Journal
CANCER RESEARCH
Volume 78, Issue 15, Pages 4303-4315Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-0116
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Funding
- NIH [R01AT004821, R01DK053620, P01CA028842, P01CA116087, 7515, R01CA190612, R01AT006896, P30DK058404, P50CA095103, R01CA100603]
- Department of Veterans Affairs [I01BX001453, IK2BX002126]
- Vanderbilt Ingram Cancer Center Support Grant [P30CA068485]
- Vanderbilt Digestive Research Center [P30DK058404]
- Vanderbilt Center for Mucosal Inflammation and Cancer
- Thomas F. Frist Sr. Endowed Chair
- American Heart Association [16POST27250138]
- Moffitt Cancer Center Support Grant [P30CA076292]
- Cortner-Couch Endowed Chair for Cancer Research
- NATIONAL CANCER INSTITUTE [P01CA116087, R01CA190612, P50CA095103, P30CA076292, R01CA100603, P30CA068485, P30CA022453, P01CA028842] Funding Source: NIH RePORTER
- National Center for Complementary & Integrative Health [R01AT004821, R01AT006896] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R01DK053620, P30DK058404] Funding Source: NIH RePORTER
- Veterans Affairs [I01BX001453, IK2BX002126] Funding Source: NIH RePORTER
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Ornithine decarboxylase (ODC) is the rate-limiting enzyme for polyamine biosynthesis and restricts M1 macrophage activation in gastrointestinal (GI) infections. However, the role of macrophage ODC in colonic epithelial-driven inflammation is unknown. Here, we investigate cell-specific effects of ODC in colitis and colitis-associated carcinogenesis (CAC). Human colonic macrophages expressed increased ODC levels in active ulcerative colitis and Crohn's disease, colitis-associated dysplasia, and CAC. Mice lacking Odc in myeloid cells (Odc(Delta mye) mice) that were treated with dextran sulfate sodium (DSS) exhibited improved survival, body weight, and colon length and reduced histologic injury versus control mice. In contrast, GI epithelial-specific Odc knockout had no effect on clinical parameters. Despite reduced histologic damage, colitis tissues of Odc(Delta mye) mice had increased levels of multiple proinflammatory cytokines and chemokines and enhanced expression of M1, but not M2 markers. In the azoxymethane-DSS model of CAC, Odc(Delta mye) mice had reduced tumor number, burden, and high-grade dysplasia. Tumors from Odc(Delta mye) mice had increased M1, but not M2 macrophages. Increased levels of histone 3, lysine 9 acetylation, a marker of open chromatin, were manifest in tumor macrophages of Odc(Delta mye) mice, consistent with our findings that macrophage ODC affects histone modifications that upregulate M1 gene transcription during GI infections. These findings support the concept that macrophage ODC augments epithelial injury-associated colitis and CAC by impairing the M1 responses that stimulate epithelial repair, antimicrobial defense, and antitumoral immunity. They also suggest that macrophage ODC is an important target for colon cancer chemoprevention. Significance: Ornithine decarboxylase contributes to the pathogenesis of colitis and associated carcinogenesis by impairing M1 macrophage responses needed for antitumoral immunity; targeting ODC in macrophages may represent a new strategy for chemoprevention. (C) 2018 AACR.
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