Current Colorectal Cancer Reports

, Volume 13, Issue 3, pp 192–204 | Cite as

Chemoprevention of Colorectal Cancer in High-Risk Patients: from Molecular Targets to Clinical Trials

  • Dora Colussi
  • Franco Bazzoli
  • Luigi Ricciardiello
Basic Science Foundations in Colorectal Cancer (J Roper, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Basic Science Foundations in Colorectal Cancer


An increased understanding of the molecular pathways involved in colorectal carcinogenesis has helped researchers to develop possible chemopreventive strategies. This has been of particular relevance for high-risk subjects, for whom chemopreventive strategies may be helpful in slowing cancer development. In order to obtain more definitive data on chemopreventive agents, there has been a great effort to develop preclinical models that resemble the clinical scenarios encountered in high-risk patients. Importantly, many compounds, in particular non-steroidal anti-inflammatory drugs, have shown significant effects in models of high-risk clinical settings. However, results from clinical trials have been somewhat disappointing and no definitive chemopreventative agent is currently given for any of the high-risk conditions. In this review, we examine the available data on the effects of chemopreventive drugs on molecular targets relevant for high-risk conditions predisposing to colorectal cancer, including data from preclinical studies that have led to clinical trials.


Chemoprevention Colorectal cancer Familial adenomatous polyposis Lynch syndrome Colitis associated colorectal cancer Aspirin Mesalamine Ecosapentainoic acid Ursodexycolic acid 



Colorectal cancer


Familial adenomatous polyposis


Adenomatous polyposis coli


Attenuated familial adenomatous polyposis


Non-steroidal anti-inflammatory drugs




Prostaglandin E2


Prostaglandin E3






Peroxisome proliferator activated receptor delta


Retinoid X receptor alpha


Nuclear factor kappa-light-chain-enhancer of activated B cells


Ornithine decarboxylase






Epidermal growth factor receptor


Prostaglandin E2 receptor


Phosphoinositide 3-kinase


Protein kinase B


Glycogen synthase kinase 3 beta


Protein phosphatase 2A


Aspirin with a covalently attached NO-releasing moiety


Colorectal adenoma/carcinoma prevention program 1


Colorectal adenoma/carcinoma prevention program 2


Tumor necrosis factor-alpha


Interferon gamma


Hypoxia-inducible factor 1-alpha


Vascular endothelial growth factor




Eicosapentaenoic acid


Docosahexaenoic acid


Eicosapentaenoic acid as free fatty acid

ω-3 PUFAs

Omega-3 polyunsaturated fatty acids






Ileorectal anastomosis


Ileal pouch-anal anastomosis


Lynch syndrome


Mismatch repair


MutL homolog 1


MutS protein homolog 2


MutS protein homolog 6


Mismatch repair endonuclease 2


Human colon cancer cells


Microsatellite instability


Microsatellite instability high


Microsatellite instability-low


Transforming growth factor beta receptor II


Activin type 2 receptors


Inflammatory bowel disease


Primary sclerosing cholangitis


Ulcerative colitis


Crohn’s disease


Colitis-associated colorectal cancer


Nitric oxide synthase 2




Signal transducer and activator of transcription 3


Modeling colitis-associated cancer with azoxymethane


Murine colitis modeling using dextran sulfate sodium


Notch homolog 1, translocation-associated (Drosophila)

IL-1 beta

Interleukin 1 beta


peroxisome proliferator-activated receptor gamma


5-Amino salicylate acid








Suppressor of cytokine signaling 3


Ursodexycolic acid


Extracellular signal-regulated kinases 1


Extracellular signal-regulated kinases 2


Epidermal growth factor


Insulin growth factor-1


Mitogen-activated protein kinases


Cyclic AMP pathway



L.R. is supported by the Italian Association for Cancer Research (AIRC) IG Investigator Grant N. 14281 and the European Community’s Seventh Framework Program FP7/2007–2013 under grant agreement 311876, Pathway-27.

Compliance with Ethical Standards

Conflict of Interest

Dora Colussi declares that she has no conflict of interest.

Franco Bazzoli declares that he has no conflict of interest.

