title: Helicobacter infection is required for inflammation and colon cancer in SMAD3-deficient mice.
abstract: Accumulating evidence suggests that intestinal microbial organisms may play an important role in triggering and sustaining inflammation in individuals afflicted with inflammatory bowel disease (IBD). Moreover, individuals with IBD are at increased risk for developing colorectal cancer, suggesting that chronic inflammation may initiate genetic or epigenetic changes associated with cancer development. We tested the hypothesis that bacteria may contribute to the development of colon cancer by synergizing with defective transforming growth factor-beta (TGF-beta) signaling, a pathway commonly mutated in human colon cancer. Although others have reported that mice deficient in the TGF-beta signaling molecule SMAD3 develop colon cancer, we found that SMAD3-deficient mice maintained free of the Gram-negative enterohepatic bacteria Helicobacter spp. for up to 9 months do not develop colon cancer. Furthermore, infection of SMAD3(-/-) mice with Helicobacter triggers colon cancer in 50% to 66% of the animals. Using real-time PCR, we found that Helicobacter organisms concentrate in the cecum, the preferred site of tumor development. Mucinous adenocarcinomas develop 5 to 30 weeks after infection and are preceded by an early inflammatory phase, consisting of increased proliferation of epithelial cells; increased numbers of cyclooxygenase-2-positive cells, CD4(+) T cells, macrophages; and increased MHC class II expression. Colonic tissue revealed increased transcripts for the oncogene c-myc and the proinflammatory cytokines interleukin-1alpha (IL-1alpha), IL-1beta, IL-6, IFN-gamma, and tumor necrosis factor-alpha, some of which have been implicated in colon cancer. These results suggest that bacteria may be important in triggering colorectal cancer, notably in the context of gene mutations in the TGF-beta signaling pathway, one of the most commonly affected cellular pathways in colorectal cancer in humans.
authors.affiliation: Department of Comparative Medicine, University of Washington, 1959 Northeast Pacific Avenue, Seattle, WA 98195, USA. lmprice@u.washington.edu
authors.forename: Lillian
authors.initials: L
authors.lastname: Maggio-Price
authors.forename: Piper
authors.initials: P
authors.lastname: Treuting
authors.forename: Weiping
authors.initials: W
authors.lastname: Zeng
authors.forename: Mark
authors.initials: M
authors.lastname: Tsang
authors.forename: Helle
authors.initials: H
authors.lastname: Bielefeldt-Ohmann
authors.forename: Brian M
authors.initials: BM
authors.lastname: Iritani
mesh_terms: D000818:Animals; D002432:Cecum / Q000382:microbiology; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000235:genetics* / Q000382:microbiology*; D016207:Cytokines / Q000096:biosynthesis; D004269:DNA, Bacterial / Q000032:analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D016481:Helicobacter Infections / Q000150:complications*; D007249:Inflammation; D008297:Male; D051379:Mice; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc; D012307:Risk Factors; D015398:Signal Transduction; D051900:Smad3 Protein / Q000235:genetics* / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology
chemical_list: D016207:Cytokines; D004269:DNA, Bacterial; D016271:Proto-Oncogene Proteins c-myc; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta