Chemoprevention of IBD-Associated Colon Cancer

Summary

Principal Investigator: LAURA HALE
Abstract: Patients with inflammatory bowel disease (IBD) have a 20 to 30-fold increased risk of colorectal cancer relative to the general population. This increased cancer risk has been attributed to genetic damage from oxidative stress caused by inflammatory mediators combined with the proliferation of colonic epithelium during mucosal repair. IBD-associated neoplasia can be detected at an early, potentially curable stage by colonoscopic screening. However, safe and effective new strategies for preventing colon cancer would be of great benefit to IBD patients and should ultimately lead to considerable cost savings. Recent animal studies have shown that inhibiting T cell-mediated colon inflammation can decrease the risk of colon cancer. Our studies show that oral administration of bromelain, a proteinase mixture derived from pineapple, significantly decreases both the incidence of spontaneous colitis and the severity of established T cell-mediated colitis in IL-10-deficient mice. Previous in vitro studies by our laboratory and others have shown that bromelain decreases T cell proliferation, signal transduction, and cytokine production. Its anti-inflammatory effects in vitro and in vivo depend on its proteolytic activity. This proposal is designed to test the hypothesis that bromelain treatment will decrease the risk of IBD-associated colon cancer by decreasing the genetic damage caused by T cell-mediated inflammation. The specific aims will determine the effect of bromelain on inflammation and development of colon neoplasia in mice with chronic T cell-mediated colitis. The severity of inflammation and the incidence of colonic neoplasia will be determined histologically. Inflammation-associated oxidative lesions in DNA and treatment-related effects on signal transduction and critical biomarker expression will be determined to directly assess effects of bromelain on pathways critical to inflammation and colorectal carcinogenesis. The proposed studies will further elucidate mechanisms that can lead to novel interventions to prevent IBD-associated colon cancers, providing great benefit to IBD patients and their families.
Funding Period: ----------------2006 - ---------------2011-
more information: NIH RePORT

Top Publications

  1. ncbi Neonatal co-infection with helicobacter species markedly accelerates the development of inflammation-associated colonic neoplasia in IL-10(-/-) mice
    Laura P Hale
    Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
    Helicobacter 12:598-604. 2007
  2. pmc Bacterial-mucosal interactions in inflammatory bowel disease: an alliance gone bad
    Maciej Chichlowski
    Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
    Am J Physiol Gastrointest Liver Physiol 295:G1139-49. 2008
  3. pmc Helicobacter infection decreases reproductive performance of IL10-deficient mice
    Julie M Sharp
    Office of Animal Welfare Assurance, Duke University Medical Center, Durham, NC, USA
    Comp Med 58:447-53. 2008
  4. pmc Helicobacter typhlonius and Helicobacter rodentium differentially affect the severity of colon inflammation and inflammation-associated neoplasia in IL10-deficient mice
    Maciej Chichlowski
    Department of Pathology, Duke University, Durham, North Carolina, USA
    Comp Med 58:534-41. 2008
  5. pmc A novel murine model of inflammatory bowel disease and inflammation-associated colon cancer with ulcerative colitis-like features
    Laura P Hale
    Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS ONE 7:e41797. 2012
  6. pmc Effects of Helicobacter infection on research: the case for eradication of Helicobacter from rodent research colonies
    Maciej Chichlowski
    Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
    Comp Med 59:10-7. 2009
  7. pmc Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10-deficient mice
    Maciej Chichlowski
    Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS ONE 5:e12220. 2010
  8. pmc Dietary supplementation with fresh pineapple juice decreases inflammation and colonic neoplasia in IL-10-deficient mice with colitis
    Laura P Hale
    Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Inflamm Bowel Dis 16:2012-21. 2010
  9. pmc Mast cells are critical for protection against peptic ulcers induced by the NSAID piroxicam
    Daniel D Hampton
    Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS ONE 6:e23669. 2011

Scientific Experts

  • LAURA HALE
  • Maciej Chichlowski
  • Julie M Sharp
  • Daniel D Hampton
  • Matthew H Myles
  • Deborah A Vanderford
  • Soman N Abraham
  • Greg S Westwood

Detail Information

Publications9

  1. ncbi Neonatal co-infection with helicobacter species markedly accelerates the development of inflammation-associated colonic neoplasia in IL-10(-/-) mice
    Laura P Hale
    Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
    Helicobacter 12:598-604. 2007
    ..However, the long lead time required before development of inflammation-associated colon neoplasia in commonly used murine models of IBD slows the development of effective chemopreventative therapies...
  2. pmc Bacterial-mucosal interactions in inflammatory bowel disease: an alliance gone bad
    Maciej Chichlowski
    Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
    Am J Physiol Gastrointest Liver Physiol 295:G1139-49. 2008
    ..This review will briefly describe the complex structure of the epithelial barrier in the context of bacterial-mucosal interactions observed in human IBD and mouse models of colitis...
  3. pmc Helicobacter infection decreases reproductive performance of IL10-deficient mice
    Julie M Sharp
    Office of Animal Welfare Assurance, Duke University Medical Center, Durham, NC, USA
    Comp Med 58:447-53. 2008
    ..We conclude that infection with H. typhlonius, H. rodentium, or both decreased the reproductive performance of IL10(-/-) mice. In addition, antihelicobacter therapy improved fecundity and enhanced pup survival...
  4. pmc Helicobacter typhlonius and Helicobacter rodentium differentially affect the severity of colon inflammation and inflammation-associated neoplasia in IL10-deficient mice
    Maciej Chichlowski
    Department of Pathology, Duke University, Durham, North Carolina, USA
    Comp Med 58:534-41. 2008
    ..This finding suggests a complex role for both Helicobacter and other intestinal microbiota in the onset and perpetuation of IBD in these susceptible hosts...
  5. pmc A novel murine model of inflammatory bowel disease and inflammation-associated colon cancer with ulcerative colitis-like features
    Laura P Hale
    Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS ONE 7:e41797. 2012
    ..The T/I mouse model will be useful for developing new rationally-based therapies to prevent and/or treat IBD and inflammation-associated colon cancer and may further provide important insights into the pathogenesis of UC in humans...
  6. pmc Effects of Helicobacter infection on research: the case for eradication of Helicobacter from rodent research colonies
    Maciej Chichlowski
    Department of Pathology, Duke University Medical Center, Durham, North Carolina, USA
    Comp Med 59:10-7. 2009
    ..Therefore, frequent screening of rodent research colonies for Helicobacter spp. and the eradication of these pathogens should be key goals of the research community...
  7. pmc Role of mast cells in inflammatory bowel disease and inflammation-associated colorectal neoplasia in IL-10-deficient mice
    Maciej Chichlowski
    Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS ONE 5:e12220. 2010
    ..Mast cells may play a critical role in IBD pathogenesis, since they are typically located just beneath the intestinal mucosal barrier and can be activated by bacterial antigens...
  8. pmc Dietary supplementation with fresh pineapple juice decreases inflammation and colonic neoplasia in IL-10-deficient mice with colitis
    Laura P Hale
    Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA
    Inflamm Bowel Dis 16:2012-21. 2010
    ....
  9. pmc Mast cells are critical for protection against peptic ulcers induced by the NSAID piroxicam
    Daniel D Hampton
    Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States of America
    PLoS ONE 6:e23669. 2011
    ..Additional studies will be required to determine whether this represents a NSAID class effect that can be exploited to develop novel therapeutic strategies to limit the incidence of NSAID-induced side effects in humans...