Luigi Ricciardiello has received research funding through grants from Takeda and SLA Pharma, and has received compensation from Tillotts Pharma AG for service as a consultant.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    •• Ferlay J, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136:E359–86. This article reviewed the latest worlwide incidence and mortality of CRC estimates for 2012 PubMedCrossRefGoogle Scholar
  2. 2.
    Ferlay J, et al. Cancer incidence and mortality patterns in Europe: estimates for 40 countries in 2012. Eur J Cancer. 2013;49:1374–403.PubMedCrossRefGoogle Scholar
  3. 3.
    Le Marchand L, Wilkens LR, Kolonel LN, Hankin JH, Lyu LC. Associations of sedentary lifestyle, obesity, smoking, alcohol use, and diabetes with the risk of colorectal cancer. Cancer Res. 1997;57:4787–94.PubMedGoogle Scholar
  4. 4.
    • Kunzmann AT, et al. Dietary fiber intake and risk of colorectal cancer and incident and recurrent adenoma in the prostate, lung, colorectal, and ovarian cancer screening trial. Am J Clin Nutr. 2015;102:881–90. This article is a large prospective study within a population based sceening, that evidenced a protective roles of the highest dietary fiber intakes and the reduction risk of incidence of colorectal adenoma and distal colon cancer PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Terzić J, Grivennikov S, Karin E, Karin M. Inflammation and colon cancer. Gastroenterology. 2010;138:2101–14.PubMedCrossRefGoogle Scholar
  6. 6.
    Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990;61:759–67.PubMedCrossRefGoogle Scholar
  7. 7.
    Bodmer WF, et al. Localization of the gene for familial adenomatous polyposis on chromosome 5. Nature. 1987;328:614–6.PubMedCrossRefGoogle Scholar
  8. 8.
    Nishisho I, et al. Mutations of chromosome 5q21 genes in FAP and colorectal cancer patients. Science. 1991;253:665–9.PubMedCrossRefGoogle Scholar
  9. 9.
    Kinzler K, et al. Identification of FAP locus genes from chromosome 5q21. Science. 1991;253(80):661–5.PubMedCrossRefGoogle Scholar
  10. 10.
    Groden J, et al. Identification and characterization of the familial adenomatous polyposis coli gene. Cell. 1991;66:589–600.PubMedCrossRefGoogle Scholar
  11. 11.
    Clevers H, Loh KM, Nusse R. Stem cell signaling. An integral program for tissue renewal and regeneration: Wnt signaling and stem cell control. Science. 2014;346(1248012)Google Scholar
  12. 12.
    Al-Tassan N, et al. Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors. Nat Genet. 2002;30:227–32.PubMedCrossRefGoogle Scholar
  13. 13.
    Giardiello FM, Spannhake EW, Dubois RN, Hylind LM, Robinson CR, et al. Prostaglandin levels in human colorectal mucosa: effects of sulindac in patients with familial adenomatous polyposis. Dig Dis Sci. 1998;43:311–6. (1998) PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Kargman SÂ!L, O’Neill 1GP, Vickers PJ, Evans JF, Mancini JA, J S. Expression of prostaglandin G/H synthase-1 and -2 protein in human colon cancer. Cancer Res. 1995;15:1–19.Google Scholar
  15. 15.
    Rice PL, et al. Sulindac metabolites induce caspase- and proteasome-dependent degradation of beta-catenin protein in human colon cancer cells. Mol Cancer Ther. 2003;2:885–92.PubMedGoogle Scholar
  16. 16.
    He TC, Chan TA, Vogelstein B, Kinzler KW. PPARdelta is an APC-regulated target of nonsteroidal anti-inflammatory drugs. Cell. 1999;99:335–45.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Zhou H, et al. NSAID sulindac and its analog bind RXRalpha and inhibit RXRalpha-dependent AKT signaling. Cancer Cell. 2010;17:560–73.PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Li X, et al. Sulindac inhibits tumor cell invasion by suppressing NF-kappaB-mediated transcription of microRNAs. Oncogene. 2012;31:4979–86.