar
  49. Kamdar K et al (2016) Genetic and metabolic signals during acute enteric bacterial infection alter the microbiota and drive progression to chronic inflammatory disease. Cell Host Microbe 19:21–31PubMedPubMedCentralCrossRefGoogle Scholar
  50. Kanzler H, Barrat FJ, Hessel EM, Coffman RL (2007) Therapeutic targeting of innate immunity with toll-like receptor agonists and antagonists. Nat Med 13:552–559PubMedCrossRefGoogle Scholar
  51. Karin M (2009) NF-κB as a critical link between inflammation and cancer. Cold Spring Harb Perspect Biol 1:a000141PubMedPubMedCentralCrossRefGoogle Scholar
  52. Kawai T, Akira S (2011) Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–650PubMedCrossRefGoogle Scholar
  53. Kim S et al (2012) Berberine suppresses the TPA-induced MMP-1 and MMP-9 expressions through the inhibition of PKC-α in breast cancer cells. J Surg Res 176:e21–e29PubMedCrossRefGoogle Scholar
  54. Klimesova K et al (2013) Altered gut microbiota promotes colitis-associated cancer in IL-1 receptor-associated kinase M-deficient mice. Inflamm Bowel Dis 19:1266–1277PubMedPubMedCentralCrossRefGoogle Scholar
  55. Kostic AD et al (2012) Genomic analysis identifies association of Fusobacterium with colorectal carcinoma. Genome Res 22:292–298PubMedPubMedCentralCrossRefGoogle Scholar
  56. Kuo W-T, Lee T-C, Yu LC-H (2016) Eritoran suppresses colon cancer by altering a functional balance in toll-like receptors that bind lipopolysaccharide. Cancer Res 76:4684–4695PubMedCrossRefGoogle Scholar
  57. Lee P, Tan KS (2014) Fusobacterium nucleatum activates the immune response through retinoic acid-inducible gene I. J Dent Res 93:162–168PubMedCrossRefGoogle Scholar
  58. Lee J, Rachmilewitz D, Raz E (2006) Homeostatic effects of TLR9 signaling in experimental colitis. Ann NY Acad Sci 1072:351–355PubMedCrossRefGoogle Scholar
  59. Lee SH et al (2010) ERK activation drives intestinal tumorigenesis in Apc(min/+) mice. Nat Med 16:665–670PubMedPubMedCentralCrossRefGoogle Scholar
  60. Li Y et al (2012) Gut microbiota accelerate tumor growth via c-jun and STAT3 phosphorylation in APCMin/+ mice. Carcinogenesis 33:1231–1238PubMedCrossRefGoogle Scholar
  61. Li Y et al (2014) Constitutive TLR4 signalling in intestinal epithelium reduces tumor load by increasing apoptosis in APC(Min/+) mice. Oncogene 33:369–377PubMedCrossRefGoogle Scholar
  62. Loh YH et al (2011) N-Nitroso compounds and cancer incidence: the European prospective investigation into cancer and nutrition (EPIC)-Norfolk study. Am J Clin Nutr 93:1053–1061PubMedCrossRefGoogle Scholar
  63. Lowe EL et al (2010) Toll-like receptor 2 signaling protects mice from tumor development in a mouse model of colitis-induced cancer. PloS One 5:e13027PubMedPubMedCentralCrossRefGoogle Scholar
  64. Lundin JI, Checkoway H (2009) Endotoxin and cancer. Environ Health Perspect 117:1344–1350PubMedPubMedCentralCrossRefGoogle Scholar
  65. McCoy AN et al (2013) Fusobacterium is associated with colorectal adenomas. PLoS One 8:e53653PubMedPubMedCentralCrossRefGoogle Scholar
  66. Melmed G et al (2003) Human intestinal epithelial cells are broadly unresponsive to toll-like receptor 2-dependent bacterial ligands: implications for host-microbial interactions in the gut. J Immunol 170:1406–1415PubMedCrossRefGoogle Scholar
  67. Mukhopadhya I, Hansen R, El-Omar EM, Hold GL (2012) IBD—what role do Proteobacteria play? Nat Rev Gastroenterol Hepatol 9:219–230PubMedCrossRefGoogle Scholar
  68. Nesić D, Hsu Y, Stebbins CE (2004) Assembly and function of a bacterial genotoxin. Nature 429:429–433PubMedCrossRefGoogle Scholar
  69. Okazaki S et al (2016) Clinical significance of TLR1 I602S polymorphism for patients with metastatic colorectal cancer treated with FOLFIRI plus Bevacizumab. Mol Cancer Ther 15:1740–1745PubMedPubMedCentralCrossRefGoogle Scholar
  70. Orlando A, Messa C, Linsalata M, Cavallini A, Russo F (2009) Effects of Lactobacillus rhamnosus GG on proliferation and polyamine metabolism in HGC-27 human gastric and DLD-1 colonic cancer cell lines. Immunopharmacol Immunotoxicol 31:108–116PubMedCrossRefGoogle Scholar
