Inflammation and Gastrointestinal Cancers pp 99-115

Part of the Recent Results in Cancer Research book series (RECENTCANCER, volume 185)

Inflammatory Bowel Disease and Colon Cancer

Abstract

The inflammatory bowel diseases (IBD); Crohn’s and Ulcerative colitis, result from an altered host response to intestinal flora. Recurrent inflammation with ulceration and tissue restitution confers an increased risk of cancer in both UC and Crohns, and genome wide searches have identified a number of disease susceptibility alleles. The carcinogenesis pathway in colitis-associated colorectal cancer (CACRC) is less clearly understood than it’s sporadic counterpart. Clonal ordering experiments have indicated the order and timing of chromosomal instability and common genetic mutations. Epigenetic changes such as DNA methylation and histone modification are thought to play an increasingly important role in inflammation induced carcinogenesis. Clonal expansion of procarcinogenic mutations can lead to large fields of mutant tissue from which colitis associated cancers can arise (field cancerisation). Endoscopic screening is the mainstay of surveillance in high-risk patients although the development of appropriate, clinically applicable biomarkers remains a research priority. Despite the expanding field of biological therapy in inflammatory bowel disease the ASA compounds remain the best-studied and most efficacious chemopreventive agents. Colitis associated CRC appears to have a different aetiology, carcinogenesis pathway and clinical course to its sporadic counterpart. Further research including long-term follow up of patient cohorts taking biological therapies will improve the detection and treatment of these important, inflammation-induced malignancies.