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Qiu W, et al. Chemoprevention by nonsteroidal anti-inflammatory drugs eliminates oncogenic intestinal stem cells via SMAC-dependent apoptosis. Proc Natl Acad Sci U S A. 2010;107:20027–32.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    • Femia AP, et al. Sulindac, 3, 3′-diindolylmethane and curcumin reduce carcinogenesis in the Pirc rat, an Apc-driven model of colon carcinogenesis. BMC Cancer. 2015;15:611. This article reinforced the hypothesis of the chemopreventive role of sulindac at different concentration in Apc-driven model of colon carcinogenesis, Pirc rat, by reducing colon tumors, total intestine tumor and increasing apoptosis of colonic mucosa; they also evidenced an enhanced effects when sulindac was used in combination to natural compounds curcumin and diindolymethane PubMedPubMedCentralCrossRefGoogle Scholar
  21. 21.
    Nugent KP, Farmer KC, Spigelman AD, Williams CB, P. R. Randomized controlled trial of the effect of sulindac on duodenal and rectal polyposis and cell proliferation in patients with familial adenomatous polyposis. Br J Surg. (1993).Google Scholar
  22. 22.
    Giardiello FM, et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993;328:1313–6.PubMedCrossRefGoogle Scholar
  23. 23.
    Waddell WR, Ganser GF, Cerise EJ, Loughry RW. Sulindac for polyposis of the colon. Am J Surg. 1989;157:175–9.PubMedCrossRefGoogle Scholar
  24. 24.
    Labayle D, et al. Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology. 1991;101:635–9.PubMedCrossRefGoogle Scholar
  25. 25.
    Cruz-Correa M, Hylind LM, Romans KE, Booker SV, Giardiello FM. Long-term treatment with sulindac in familial adenomatous polyposis: a prospective cohort study. Gastroenterology. 2002;122:641–5.PubMedCrossRefGoogle Scholar
  26. 26.
    Winde G, Schmid KW, Schlegel W, Fischer R, Osswald H. B. H. Complete reversion and prevention of rectal adenomas in colectomized patients with familial adenomatous polyposis by rectal low-dose sulindac maintenance treatment. Advantages of a low-dose nonsteroidal anti-inflammatory drug regimen in reversing adenomas. Dis Colon rectum. (1995).Google Scholar
  27. 27.
    Niv Y, Fraser GM. Adenocarcinoma in the rectal segment in familial polyposis coli is not prevented by sulindac therapy. Gastroenterology. 1994;107:854–7.PubMedCrossRefGoogle Scholar
  28. 28.
    Lynch HT, Thorson AG, Smyrk T. Rectal cancer after prolonged sulindac chemoprevention: a case report. Cancer. 1995;75:936–8.PubMedCrossRefGoogle Scholar
  29. 29.
    Giardiello FM, Ang Vincent WY, Linda H, Krush Anne J, Petersen Gloria M, Trimbath Ill D, Piantadosi Steven GE. Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med. 2002;346:1054–9.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Hixson LJ, et al. Ornithine decarboxylase and polyamines in colorectal neoplasia and mucosa. Cancer Epidemiol Biomark Prev. 1993;2:369–74.Google Scholar
  31. 31.
    Ignatenko NA, et al. Combination chemoprevention of intestinal carcinogenesis in a murine model of familial adenomatous polyposis. Nutr Cancer. 2008;60(Suppl 1):30–5.PubMedCrossRefGoogle Scholar
  32. 32.
    MacKenzie GG, et al. Phospho-sulindac (OXT-328), a novel sulindac derivative, is safe and effective in colon cancer prevention in mice. Gastroenterology. 2010;139:1320–32.PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Coffey RJ, et al. Epidermal growth factor receptor activation induces nuclear targeting of cyclooxygenase-2, basolateral release of prostaglandins, and mitogenesis in polarizing colon cancer cells. Proc Natl Acad Sci U S A. 1997;94:657–62.PubMedPubMedCentralCrossRefGoogle Scholar
  34. 34.