  71. Otto F et al (1996) Phase II trial of intravenous endotoxin in patients with colorectal and non-small cell lung cancer. Eur J Cancer 1990 32A:1712–1718Google Scholar
  72. Pala V et al (2011) Yogurt consumption and risk of colorectal cancer in the Italian European prospective investigation into cancer and nutrition cohort. Int J Cancer 129:2712–2719PubMedCrossRefGoogle Scholar
  73. Pamer EG (2014) Fecal microbiota transplantation: effectiveness, complexities, and lingering concerns. Mucosal Immunol 7:210–214PubMedCrossRefGoogle Scholar
  74. Paolillo R, Romano Carratelli C, Sorrentino S, Mazzola N, Rizzo A (2009) Immunomodulatory effects of Lactobacillus plantarum on human colon cancer cells. Int Immunopharmacol 9:1265–1271PubMedCrossRefGoogle Scholar
  75. Park E, Jeon G-I, Park J-S, Paik H-D (2007) A probiotic strain of Bacillus polyfermenticus reduces DMH induced precancerous lesions in F344 male rat. Biol Pharm Bull 30:569–574PubMedCrossRefGoogle Scholar
  76. Pasare C, Medzhitov R (2004) Toll-like receptors: linking innate and adaptive immunity. Microbes Infect 6:1382–1387PubMedCrossRefGoogle Scholar
  77. Prorok-Hamon M et al (2014) Colonic mucosa-associated diffusely adherent afaC+ Escherichia coli expressing lpfA and pks are increased in inflammatory bowel disease and colon cancer. Gut 63:761–770PubMedCrossRefGoogle Scholar
  78. Qin H, Zhang Z, Hang X, Jiang Y (2009) L. plantarum prevents enteroinvasive Escherichia coli-induced tight junction proteins changes in intestinal epithelial cells. BMC Microbiol 9:63PubMedPubMedCentralCrossRefGoogle Scholar
  79. Qin J et al (2010) A human gut microbial gene catalog established by metagenomic sequencing. Nature 464:59–65PubMedPubMedCentralCrossRefGoogle Scholar
  80. Rachmilewitz D et al (2002) Immunostimulatory DNA ameliorates experimental and spontaneous murine colitis. Gastroenterology 122:1428–1441PubMedCrossRefGoogle Scholar
  81. Rafter J et al (2007) Dietary synbiotics reduce cancer risk factors in polypectomized and colon cancer patients. Am J Clin Nutr 85:488–496PubMedGoogle Scholar
  82. Rakoff-Nahoum S, Medzhitov R (2007) Regulation of spontaneous intestinal tumorigenesis through the adaptor protein MyD88. Science 317:124–127PubMedCrossRefGoogle Scholar
  83. Raz I, Gollop N, Polak-Charcon S, Schwartz B (2007) Isolation and characterisation of new putative probiotic bacteria from human colonic flora. Br J Nutr 97:725–734PubMedCrossRefGoogle Scholar
  84. Ren C et al (2016) Identification of TLR2/TLR6 signalling lactic acid bacteria for supporting immune regulation. Sci Rep 6:34561PubMedPubMedCentralCrossRefGoogle Scholar
  85. Resta-Lenert S, Barrett KE (2003) Live probiotics protect intestinal epithelial cells from the effects of infection with enteroinvasive Escherichia coli (EIEC). Gut 52:988–997PubMedPubMedCentralCrossRefGoogle Scholar
  86. Reuter S, Gupta SC, Chaturvedi MM, Aggarwal BB (2010) Oxidative stress, inflammation, and cancer: how are they linked? Free Radic Biol Med 49:1603–1616PubMedPubMedCentralCrossRefGoogle Scholar
  87. Reynolds JG, Silva E, McCormack WM (1983) Association of Streptococcus bovis Bacteremia with bowel disease. J Clin Microbiol 17:696–697PubMedPubMedCentralGoogle Scholar
  88. Rhee SH, Im E, Pothoulakis C (2008) Toll-like receptor 5 engagement modulates tumor development and growth in a mouse xenograft model of human colon cancer. Gastroenterology 135:518–528PubMedCrossRefGoogle Scholar
  89. Roisin Hughes IRR (2000) Metabolic activities of the gut microflora in relation to cancer. Microb Ecol Health Dis 12:179–185CrossRefGoogle Scholar
  90. Rubinstein MR et al (2013) Fusobacterium nucleatum promotes colorectal carcinogenesis by modulating E-cadherin/β-catenin signaling via its FadA adhesin. Cell Host Microbe 14:195–206PubMedPubMedCentralCrossRefGoogle Scholar
  91. Russo F, Linsalata M, Orlando A (2014) Probiotics against neoplastic transformation of gastric mucosa: effects on cell proliferation and polyamine metabolism. World J Gastroenterol 20:13258–13272PubMedPubMedCentralCrossRefGoogle Scholar
  92. Rutter MD et al (2004) Cancer surveillance in longstanding ulcerative colitis: endoscopic appearances help predict cancer risk. Gut 53:1813–1816PubMedPubMedCentralCrossRefGoogle Scholar