References

  1. Allen DC, Biggart JD, Pyper PC (1985) Large bowel mucosal dysplasia and carcinoma in ulcerative colitis. J Clin Pathol 38:30–43PubMedCrossRefGoogle Scholar
  2. Allgayer H (2003) Review article: mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease. Aliment Pharmacol Ther 18(suppl 2):10–14PubMedCrossRefGoogle Scholar
  3. Asano K, Matsushita T, Umeno J et al (2009) A genome-wide association study identifies three new susceptibility loci for ulcerative colitis in the Japanese population. Nat Genet 41:1325–1329PubMedCrossRefGoogle Scholar
  4. Bamba S, Lee CY, Brittan M et al (2006) Bone marrow transplantation ameliorates pathology in interleukin-10 knockout colitic mice. J Pathol 209:265–273PubMedCrossRefGoogle Scholar
  5. Barrett JC, Lee JC, Lees CW et al (2009) Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nat Genet 41:1330–1334PubMedCrossRefGoogle Scholar
  6. Befrits R, Hammarberg C, Rubio C et al (1994) DNA aneuploidy and histologic dysplasia in long-standing ulcerative colitis. A 10-year follow-up study. Dis Colon Rectum 37:313–319 discussion 319-20PubMedCrossRefGoogle Scholar
  7. Biancone L, Michetti P, Travis S, Escher JC, Moser G, Forbes A, Hoffmann JC, Dignass A, Gionchetti P, Jantschek G, Kiesslich R, Kolacek S et al (2008) European evidence-based consensus on the management of ulcerative colitis: special situations. J Crohn’s Colitis 2:63–92CrossRefGoogle Scholar
  8. Bodmer W (2008) Genetic instability is not a requirement for tumor development. Cancer Res 68:3558–3560 discussion 3560-1PubMedCrossRefGoogle Scholar
  9. Bos CL, Diks SH, Hardwick JC et al (2006) Protein phosphatase 2A is required for mesalazine-dependent inhibition of Wnt/beta-catenin pathway activity. Carcinogenesis 27:2371–2382PubMedCrossRefGoogle Scholar
  10. Braakhuis BJ, Tabor MP, Kummer JA et al (2003) A genetic explanation of Slaughter’s concept of field cancerization: evidence and clinical implications. Cancer Res 63:1727–1730PubMedGoogle Scholar
  11. Brentnall TA, Crispin DA, Rabinovitch PS et al (1994) Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenterology 107:369–378PubMedGoogle Scholar
  12. Brittan M, Hunt T, Jeffery R et al (2002) Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon. Gut 50:752–757PubMedCrossRefGoogle Scholar
  13. Brittan M, Chance V, Elia G et al (2005) A regenerative role for bone marrow following experimental colitis: contribution to neovasculogenesis and myofibroblasts. Gastroenterology 128:1984–1995PubMedCrossRefGoogle Scholar
  14. Burmer GC, Rabinovitch PS, Haggitt RC et al (1992) Neoplastic progression in ulcerative colitis: histology, DNA content, and loss of a p53 allele. Gastroenterology 103:1602–1610PubMedGoogle Scholar
  15. Cao D, Bromberg PA, Samet JM (2007) COX-2 expression induced by diesel particles involves chromatin modification and degradation of HDAC1. Am J Respir Cell Mol Biol 37:232–239PubMedCrossRefGoogle Scholar
  16. Chen R, Rabinovitch PS, Crispin DA et al (2003) DNA fingerprinting abnormalities can distinguish ulcerative colitis patients with dysplasia and cancer from those who are dysplasia/cancer-free. Am J Pathol 162:665–672PubMedCrossRefGoogle Scholar
  17. Chen R, Bronner MP, Crispin DA et al (2005a) Characterization of genomic instability in ulcerative colitis neoplasia leads to discovery of putative tumor suppressor regions. Cancer Genet Cytogenet 162:99–106PubMedCrossRefGoogle Scholar
  18. Chen R, Rabinovitch PS, Crispin DA et al (2005b) The initiation of colon cancer in a chronic inflammatory setting. Carcinogenesis 26:1513–1519PubMedCrossRefGoogle Scholar
  19. Cho JH, Nicolae DL, Gold LH et al (1998) Identification of novel susceptibility loci for inflammatory bowel disease on chromosomes 1p, 3q, and 4q: evidence for epistasis between 1p and IBD1. Proc Natl Acad Sci USA 95:7502–7507PubMedCrossRefGoogle Scholar
  20. Dekker E, van den Broek FJ, Reitsma JB et al (2007) Narrow-band imaging compared with conventional colonoscopy for the detection of dysplasia in patients with longstanding ulcerative colitis. Endoscopy 39:216–221PubMedCrossRefGoogle Scholar
  21. Direkze NC, Hodivala-Dilke K, Jeffery R et al (2004) Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res 64:8492–8495PubMedCrossRefGoogle Scholar