    •• Samadder NJ, et al. Effect of sulindac and erlotinib vs placebo on duodenal neoplasia in familial adenomatous polyposis. JAMA. 2016;315:1266. They first evidence the combined preventive effect of sulindac at 300 mg daily and erlotinib at 75 mg daily for 6 months by reducing the total duodenal polyp burden in FAP patients PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Hixson LJ, et al. Antiproliferative effect of nonsteroidal antiinflammatory drugs against human colon cancer cells. Cancer Epidemiol Biomark Prev. 1994;3:433–8.Google Scholar
  36. 36.
    Wang D, DuBois RN. The role of COX-2 in intestinal and colorectal cancer. Oncogene. 2011;29:781–8.CrossRefGoogle Scholar
  37. 37.
    •• Drew DA, Cao Y, Chan AT. Aspirin and colorectal cancer: the promise of precision chemoprevention. Nat Rev Cancer. 2016;16:173–86. Latest review on the evidence of the strong chemopreventive role of the long term aspirin use in CRC PubMedCrossRefGoogle Scholar
  38. 38.
    Castellone, M. D. & Teramoto, H. Prostaglandin E 2 promotes colon cancer cell growth through a G s -Axin- b -catenin signaling axis. 1504–1511 (2005).Google Scholar
  39. 39.
    Bos CL, et al. Effect of aspirin on the Wnt/beta-catenin pathway is mediated via protein phosphatase 2A. Oncogene. 2006;25:6447–56.PubMedCrossRefGoogle Scholar
  40. 40.
    Sansom OJ, Stark LA, Dunlop MG, Clarke AR. Suppression of intestinal and mammary neoplasia by lifetime administration of aspirin in ApcMin/+ and ApcMin/+, Msh2−/− mice. Cancer Res. 2001;61:7060–4.PubMedGoogle Scholar
  41. 41.
    Reuter BK, Zhang X-J, Miller MJS. Therapeutic utility of aspirin in the ApcMin/+ murine model of colon carcinogenesis. BMC Cancer. 2002;2:19.PubMedPubMedCentralCrossRefGoogle Scholar
  42. 42.
    Williams JL, et al. Nitric oxide-releasing nonsteroidal anti-inflammatory drugs (NSAIDs) alter the kinetics of human colon cancer cell lines more effectively than traditional NSAIDs: implications for colon cancer chemoprevention. Cancer Res. 2001;61:3285–9.PubMedGoogle Scholar
  43. 43.
    Gao J, Liu X, Rigas B. Nitric oxide-donating aspirin induces apoptosis in human colon cancer cells through induction of oxidative stress. Proc Natl Acad Sci U S A. 2005;102:17207–12.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Williams JL, et al. NO-donating aspirin inhibits intestinal carcinogenesis in min (APC min/+) mice. Biochem Biophys Res Commun. 2004;313:784–8.PubMedCrossRefGoogle Scholar
  45. 45.
    Rothwell PM, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010;376:1741–50.PubMedCrossRefGoogle Scholar
  46. 46.
    Liao X, et al. Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med. 2012;367:1596–606.PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Burn J, et al. A randomized placebo-controlled prevention trial of aspirin and/or resistant starch in young people with familial adenomatous polyposis. Cancer Prev Res. 2011;4:655–65.CrossRefGoogle Scholar
  48. 48.
    Ishikawa H, et al. Preventive effects of low-dose aspirin on colorectal adenoma growth in patients with familial adenomatous polyposis: double-blind, randomized clinical trial. Cancer Med. 2013;2:50–6.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Wang D. Prostaglandins and cancer. Gut. 2006;55:115–22.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Dubois RN, et al. Cyclooxygenase in biology and disease. FASEB J. 1998;12:1063–73.PubMedGoogle Scholar
  51. 51.
    Kawamori T, Uchiya N, Sugimura T, Wakabayashi K. Enhancement of colon carcinogenesis by prostaglandin E2 administration. Carcinogenesis. 2003;24:985–90.PubMedCrossRefGoogle Scholar
  52. 52.
    Wang D, et al. Prostaglandin E2 promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor ?? Cancer Cell. 2004;6:285–95.PubMedCrossRefGoogle Scholar
  53. 53.
    Nakanishi M, et al. Genetic deletion of mPGES-1 suppresses intestinal tumorigenesis. Cancer Res. 2008;68:3251–9.PubMedCrossRefGoogle Scholar
  54. 54.
    Oshima M, Dinchuk E, Kargman SL. Suppression of intestinal polyposis in APC D716 knockout mice by inhibition of cyclooxygenase-2 (. COX-2). Cell. 1996;87:803–9.PubMedCrossRefGoogle Scholar
