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Mechanisms of Disease: inflammatory mediators and cancer prevention

Nature Clinical Practice Oncology volume 2, pages 202–210 (2005)Cite this article

Abstract

Discovery of molecular pathways critical to carcinogenesis is revolutionizing the treatment and prevention of cancer. Traditional chemotherapeutic approaches usually cause 'global' cytotoxicity to both normal and carcinoma cells. Over the past decade, however, investigators have developed compounds that inhibit tumor formation more selectively by targeting specific signaling pathways, including those involving the epidermal growth factor receptor (EGFR) and cyclooxygenase 2 (COX2). COX2-derived bioactive lipids, including prostaglandin E2, are potent inflammatory mediators that promote tumor growth and metastasis through stimulation of cell proliferation, invasion, and angiogenesis. Recent work has demonstrated significant crosstalk between the COX2 and EGFR pathways, while preclinical data demonstrates a synergistic effect when both pathways are targeted simultaneously. Combination therapy, a common strategy in cancer treatment, is likely to improve outcomes in cancer prevention as well. Ongoing clinical trials designed to assess whether low doses of COX2 and EGFR inhibitors used in combination could prove more effective and result in reduced toxicity than either agent alone may provide new options for cancer prevention and treatment. We discuss advances in cancer prevention by focusing on mechanisms by which bioactive lipids contribute to tumor formation. While cancer chemoprevention is a relatively young field, we argue that this approach to malignant disease bears significant potential.

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Figure 1: Prostaglandin E2 as a central mediator in cancer.
Figure 2: Combination therapy targeting cyclooxygenase 2 and epidermal growth factor receptor signaling.

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References

  1. Edwards BK et al. (2002) Annual report to the nation on the status of cancer, 1973–1999, featuring implications of age and aging on US cancer burden. Cancer 94: 2766–2792

    Article  Google Scholar 

  2. Sporn MB (1976) Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res 36 (Pt 2): 2699–2702

    Google Scholar 

  3. Sabichi AL et al. (2003) Frontiers in cancer prevention research. Cancer Res 63: 5649–5655

    CAS  PubMed  Google Scholar 

  4. Sudbo J et al. (2001) DNA content as a prognostic marker in patients with oral leukoplakia. N Engl J Med 344: 1270–1278

    Article  CAS  Google Scholar 

  5. Fisher B et al. (1998) Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90: 1371–1388

    Article  CAS  Google Scholar 

  6. Steinbach G et al. (2000) The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342: 1946–1952

    Article  CAS  Google Scholar 

  7. Tsao AS et al. (2004) Chemoprevention of cancer. CA Cancer J Clin 54: 150–180

    Article  Google Scholar 

  8. Saltz LB et al. (2000) Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 343: 905–914

    Article  CAS  Google Scholar 

  9. Eberhart CE et al. (1994) Up-regulation of cyclooxygenase-2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology 107: 1183–1188

    Article  CAS  Google Scholar 

  10. Gupta RA and DuBois RN (2001) Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 1: 11–21

    Article  CAS  Google Scholar 

  11. Marnett LJ and DuBois RN (2002) COX-2: A target for colon cancer prevention. Annu Rev Pharmacol Toxicol 42: 55–80

    Article  CAS  Google Scholar 

  12. Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nature 231: 232–235

    CAS  Google Scholar 

  13. Shureiqi I et al. (2000) 15-Lipoxygenase-1 mediates nonsteroidal anti-inflammatory drug-induced apoptosis independently of cyclooxygenase-2 in colon cancer cells. Cancer Res 60: 6846–6850

    CAS  PubMed  Google Scholar 

  14. Benamouzig R et al. (2003) Daily soluble aspirin and prevention of colorectal adenoma recurrence: one-year results of the APACC trial. Gastroenterology 125: 328–336

    Article  CAS  Google Scholar 

  15. Smalley WE and DuBois RN (1997) Colorectal cancer and nonsteroidal anti-inflammatory drugs. Adv Pharmacol 39: 1–20

    Article  CAS  Google Scholar 

  16. Thun MJ et al. (1991) Aspirin use and reduced risk of fatal colon cancer. N Engl J Med 325: 1593–1596

    Article  CAS  Google Scholar 

  17. Sandler RS et al. (2003) A randomized trial of aspirin to prevent colorectal adenomas in patients with previous colorectal cancer. N Engl J Med 348: 883–890

    Article  CAS  Google Scholar 

  18. Baron JA et al. (2003) A randomized trial of aspirin to prevent colorectal adenomas. N Engl J Med 348: 891–899

    Article  CAS  Google Scholar 

  19. DuBois RN et al. (1996) Nonsteroidal anti-inflammatory drugs, eicosanoids and colorectal cancer prevention. Gastroenterol Clin North Am 25: 773–791