  22. Dubuquoy L, Rousseaux C, Thuru X et al (2006) PPARgamma as a new therapeutic target in inflammatory bowel diseases. Gut 55:1341–1349PubMedCrossRefGoogle Scholar
  23. Duerr RH, Barmada MM, Zhang L et al (2000) High-density genome scan in Crohn disease shows confirmed linkage to chromosome 14q11–12. Am J Hum Genet 66:1857–1862PubMedCrossRefGoogle Scholar
  24. Eaden JA, Mayberry JF (2002) Guidelines for screening and surveillance of asymptomatic colorectal cancer in patients with inflammatory bowel disease. Gut 51(Suppl 5):V10–V12PubMedCrossRefGoogle Scholar
  25. East JE, Suzuki N, von Herbay A et al (2006) Narrow band imaging with magnification for dysplasia detection and pit pattern assessment in ulcerative colitis surveillance: a case with multiple dysplasia associated lesions or masses. Gut 55:1432–1435PubMedCrossRefGoogle Scholar
  26. Ekbom A, Helmick C, Zack M et al (1990) Ulcerative colitis and colorectal cancer. A population-based study. N Engl J Med 323:1228–1233PubMedCrossRefGoogle Scholar
  27. Fellermann K, Stange DE, Schaeffeler E et al (2006) A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon. Am J Hum Genet 79:439–448PubMedCrossRefGoogle Scholar
  28. Ferrari SL, Ahn-Luong L, Garnero P et al (2003) Two promoter polymorphisms regulating interleukin-6 gene expression are associated with circulating levels of C-reactive protein and markers of bone resorption in postmenopausal women. J Clin Endocrinol Metab 88:255–259PubMedCrossRefGoogle Scholar
  29. Fisher SA, Tremelling M, Anderson CA et al (2008) Genetic determinants of ulcerative colitis include the ECM1 locus and five loci implicated in Crohn’s disease. Nat Genet 40:710–712PubMedCrossRefGoogle Scholar
  30. Franke A, Balschun T, Karlsen TH et al (2008) Sequence variants in IL10, ARPC2 and multiple other loci contribute to ulcerative colitis susceptibility. Nat Genet 40:1319–1323PubMedCrossRefGoogle Scholar
  31. Garcia-Olmo D, Garcia-Arranz M, Herreros D et al (2005) A phase I clinical trial of the treatment of Crohn’s fistula by adipose mesenchymal stem cell transplantation. Dis Colon Rectum 48:1416–1423PubMedCrossRefGoogle Scholar
  32. Gillen CD, Walmsley RS, Prior P et al (1994) Ulcerative colitis and Crohn’s disease: a comparison of the colorectal cancer risk in extensive colitis. Gut 35:1590–1592PubMedCrossRefGoogle Scholar
  33. Greaves LC, Preston SL, Tadrous PJ et al (2006) Mitochondrial DNA mutations are established in human colonic stem cells, and mutated clones expand by crypt fission. Proc Natl Acad Sci USA 103:714–719PubMedCrossRefGoogle Scholar
  34. Greten FR, Eckmann L, Greten TF et al (2004) IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 118:285–296PubMedCrossRefGoogle Scholar
  35. Hampe J, Schreiber S, Shaw SH et al (1999) A genomewide analysis provides evidence for novel linkages in inflammatory bowel disease in a large European cohort. Am J Hum Genet 64:808–816PubMedCrossRefGoogle Scholar
  36. Hasko G, Szabo C, Nemeth ZH et al (2001) Sulphasalazine inhibits macrophage activation: inhibitory effects on inducible nitric oxide synthase expression, interleukin-12 production and major histocompatibility complex II expression. Immunology 103:473–478PubMedCrossRefGoogle Scholar
  37. Huang Z, Li L, Wang J (2007) Hypermethylation of SFRP2 as a potential marker for stool-based detection of colorectal cancer and precancerous lesions. Dig Dis Sci 52:2287–2291PubMedCrossRefGoogle Scholar
  38. Hugot JP, Laurent-Puig P, Gower-Rousseau C et al (1996) Mapping of a susceptibility locus for Crohn’s disease on chromosome 16. Nature 379:821–823PubMedCrossRefGoogle Scholar
  39. Hussain SP, Amstad P, Raja K et al (2000) Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res 60:3333–3337PubMedGoogle Scholar
  40. Imielinski M, Baldassano RN, Griffiths A et al (2009) Common variants at five new loci associated with early-onset inflammatory bowel disease. Nat Genet 41:1335–1340PubMedCrossRefGoogle Scholar
  41. Issa JP, Ahuja N, Toyota M et al (2001) Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res 61:3573–3577PubMedGoogle Scholar
  42. Itzkowitz SH, Yio X (2004) Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol 287:G7–G17PubMedCrossRefGoogle Scholar
  43. Keller R, Foerster EC, Kohler A et al (2001) Diagnostic value of DNA image cytometry in ulcerative colitis. Dig Dis Sci 46:870–878PubMedCrossRefGoogle Scholar