  55. 55.
    Steinbach G, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000;342:1946–52.PubMedCrossRefGoogle Scholar
  56. 56.
    Stolfi C, et al. Cyclooxygenase-2-dependent and -independent inhibition of proliferation of colon cancer cells by 5-aminosalicylic acid. Biochem Pharmacol. 2008;75:668–76.PubMedCrossRefGoogle Scholar
  57. 57.
    Lu D, Cottam HB, Corr M, Carson DA. Repression of beta-catenin function in malignant cells by nonsteroidal antiinflammatory drugs. Proc Natl Acad Sci U S A. 2005;102:18567–71.PubMedPubMedCentralCrossRefGoogle Scholar
  58. 58.
    Gasche C, Goel A, Natarajan L, Boland CR. Mesalazine improves replication fidelity in cultured colorectal cells. Cancer Res. 2005;65:3993–7.PubMedCrossRefGoogle Scholar
  59. 59.
    •• Lynch PM, et al. An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis. Gut. 2015:1–10. doi: 10.1136/gutjnl-2014-307235. They first demonstrated no chemopreventive role in reducing adenoma count and burden in FAP patients treated with celocoxib associated to DFMO instead celecoxib alone
  60. 60.
    Cockbain AJ, Toogood GJ, Hull MA. Omega-3 polyunsaturated fatty acids for the treatment and prevention of colorectal cancer. Gut. 2012;61:135–49.PubMedCrossRefGoogle Scholar
  61. 61.
    Serhan CN, Gotlinger K, Hong S, Arita M. Resolvins, docosatrienes, and neuroprotectins, novel omega-3-derived mediators, and their aspirin-triggered endogenous epimers: an overview of their protective roles in catabasis. Prostaglandins and Other Lipid Mediators. 2004;73:155–72.PubMedCrossRefGoogle Scholar
  62. 62.
    Novak TE, Babcock TA, Jho DH, Helton WS, Espat NJ. NF-kappa B inhibition by omega −3 fatty acids modulates LPS-stimulated macrophage TNF-alpha transcription. Am J Physiol Cell Mol Physiol. 2003;284:L84–9.CrossRefGoogle Scholar
  63. 63.
    Fini L, et al. Highly purified eicosapentaenoic acid as free fatty acids strongly suppresses polyps in ApcMin/+ mice. Clin Cancer Res. 2010;16:5703–11.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    West NJ, et al. Eicosapentaenoic acid reduces rectal polyp number and size in familial adenomatous polyposis. Gut. 2010;59:918–25.PubMedCrossRefGoogle Scholar
  65. 65.
    Mahmoud NN, et al. Plant phenolics decrease intestinal tumors in an animal model of familial adenomatous polyposis. Carcinogenesis. 2000;21:921–7.PubMedCrossRefGoogle Scholar
  66. 66.
    Cruz-Correa M, et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2006;4:1035–8.PubMedCrossRefGoogle Scholar
  67. 67.
    Ruschoff J, et al. Aspirin suppresses the mutator phenotype associated with hereditary nonpolyposis colorectal cancer by genetic selection. Proc Natl Acad Sci U S A. 1998;95:11301–6.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Goel A, Chang DK, Ricciardiello L, Gasche C, Boland CR. A novel mechanism for aspirin-mediated growth inhibition of human colon cancer cells. Clin Cancer Res. 2003;9:383–90.PubMedGoogle Scholar
  69. 69.
    McIlhatton MA, et al. Nitric oxide-donating aspirin derivatives suppress microsatellite instability in mismatch repair-deficient and hereditary nonpolyposis colorectal cancer cells. Cancer Res. 2007;67:10966–75.PubMedCrossRefGoogle Scholar
  70. 70.
    Mcilhatton MA, et al. Aspirin and low-dose nitric oxide-donating aspirin increase life span in a Lynch syndrome mouse model. Cancer Prev Res. 2011;4:684–93.CrossRefGoogle Scholar
  71. 71.
    Burn J, et al. Effect of aspirin or resistant starch on colorectal neoplasia in the Lynch syndrome. N Engl J Med. 2008;359:2567–78.PubMedCrossRefGoogle Scholar
  72. 72.
    Burn J, et al. Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011;378:2081–7.PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Luciani MG, Campregher C, Fortune JM, Kunkel TA, Gasche C. 5-ASA affects cell cycle progression in colorectal cells by reversibly activating a replication checkpoint. Gastroenterology. 2007;132:221–35.PubMedCrossRefGoogle Scholar