  93. Salcedo R et al (2010) MyD88-mediated signaling prevents development of adenocarcinomas of the colon: role of interleukin 18. J Exp Med 207:1625–1636PubMedPubMedCentralCrossRefGoogle Scholar
  94. Santaolalla R et al (2013) TLR4 activates the β-catenin pathway to cause intestinal neoplasia. PloS One 8:e63298PubMedPubMedCentralCrossRefGoogle Scholar
  95. Schumann RR, Tapping RI (2007) Genomic variants of TLR1—it takes (TLR-)two to tango. Eur J Immunol 37:2059–2062PubMedCrossRefGoogle Scholar
  96. Sears CL, Garrett WS (2014) Microbes, microbiota, and colon cancer. Cell Host Microbe 15:317–328PubMedPubMedCentralCrossRefGoogle Scholar
  97. Selgrad M et al (2008) The role of viral and bacterial pathogens in gastrointestinal cancer. J Cell Physiol 216:378–388PubMedPubMedCentralCrossRefGoogle Scholar
  98. Shen XJ et al (2010) Molecular characterization of mucosal adherent bacteria and associations with colorectal adenomas. Gut Microbes 1:138–147PubMedPubMedCentralCrossRefGoogle Scholar
  99. Sobhani I et al (2011) Microbial dysbiosis in colorectal cancer (CRC) patients. PLoS One 6:e16393PubMedPubMedCentralCrossRefGoogle Scholar
  100. Soler AP et al (1999) Increased tight junctional permeability is associated with the development of colon cancer. Carcinogenesis 20:1425–1431PubMedCrossRefGoogle Scholar
  101. Strauss J et al (2011) Invasive potential of gut mucosa-derived Fusobacterium nucleatum positively correlates with IBD status of the host. Inflamm Bowel Dis 17:1971–1978PubMedCrossRefGoogle Scholar
  102. Swidsinski A, Weber J, Loening-Baucke V, Hale LP, Lochs H (2005) Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J Clin Microbiol 43:3380–3389PubMedPubMedCentralCrossRefGoogle Scholar
  103. Toprak NU et al (2006) A possible role of Bacteroides fragilis enterotoxin in the aetiology of colorectal cancer. Clin Microbiol Infect 12:782–786PubMedCrossRefGoogle Scholar
  104. Troutman TD, Bazan JF, Pasare C (2012) Toll-like receptors, signaling adapters and regulation of the pro-inflammatory response by PI3K. Cell Cycle 11:3559–3567PubMedPubMedCentralCrossRefGoogle Scholar
  105. Uematsu S, Akira S (2008) Toll-Like receptors (TLRs) and their ligands. Handb Exp Pharmacol 183:1–20. CrossRefGoogle Scholar
  106. Urbanska AM, Bhathena J, Cherif S, Prakash S (2016) Orally delivered microencapsulated probiotic formulation favorably impacts polyp formation in APC (Min/+) model of intestinal carcinogenesis. Artif Cells Nanomed Biotechnol 44:1–11PubMedCrossRefGoogle Scholar
  107. Valle L (2014) Genetic predisposition to colorectal cancer: where we stand and future perspectives. World J Gastroenterol 20:9828–9849PubMedPubMedCentralCrossRefGoogle Scholar
  108. Wang X et al (2012) 4-hydroxy-2-nonenal mediates genotoxicity and bystander effects caused by Enterococcus faecalis-infected macrophages. Gastroenterology 142:543–551.e7PubMedCrossRefGoogle Scholar
  109. Westwood JA et al (2009) Toll-like receptor triggering and T-cell costimulation induce potent antitumor immunity in mice. Clin Cancer Res 15:7624–7633PubMedCrossRefGoogle Scholar
  110. Wu S et al (2009) A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses. Nat Med 15:1016–1022PubMedPubMedCentralCrossRefGoogle Scholar
  111. Yu L, Wang L, Chen S (2010) Endogenous toll-like receptor ligands and their biological significance. J Cell Mol Med 14:2592–2603PubMedPubMedCentralCrossRefGoogle Scholar
  112. Zackular JP et al (2013) The gut microbiome modulates colon tumorigenesis. mBio 4:e00692-613CrossRefGoogle Scholar
  113. Zhang Z-H, Ouyang Q, Gan H-T (2004) Targeting cyclooxygenase-2 with sodium butyrate and NSAIDs on colorectal adenoma/carcinoma cells. World J Gastroenterol 10:2954–2957PubMedPubMedCentralCrossRefGoogle Scholar
  114. Zoglmeier C et al (2011) CpG blocks immunosuppression by myeloid-derived suppressor cells in tumor-bearing mice. Clin Cancer Res 17:1765–1775PubMedCrossRefGoogle Scholar

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© The American Physiological Society 2018

Authors and Affiliations

  1. 1.Department of PathologyUniversity of WashingtonSeattleUSA

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