    Article  CAS  Google Scholar 

  20. Giardiello FM et al. (1993) Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med 328: 1313–1316

    Article  CAS  Google Scholar 

  21. Labayle D et al. (1991) Sulindac causes regression of rectal polyps in familial adenomatous polyposis. Gastroenterology 101: 635–639

    Article  CAS  Google Scholar 

  22. Steinbach G et al. (2000) The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342: 1946–1952

    Article  CAS  Google Scholar 

  23. Giardiello FM et al. (2002) Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med 346: 1054–1059

    Article  CAS  Google Scholar 

  24. Wolfe MM et al. (1999) Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 340: 1888–1899

    Article  CAS  Google Scholar 

  25. Taha AS et al. (1996) Famotidine for the prevention of gastric and duodenal ulcers caused by nonsteroidal antiinflammatory drugs. N Engl J Med 334: 1435–1439

    Article  CAS  Google Scholar 

  26. Laine L et al. (1999) A randomized trial comparing the effect of rofecoxib, a cyclooxygenase 2-specific inhibitor, with that of ibuprofen on the gastroduodenal mucosa of patients with osteoarthritis. Rofecoxib Osteoarthritis Endoscopy Study Group. Gastroenterology 117: 776–783

    Article  CAS  Google Scholar 

  27. Bombardier C et al. (2000) Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med 343: 1520–1528

    Article  CAS  Google Scholar 

  28. Grover JK et al. (2003) Cyclo-oxygenase 2 inhibitors: emerging roles in the gut. Int J Colorectal Dis 18: 279–291

    CAS  PubMed  Google Scholar 

  29. Hernandez MR et al. (2004) Evaluation of effects of rofecoxib on platelet function in an in vitro model of thrombosis with circulating human blood. Eur J Clin Invest 34: 297–302

    Article  CAS  Google Scholar 

  30. Brinker A et al. (2004) Spontaneous reports of hypertension leading to hospitalisation in association with rofecoxib, celecoxib, nabumetone and oxaprozin. Drugs Aging 21: 479–484

    Article  CAS  Google Scholar 

  31. Kimmel SE et al. (2005) Patients exposed to rofecoxib and celecoxib have different odds of nonfatal myocardial infarction. Ann Intern Med 142: 157–164

    Article  CAS  Google Scholar 

  32. Bresalier R et al. (2004) Rofecoxib APPROVe Study Results and Their Implications. In 2004 ACR/ARHP Annual Scientific Meeting: 2004; October 16–21; Texas

    Google Scholar 

  33. Silverstein FE et al. (2000) Gastrointestinal toxicity with celecoxib vs nonsteroidal anti-inflammatory drugs for osteoarthritis and rheumatoid arthritis: the CLASS study: A randomized controlled trial. Celecoxib Long-term Arthritis Safety Study. JAMA 284: 1247–1255

    Article  CAS  Google Scholar 

  34. Tortora G et al. (2003) Combination of a selective cyclooxygenase-2 inhibitor with epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 and protein kinase A antisense causes cooperative antitumor and antiangiogenic effect. Clin Cancer Res 9: 1566–1572

    CAS  PubMed  Google Scholar 

  35. Torrance CJ et al. (2000) Combinatorial chemoprevention of intestinal neoplasia. Nature Med 6: 1024–1028

    Article  CAS  Google Scholar 

  36. Baselga J et al. (2002) Phase I safety, pharmacokinetic, and pharmacodynamic trial of ZD1839, a selective oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with five selected solid tumor types. J Clin Oncol 20: 4292–4302

    Article  CAS  Google Scholar 

  37. Rigas B et al. (1993) Altered eicosanoid levels in human colon cancer. J Lab Clin Med 122: 518–523

    CAS  PubMed  Google Scholar 

  38. Turini ME and DuBois RN (2002) Cyclooxygenase-2: a therapeutic target. Annu Rev Med 53: 35–57

    Article  CAS  Google Scholar 

  39. Hansen-Petrik MB et al. (2002) Prostaglandin E(2) protects intestinal tumors from nonsteroidal anti-inflammatory drug-induced regression in Apc(Min/+) mice. Cancer Res 62: 403–408

    CAS  PubMed  Google Scholar 

  40. Kawamori T et al. (2003) Enhancement of colon carcinogenesis by prostaglandin E2 administration. Carcinogenesis 24: 985–990

    Article  CAS  Google Scholar 

  41. Wang D et al. (2004) Prostaglandin E(2) promotes colorectal adenoma growth via transactivation of the nuclear peroxisome proliferator-activated receptor delta. Cancer Cell 6: 285–295

    Article  CAS  Google Scholar 

  42. Watanabe K et al. (1999) Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis. Cancer Res 59: 5093–5096

    CAS  PubMed  Google Scholar 

  43. Mutoh M et al. (2002) Involvement of prostaglandin E receptor subtype EP(4) in colon carcinogenesis. Cancer Res 62: 28–32

    CAS  PubMed  Google Scholar 

  44. Sonoshita M et al. (2001) Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc (Delta 716) knockout mice. Nat Med 7: 1048–1051