  74. 74.
    Campregher C, Honeder C, Chung H, Carethers JM, Gasche C. Mesalazine reduces mutations in transforming growth factor ?? receptor II and activin type II receptor by improvement of replication fidelity in mononucleotide repeats. Clin Cancer Res. 2010;16:1950–6.PubMedPubMedCentralCrossRefGoogle Scholar
  75. 75.
    • Kortüm B, et al. Mesalazine and thymoquinone attenuate intestinal tumour development in Msh2(loxP/loxP) Villin-Cre mice. Gut. 2015;64:1905–12. They first evidenced in mouse model for Lynch syndrome a chemopreventive role of natural compound thymoquinone in reducing tumor incidence and number better that mesalazine by reduction of MSI independent of a functional mismach repair system PubMedCrossRefGoogle Scholar
  76. 76.
    Eaden JA, Abrams KR, Mayberry JF. The risk of colorectal cancer in ulcerative colitis: a meta-analysis. Gut. 2001;48:526–35.PubMedPubMedCentralCrossRefGoogle Scholar
  77. 77.
    Ekbom A, Helmick C, Zack M, Adami H-O. Ulcerative colitis and colorectal cancer. N Engl J Med. 1990;323:1228–33.PubMedCrossRefGoogle Scholar
  78. 78.
    Jess T, et al. Decreasing risk of colorectal cancer in patients with inflammatory bowel disease over 30 years. Gastroenterology. 2012;143:375–81.PubMedCrossRefGoogle Scholar
  79. 79.
    Askling J, et al. Family history as a risk factor for colorectal cancer in inflammatory bowel disease. Gastroenterology. 2001;120:1356–62.PubMedCrossRefGoogle Scholar
  80. 80.
    Gupta RB, et al. {A figure is presented} Histologic inflammation is a risk factor for progression to colorectal neoplasia in ulcerative colitis: a cohort study. Gastroenterology. 2007;133:1099–105.PubMedPubMedCentralCrossRefGoogle Scholar
  81. 81.
    Canavan C, Abrams KR, Mayberry J. Meta-analysis: colorectal and small bowel cancer risk in patients with Crohn’s disease. Aliment Pharmacol Ther. 2006;23:1097–104.PubMedCrossRefGoogle Scholar
  82. 82.
    • Longo DL, Beaugerie L, Itzkowitz SH. Cancers complicating inflammatory bowel disease. N Engl J Med. 2015;372:1441–52. This article review the latest surveillance and reccomandation of CAC CrossRefGoogle Scholar
  83. 83.
    Itzkowitz SH, Yio X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am J Physiol Gastrointest Liver Physiol. 2004;287:G7–G17.PubMedCrossRefGoogle Scholar
  84. 84.
    Brentnall T a, et al. Mutations in the p53 gene: an early marker of neoplastic progression in ulcerative colitis. Gastroenterology. 1994;107:369–78.PubMedCrossRefGoogle Scholar
  85. 85.
    Aust DE, et al. The APC/??-catenin pathway in ulcerative colitis-related colorectal carcinomas: a mutational analysis. Cancer. 2002;94:1421–7.PubMedCrossRefGoogle Scholar
  86. 86.
    Issa JPJ, Ahuja N, Toyota M, Bronner MP, Brentnall TA. Accelerated age-related CpG island methylation in ulcerative colitis. Cancer Res. 2001;61:3573–7.PubMedGoogle Scholar
  87. 87.
    Fleisher AS, et al. Microsatellite instability in inflammatory bowel disease-associated neoplastic lesions is associated with hypermethylation and diminished expression of the DNA mismatch repair gene, hMLH1. Cancer Res. 2000;60:4864–8.PubMedGoogle Scholar
  88. 88.
    Sato F, et al. Hypermethylation of the p14ARF gene in ulcerative colitis-associated colorectal carcinogenesis. Cancer Res. 2002;62:1148–51.PubMedGoogle Scholar
  89. 89.
    Hsieh CJ, et al. Hypermethylation of the p16(INK4a) promoter in colectomy specimens of patients with long-standing and extensive ulcerative colitis. Cancer Res. 1998;58:3942–5.PubMedGoogle Scholar
  90. 90.
    Arai N., Mitomi H., Ohtani Y, Igarashi M, Kakita A. O.I. Enhanced epithelial cell turnover associated with p53 accumulation and high p21WAF1/CIP1 expression in ulcerative colitis. Mod Pathol. (1999).Google Scholar