  44. Kennedy M, Wilson L, Szabo C et al (1999) 5-aminosalicylic acid inhibits iNOS transcription in human intestinal epithelial cells. Int J Mol Med 4:437–443PubMedGoogle Scholar
  45. Kim KM, Shibata D (2002) Methylation reveals a niche: stem cell succession in human colon crypts. Oncogene 21:5441–5449PubMedCrossRefGoogle Scholar
  46. Kinzler KW, Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87:159–170PubMedCrossRefGoogle Scholar
  47. Kukitsu T, Takayama T, Miyanishi K et al (2008) Aberrant crypt foci as precursors of the dysplasia-carcinoma sequence in patients with ulcerative colitis. Clin Cancer Res 14:48–54PubMedCrossRefGoogle Scholar
  48. Lanzoni G, Roda G, Belluzzi A et al (2008) Inflammatory bowel disease: moving toward a stem cell-based therapy. World J Gastroenterol 14:4616–4626PubMedCrossRefGoogle Scholar
  49. Leedham SJ, Graham TA, Oukrif D et al (2009) Clonality, founder mutations, and field cancerization in human ulcerative colitis-associated neoplasia. Gastroenterology 136:542–506PubMedCrossRefGoogle Scholar
  50. Loeb KR, Loeb LA (1999) Genetic instability and the mutator phenotype. Studies in ulcerative colitis. Am J Pathol 154:1621–1626PubMedCrossRefGoogle Scholar
  51. Lofberg R, Brostrom O, Karlen P et al (1992) DNA aneuploidy in ulcerative colitis: reproducibility, topographic distribution, and relation to dysplasia. Gastroenterology 102:1149–1154PubMedGoogle Scholar
  52. Lyda MH, Noffsinger A, Belli J et al (1998) Multifocal neoplasia involving the colon and appendix in ulcerative colitis: pathological and molecular features. Gastroenterology 115:1566–1573PubMedCrossRefGoogle Scholar
  53. Lyda MH, Noffsinger A, Belli J et al (2000) Microsatellite instability and K-ras mutations in patients with ulcerative colitis. Hum Pathol 31:665–671PubMedCrossRefGoogle Scholar
  54. Ma Y, Ohmen JD, Li Z et al (1999) A genome-wide search identifies potential new susceptibility loci for Crohn’s disease. Inflamm Bowel Dis 5:271–278PubMedCrossRefGoogle Scholar
  55. Macarthur M, Sharp L, Hold GL et al (2005) The role of cytokine gene polymorphisms in colorectal cancer and their interaction with aspirin use in the northeast of Scotland. Cancer Epidemiol Biomarkers Prev 14:1613–1618PubMedCrossRefGoogle Scholar
  56. Moum B, Ekbom A, Vatn MH et al (1999) Change in the extent of colonoscopic and histological involvement in ulcerative colitis over time. Am J Gastroenterol 94:1564–1569PubMedCrossRefGoogle Scholar
  57. Nakamizo A, Marini F, Amano T et al (2005) Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas. Cancer Res 65:3307–3318PubMedGoogle Scholar
  58. O’Sullivan JN, Bronner MP, Brentnall TA et al (2002) Chromosomal instability in ulcerative colitis is related to telomere shortening. Nat Genet 32:280–284PubMedCrossRefGoogle Scholar
  59. Park HS, Goodlad RA, Wright NA (1995) Crypt fission in the small intestine and colon. A mechanism for the emergence of G6PD locus-mutated crypts after treatment with mutagens. Am J Pathol 147:1416–1427PubMedGoogle Scholar
  60. Powell SM, Zilz N, Beazer-Barclay Y et al (1992) APC mutations occur early during colorectal tumorigenesis. Nature 359:235–237PubMedCrossRefGoogle Scholar
  61. Rioux JD, Silverberg MS, Daly MJ et al (2000) Genomewide search in Canadian families with inflammatory bowel disease reveals two novel susceptibility loci. Am J Hum Genet 66:1863–1870PubMedCrossRefGoogle Scholar
  62. Rosh JR, Gross T, Mamula P et al (2007) Hepatosplenic T-cell lymphoma in adolescents and young adults with Crohn’s disease: a cautionary tale? Inflamm Bowel Dis 13:1024–1030PubMedCrossRefGoogle Scholar
  63. Rousseaux C, Lefebvre B, Dubuquoy L et al (2005) Intestinal antiinflammatory effect of 5-aminosalicylic acid is dependent on peroxisome proliferator-activated receptor-gamma. J Exp Med 201:1205–1215PubMedCrossRefGoogle Scholar
  64. Rubin CE, Haggitt RC, Burmer GC et al (1992) DNA aneuploidy in colonic biopsies predicts future development of dysplasia in ulcerative colitis. Gastroenterology 103:1611–1620PubMedGoogle Scholar
  65. Rutgeerts P, Vermeire S, Van Assche G (2009) Biological therapies for inflammatory bowel diseases. Gastroenterology 136:1182–1197PubMedCrossRefGoogle Scholar
  66. Rutter M, Saunders B, Wilkinson K et al (2004) Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126:451–459PubMedCrossRefGoogle Scholar