    Article  CAS  Google Scholar 

  45. Quidville V et al. (2004) Tumor growth inhibition by indomethacin in a mouse model of human medullary thyroid cancer: implication of cyclooxygenases and 15-hydroxyprostaglandin dehydrogenase. Endocrinology 145: 2561–2571

    Article  CAS  Google Scholar 

  46. Gee JR et al. (2003) Cytokeratin 20, AN43, PGDH, and COX-2 expression in transitional and squamous cell carcinoma of the bladder. Urol Oncol 21: 266–270

    Article  CAS  Google Scholar 

  47. Backlund MG et al. (2005) 15-hydroxyprostaglandin dehydrogenase is downregulated in colorectal cancer. J Biol Chem 280: 3217–3223

    Article  CAS  Google Scholar 

  48. Davis TW et al. (2004) Synergy between celecoxib and radiotherapy results from inhibition of cyclooxygenase-2-derived prostaglandin E2, a survival factor for tumor and associated vasculature. Cancer Res 64: 279–285

    Article  CAS  Google Scholar 

  49. Liu W et al. (2003) Combination of radiation and celebrex (celecoxib) reduce mammary and lung tumor growth. Am J Clin Oncol 26: S103–S109

    PubMed  Google Scholar 

  50. Rich TA and Shepard R (2003) COX-2 inhibitors as radiation sensitizers for upper GI tract cancers: esophagus, stomach, and pancreas. Am J Clin Oncol 26: S110–S113

    PubMed  Google Scholar 

  51. Solomon SD et al. (2005) Cardiovascular risk associated with celecoxib in a clinical trial for colorectal adenoma prevention. N Engl J Med [10.1056/NEJMoa050405]

  52. Bresalier RS et al. (2005) Cardiovascular events associated with rofecoxib in a colorectal adenoma chemoprevention trial. N Engl J Med [10.1056/NEJMoa050493]

  53. Nussmeier NA et al. (2005) Complications of the COX-2 Inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med [10.1056/NEJMoa050330]

  54. Gann PH et al. (1993) Low-dose aspirin and incidence of colorectal tumors in a randomized trial. J Natl Cancer Inst 85: 1220–1224

    Article  CAS  Google Scholar 

  55. Ladenheim J et al. (1995) Effect of sulindac on sporadic colonic polyps. Gastroenterology 108: 1083–1087

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge support from the United States Public Health Services Grants RO-DK-62112 and PO-CA77839. R DuBois is the Hortense B. Ingram Professor of Molecular Oncology and the recipient of an NIH MERIT award (R37-DK47297). We are grateful to the TJ Martell Foundation and the National Colorectal Cancer Research Alliance (NCCRA) for generous support.

Author information

Authors and Affiliations

  1. PhD student in the Medical Scientist Training Program at the Vanderbilt University School of Medicine, Nashville, Tennessee

    Jason R Mann

  2. Postdoctoral Fellow at the Vanderbilt University Medical Center, Nashville, Tennessee

    Michael G Backlund

  3. B.F. Byrd Professor of Molecular Oncology, Professor of Medicine, Cancer Biology, and Cell & Developmental Biology, and Director of the Vanderbilt-Ingram Cancer Center, Nashville, Tennessee

    Raymond N DuBois

Authors
  1. Jason R Mann
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  2. Michael G Backlund
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  3. Raymond N DuBois
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Corresponding author

Correspondence to Raymond N DuBois.

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Glossary

PRIMARY PREVENTION

Prevention of tumor formation in otherwise healthy patients

SECONDARY PREVENTION

Prevention of progression from premalignant lesion to invasive cancer

TERTIARY PREVENTION

Prevention of second primary tumor formation in patients cured of their initial tumor

SECOND PRIMARY TUMORS

Neoplasia developing from genetically related dysplastic epithelium bordering areas of fully invasive neoplasia. These tumours typically arise following successful removal of the first primary tumor and are associated with high mortality rates

HISTAMINE 2 RECEPTOR ANTAGONISTS

Histamine 2 receptor antagonists are used to block the action of histamine on parietal cells in the stomach, decreasing production of gastric acid

PROTON-PUMP INHIBITORS

Reduce the production of acid by irreversibly blocking the hydrogen-potassium adenosine triphosphatase enzyme, thereby limiting acid production in the stomach

THERAPEUTIC RATIO

This defines the difference between a minimum therapeutically effective dose and a maximum dose capable of inducing intolerable side effects; the difference between the minimum and maximum effective doses. Also known as the therapeutic window

AZOXYMETHANE

A potent carcinogen used to induce colon cancer in rats and mice

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Mann, J., Backlund, M. & DuBois, R. Mechanisms of Disease: inflammatory mediators and cancer prevention. Nat Rev Clin Oncol 2, 202–210 (2005). https://doi.org/10.1038/ncponc0140

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