  91. 91.
    Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer. 2003;3:276–85.PubMedCrossRefGoogle Scholar
  92. 92.
    Agoff SN, et al. The role of cyclooxygenase 2 in ulcerative colitis-associated neoplasia. Am J Pathol. 2000;157:737–45.PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Hussain SP, et al. Increased p53 mutation load in noncancerous colon tissue from ulcerative colitis: a cancer-prone chronic inflammatory disease. Cancer Res. 2000;60:3333–7.PubMedGoogle Scholar
  94. 94.
    Dmitrieva OS, Shilovskiy IP, Khaitov MR, Grivennikov SI. Interleukins 1 and 6 as main mediators of inflammation and cancer. Biokhimiya/Biochemistry. 2016;81:80–90.Google Scholar
  95. 95.
    Grivennikov SI, Karin M. Inflammatory cytokines in cancer: tumour necrosis factor and interleukin 6 take the stage. Ann Rheum Dis. 2011;70(Suppl 1):i104–8.PubMedCrossRefGoogle Scholar
  96. 96.
    Grivennikov S, et al. IL-6 and Stat3 are required for survival of intestinal epithelial cells and development of colitis-associated cancer. Cancer Cell. 2009;15:103–13.PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Popivanova BK, et al. Blocking TNF-alpha in mice reduces colorectal carcinogenesis associated with chronic colitis. J Clin Invest. 2008;118:560–70.PubMedPubMedCentralGoogle Scholar
  98. 98.
    Garg P, et al. Matrix metalloproteinase-9 functions as a tumor suppressor in colitis-associated cancer. Cancer Res. 2010;70:792–801.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Clapper ML, et al. 5-Aminosalicylic acid inhibits colitis-associated colorectal dysplasias in the mouse model of azoxymethane/dextran sulfate sodium-induced colitis. Inflamm Bowel Dis. 2008;14:1341–7.PubMedCrossRefGoogle Scholar
  100. 100.
    Velayos FS, Terdiman JP, Walsh JM. Effect of 5-aminosalicylate use on colorectal cancer and dysplasia risk: a systematic review and metaanalysis of observational studies. Am J Gastroenterol. 2005;100:1345–53.PubMedCrossRefGoogle Scholar
  101. 101.
    Rubin DT, LoSavio A, Yadron N, Huo D, Hanauer SB. Aminosalicylate therapy in the prevention of dysplasia and colorectal cancer in ulcerative colitis. Clin Gastroenterol Hepatol. 2006;4:1346–50.PubMedCrossRefGoogle Scholar
  102. 102.
    Ullman T, et al. Progression to colorectal neoplasia in ulcerative colitis: effect of mesalamine. Clin Gastroenterol Hepatol. 2008;6:1225–30.PubMedCrossRefGoogle Scholar
  103. 103.
    Jess T, et al. Risk factors for colorectal neoplasia in inflammatory bowel disease: a nested case-control study from Copenhagen County, Denmark and Olmsted County. Minnesota Am J Gastroenterol. 2007;102:829–36.PubMedCrossRefGoogle Scholar
  104. 104.
    Terdiman JP, Steinbuch M, Blumentals WA, Ullman TA, Rubin DT. 5-Aminosalicylic acid therapy and the risk of colorectal cancer among patients with inflammatory bowel disease. Inflamm Bowel Dis. 2007;13:367–71.PubMedCrossRefGoogle Scholar
  105. 105.
    Balzola F, Cullen G, Ho GT, Russell RK, Wehkamp J. 5-aminosalicylic acid is not protective against colorectal cancer in inflammatory bowel disease: a meta-analysis of non-referral populations. Inflamm Bowel Dis Monit. 2012;13:76.Google Scholar
  106. 106.
    Eaden J, Abrams K, Ekbom A, Jackson E, Mayberry J. Colorectal cancer prevention in ulcerative colitis: a case-control study. Aliment Pharmacol Ther. 2000;14:145–53.PubMedCrossRefGoogle Scholar
  107. 107.
    Velayos FS, et al. Predictive and protective factors associated with colorectal cancer in ulcerative colitis: a case-control study. Gastroenterology. 2006;130:1941–9.PubMedCrossRefGoogle Scholar
  108. 108.
    van Staa TP, Card T, Logan RF, Leufkens HGM. 5-Aminosalicylate use and colorectal cancer risk in inflammatory bowel disease: a large epidemiological study. Gut. 2005;54:1573–8.PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Matula S, et al. Chemoprevention of colorectal neoplasia in ulcerative colitis: the effect of 6-mercaptopurine. Clin Gastroenterol Hepatol. 2005;3:1015–21.PubMedCrossRefGoogle Scholar