  67. Satsangi J, Parkes M, Louis E et al (1996) Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12. Nat Genet 14:199–202PubMedCrossRefGoogle Scholar
  68. Seril DN, Liao J, Yang GY et al (2003) Oxidative stress and ulcerative colitis-associated carcinogenesis: studies in humans and animal models. Carcinogenesis 24:353–362PubMedCrossRefGoogle Scholar
  69. Shivananda S, Lennard-Jones J, Logan R et al (1996) Incidence of inflammatory bowel disease across Europe: is there a difference between north and south? Results of the European Collaborative Study on Inflammatory Bowel Disease (EC-IBD). Gut 39:690–697PubMedGoogle Scholar
  70. Sieber OM, Heinimann K, Gorman P et al (2002) Analysis of chromosomal instability in human colorectal adenomas with two mutational hits at APC. Proc Natl Acad Sci USA 99:16910–16915PubMedCrossRefGoogle Scholar
  71. Slattery ML, Wolff RK, Herrick JS et al (2007) IL6 genotypes and colon and rectal cancer. Cancer Causes Control 18:1095–1105PubMedCrossRefGoogle Scholar
  72. Slaughter DP, Southwick HW, Smejkal W (1953) Field cancerization in oral stratified squamous epithelium; clinical implications of multicentric origin. Cancer 6:963–968PubMedCrossRefGoogle Scholar
  73. Studeny M, Marini FC, Champlin RE et al (2002) Bone marrow-derived mesenchymal stem cells as vehicles for interferon-beta delivery into tumors. Cancer Res 62:3603–3608PubMedGoogle Scholar
  74. Swidsinski A, Weber J, Loening-Baucke V et al (2005) Spatial organization and composition of the mucosal flora in patients with inflammatory bowel disease. J Clin Microbiol 43:3380–3389PubMedCrossRefGoogle Scholar
  75. Tomlinson I, Bodmer W (1999) Selection, the mutation rate and cancer: ensuring that the tail does not wag the dog. Nat Med 5:11–12PubMedCrossRefGoogle Scholar
  76. van den Broek FJ, Fockens P, van Eeden S et al (2008) Endoscopic tri-modal imaging for surveillance in ulcerative colitis: randomised comparison of high-resolution endoscopy and autofluorescence imaging for neoplasia detection; and evaluation of narrow-band imaging for classification of lesions. Gut 57:1083–1089PubMedCrossRefGoogle Scholar
  77. Velayos F (2008) Colon cancer surveillance in inflammatory bowel disease patients: current and emerging practices. Expert Rev Gastroenterol Hepatol 2:817–825PubMedCrossRefGoogle Scholar
  78. Vogelstein B, Fearon ER, Hamilton SR et al (1988) Genetic alterations during colorectal-tumor development. N Engl J Med 319:525–532PubMedCrossRefGoogle Scholar
  79. von Roon AC, Karamountzos L, Purkayastha S et al (2007) Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy. Am J Gastroenterol 102:803–813CrossRefGoogle Scholar
  80. Wahl C, Liptay S, Adler G et al (1998) Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Invest 101:1163–1174PubMedCrossRefGoogle Scholar
  81. Willenbucher RF, Zelman SJ, Ferrell LD et al (1997) Chromosomal alterations in ulcerative colitis-related neoplastic progression. Gastroenterology 113:791–801PubMedCrossRefGoogle Scholar
  82. Winawer S, Fletcher R, Rex D et al (2003) Colorectal cancer screening and surveillance: clinical guidelines and rationale-update based on new evidence. Gastroenterology 124:544–560PubMedCrossRefGoogle Scholar
  83. Yin J, Harpaz N, Tong Y et al (1993) p53 point mutations in dysplastic and cancerous ulcerative colitis lesions. Gastroenterology 104:1633–1639PubMedGoogle Scholar
  84. Yoshida T, Mikami T, Mitomi H et al (2003) Diverse p53 alterations in ulcerative colitis-associated low-grade dysplasia: full-length gene sequencing in microdissected single crypts. J Pathol 199:166–175PubMedCrossRefGoogle Scholar
  85. Zimmerman MJ, Jewell DP (1996) Cytokines and mechanisms of action of glucocorticoids and aminosalicylates in the treatment of ulcerative colitis and Crohn’s disease. Aliment Pharmacol Ther 10 (suppl 2):93–98 discussion 99PubMedGoogle Scholar

Copyright information

© Springer-Velag Berlin Heidelberg 2011

Authors and Affiliations

  • Noor Jawad
    • 1
  • Natalie Direkze
    • 2
  • Simon J. Leedham
    • 3
  1. 1.Blizard Institute of Cell and Molecular Science, Bart’s and The London School of Medicine and Dentistry, Queen Mary, University of LondonLondonUK
  2. 2.Frimley Park Hospital NHS Foundation TrustSurreyUK
  3. 3.Wellcome Trust Centre for Human Genetics, University of OxfordOxfordUK

Personalised recommendations