  110. 110.
    van Schaik FDM, et al. Thiopurines prevent advanced colorectal neoplasia in patients with inflammatory bowel disease. Gut. 2012;61:235–40.PubMedCrossRefGoogle Scholar
  111. 111.
    Fazio C, et al. Inflammation increases NOTCH1 activity via MMP9 and is counteracted by Eicosapentaenoic acid-free fatty acid in colon cancer cells. Sci Rep. 2016;6:20670.PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    •• Piazzi G, et al. Eicosapentaenoic acid free fatty acid prevents and suppresses colonic neoplasia in colitis-associated colorectal cancer acting on Notch signaling and gut microbiota. Int J Cancer. 2014;135:2004–13. First evidence of the effect of EPA-FFA in reducing the tumor multiplicity, incidence and maximum tumor size of CRC promotion and initiation in CAC mice model by modulation of Notch signaling and intestinal microbiota PubMedCrossRefGoogle Scholar
  113. 113.
    Nagengast FM, Grubben MJAL, van Munster IP. Role of bile acids in colorectal carcinogenesis. Eur J Cancer. 1995;31:1067–70.CrossRefGoogle Scholar
  114. 114.
    Hill MJ, Lennard-Jones JE, Melville DM, Neale K, Ritchie J. Faecal bile acids, dysplasia, and carcinoma in ulcerative colitis. Lancet. 1987;330(185–186)Google Scholar
  115. 115.
    Krishna-Subramanian S, et al. UDCA slows down intestinal cell proliferation by inducing high and sustained ERK phosphorylation. Int J Cancer. 2012;130:2771–82.PubMedCrossRefGoogle Scholar
  116. 116.
    Saeki T, et al. Ursodeoxycholic acid protects colon cancer HCT116 cells from deoxycholic acid-induced apoptosis by inhibiting apoptosome formation. Nutr Cancer. 2012;64:617–26.PubMedCrossRefGoogle Scholar
  117. 117.
    Feldman R, Martinez JD. Growth suppression by ursodeoxycholic acid involves caveolin-1 enhanced degradation of EGFR. Biochim Biophys Acta-Mol Cell Res. 2009;1793:1387–94.CrossRefGoogle Scholar
  118. 118.
    Wali, R. K. et al. Ursodeoxycholic acid and F 6 -D 3 inhibit aberrant crypt proliferation in the rat azoxymethane model of colon cancer: roles of cyclin D1 and E-cadherin ursodeoxycholic acid and F 6-D 3 inhibit aberrant crypt proliferation in the rat azoxymethane model o. 11; 1653–1662 (2002).Google Scholar
  119. 119.
    Kohno H, et al. Ursodeoxycholic acid versus sulfasalazine in colitis-related colon carcinogenesis in mice. Clin Cancer Res. 2007;13:2519–25.PubMedCrossRefGoogle Scholar
  120. 120.
    Pardi D, Loftus E, Kremers W, Keach J, LINDOR K. Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology. 2003;124:889–93.PubMedCrossRefGoogle Scholar
  121. 121.
    Tung BY, et al. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med. 2001;134:89–95.PubMedCrossRefGoogle Scholar
  122. 122.
    Eaton JE, Silveira MG, Pardi DS, Sinakos E, Kowdley KV, Luketic VAC, Edwyn Harrison M, McCashland T, Befeler AS, Harnois D, Roberta Jorgensen R, Petz J, Keith D, Lindor M. High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol. 2011;25:2586–90.Google Scholar
  123. 123.
    Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo primary sclerosing cholangitis-ursodeoxycholic acid study group. N Engl J Med. 1997;336:691–5.PubMedCrossRefGoogle Scholar
  124. 124.
    •• Ricciardiello L, Ahnen DJ, Lynch PM. Chemoprevention of hereditary colon cancers: time for new strategies. Nat Rev Gastroenterol Hepatol. 2016;13 Latest review on chemoprevention in hereditary colon cancerAhead of Print Google Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Dora Colussi
    • 1
  • Franco Bazzoli
    • 1
  • Luigi Ricciardiello
    • 1
  1. 1.Department of Medical and Surgical SciencesUniversity of BolognaBolognaItaly

Personalised recommendations